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Li F, Shen F. Metastatic pancreatic cancer with activating BRAF V600E mutations: A case report. World J Clin Cases 2025; 13:101665. [DOI: 10.12998/wjcc.v13.i16.101665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/06/2024] [Accepted: 01/11/2025] [Indexed: 02/10/2025] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is a highly malignant tumor that is resistant to chemotherapy, radiotherapy and immunotherapy. Combination chemotherapy regimens are the standard first-line regimens for metastatic disease, with a median survival < 12 months. Although recurrent genomic alterations such as the BRAF V600E mutation have been reported in PC, evidence supporting the clinical effectiveness of molecularly guided targeted therapies is limited.
CASE SUMMARY We report a case of a 33-year-old male who was referred to our department with weight loss of 5 kg in 2 months, anorexia and abdominal pain. Imaging showed extensive lesions involving the pancreas, liver, bones, muscles and lymph nodes accompanied by elevated carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). Biopsy yielded a diagnosis of PC. Treatment with gemcitabine and nab-paclitaxel was initiated, but the disease progressed in < 2 months even though the patient’s general condition improved. Molecular testing revealed the presence of BRAF mutation. Dabrafenib/trametinib combination therapy was introduced, and the patient was treated for 2 months with a decrease in CA19-9 and CEA levels, but he died after 2 months of treatment.
CONCLUSION BRAF alterations are infrequent in PC. This case highlights the significance of molecular profiling in patients with PC, especially in patients with a high tumor burden.
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Affiliation(s)
- Fang Li
- Department of Medical Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, Fujian Province, China
- Xiamen Clinical Research Center for Cancer, Xiamen 361015, Fujian Province, China
- Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen 361015, Fujian Province, China
| | - Feng Shen
- Department of Medical Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, Fujian Province, China
- Xiamen Clinical Research Center for Cancer, Xiamen 361015, Fujian Province, China
- Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen 361015, Fujian Province, China
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Dreyer SB, Beer P, Hingorani SR, Biankin AV. Improving outcomes of patients with pancreatic cancer. Nat Rev Clin Oncol 2025; 22:439-456. [PMID: 40329051 DOI: 10.1038/s41571-025-01019-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2025] [Indexed: 05/08/2025]
Abstract
Research studies aimed at improving the outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) have brought about limited progress, and in clinical practice, the optimized use of surgery, chemotherapy and supportive care have led to modest improvements in survival that have probably reached a plateau. As a result, PDAC is expected to be the second leading cause of cancer-related death in Western societies within a decade. The development of therapeutic advances in PDAC has been challenging owing to a lack of actionable molecular targets, a typically immunosuppressive microenvironment, and a disease course characterized by rapid progression and clinical deterioration. Yet, the progress in our understanding of PDAC and identification of novel therapeutic opportunities over the past few years is leading to a strong sense of optimism in the field. In this Perspective, we address the aforementioned challenges, including biological aspects of PDAC that make this malignancy particularly difficult to treat. We explore specific areas with potential for therapeutic advances, including targeting mutant KRAS, novel strategies to harness the antitumour immune response and approaches to early detection, and propose mechanisms to improve clinical trial design and to overcome various community and institutional barriers to progress.
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Affiliation(s)
- Stephan B Dreyer
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
- West of Scotland Hepato-Biliary and Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
- Department of Hepatobiliary Surgery, Royal Liverpool University Hospital, Liverpool, UK
| | - Philip Beer
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
- Hull York Medical School, University of York, York, UK
| | - Sunil R Hingorani
- Department of Internal Medicine, Division of Hemotology/Oncology, University of Nebraska Medical Center, Omaha, NE, USA
- Pancreatic Cancer Center of Excellence, University of Nebraska Medical Center, Omaha, NE, USA
| | - Andrew V Biankin
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK.
- West of Scotland Hepato-Biliary and Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK.
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3
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King GG, Baker KK, Coveler AL, Harris WP, Cohen SA, Shankaran V, Zhen DB, Safyan RA, Lee HH, Alidina A, Hensel J, Hibbert R, Durm GA, LaFary YC, Younger A, Kugel S, Collisson E, Konnick EQ, Redman MW, Schneider BP, Pritchard CC, Shahda S, Chiorean EG. Phase Ia/Ib Study of Afatinib with Capecitabine in Patients with Refractory Solid Tumors and Pancreaticobiliary Cancers. Cancers (Basel) 2025; 17:1830. [PMID: 40507311 PMCID: PMC12153597 DOI: 10.3390/cancers17111830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 05/15/2025] [Accepted: 05/28/2025] [Indexed: 06/16/2025] Open
Abstract
BACKGROUND The epidermal growth factor receptor (EGFR) is overactive in many tumors. This phase I trial evaluated the safety and preliminary efficacy of afatinib plus capecitabine in refractory pancreatic ductal adenocarcinoma (PDA), biliary tract cancers (BTC), and other solid tumors. PATIENTS AND METHODS The phase Ia study had a 3 + 3 design with capecitabine 1000 mg/m2 twice daily on days 1-14 and afatinib 20 mg, 30 mg, or 40 mg daily in 21-day cycles. In phase Ib, 15 patients, each with PDA and BTC, were treated at maximum tolerated dose (MTD). RESULTS A total of 41 patients were enrolled. No dose-limiting toxicities were observed, and the MTD was 40 mg afatinib plus capecitabine. Among 36 response-evaluable patients, one had a partial response (3%), and eight (22%) had stable disease. Median progression-free survival (PFS) was 1.9 months (95% CI 1.0, 2.0) for PDA and 1.9 months (95% CI 1.6, 3.4) for BTC. Median overall survival (OS) was 3.2 months (95% CI 2.0, 5.8) for PDA, and 4.6 months (95% CI 1.9, 6.1) for BTC. Median OS was 5.8 months (95% CI 2.0, 9.6) for KRASWT PDA, and 5.0 months (95% CI 1.6, 6.1) for KRASWT BTC, vs. 3.9 months (95% CI 1.9, 5.8) for KRASMUT PDA and 3.1 months (95% CI 1.0, 22.8) for KRASMUT BTC, respectively. CONCLUSIONS Afatinib plus capecitabine is tolerable but does not have clinically meaningful efficacy in refractory PDA/BTC. Future studies should test novel anti-EGFR/HER2 therapies in KRASWT cancers further selected with a comprehensive molecular profile.
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Affiliation(s)
- Gentry G. King
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
| | - Kelsey K. Baker
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
| | - Andrew L. Coveler
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
| | - William P. Harris
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
| | - Stacey A. Cohen
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
| | - Veena Shankaran
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
| | - David B. Zhen
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
| | - Rachael A. Safyan
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
| | - Hannah H. Lee
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
| | - Annie Alidina
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
| | - Jeniece Hensel
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
| | - Reina Hibbert
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
| | - Greg A. Durm
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA; (G.A.D.); (Y.C.L.); (A.Y.); (B.P.S.); (S.S.)
| | - Yvonne C. LaFary
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA; (G.A.D.); (Y.C.L.); (A.Y.); (B.P.S.); (S.S.)
| | - Anne Younger
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA; (G.A.D.); (Y.C.L.); (A.Y.); (B.P.S.); (S.S.)
| | - Sita Kugel
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
| | - Eric Collisson
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
| | - Eric Q. Konnick
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
| | - Mary W. Redman
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
| | - Bryan P. Schneider
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA; (G.A.D.); (Y.C.L.); (A.Y.); (B.P.S.); (S.S.)
| | - Colin C. Pritchard
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
| | - Safi Shahda
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA; (G.A.D.); (Y.C.L.); (A.Y.); (B.P.S.); (S.S.)
- Intellia Therapeutics, Cambridge, MA 02139, USA
| | - Elena Gabriela Chiorean
- University of Washington School of Medicine, Seattle, WA 98195, USA; (G.G.K.); (A.L.C.); (W.P.H.); (S.A.C.); (V.S.); (D.B.Z.); (R.A.S.); (H.H.L.); (A.A.); (J.H.); (R.H.); (E.Q.K.); (C.C.P.)
- Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (K.K.B.); (S.K.); (E.C.); (M.W.R.)
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Conn BP, Dietze JL, Yee CJ, Hallisey MM, Ortiz-Caraveo I, van Buuren MM, Gaynor RB, Foley KC, Choi J, Juneja VR. Generation of T cell responses against broad KRAS hotspot neoantigens for cell therapy or TCR discovery. CELL REPORTS METHODS 2025; 5:101049. [PMID: 40359936 DOI: 10.1016/j.crmeth.2025.101049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/22/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025]
Abstract
Adoptive cell therapy (ACT) with T cells targeting Kirsten rat sarcoma (KRAS) neoantigens can drive anti-tumor immunity but has so far been focused on a small fraction of known KRAS neoantigens. Here, we develop a single process starting from peripheral blood that can prime and expand T cell responses ex vivo to any KRAS neoantigen based on each individual's human leukocyte antigen (HLA) profile. We conducted the process in 20 healthy donors and generated T cell responses to 46 of 47 evaluated neoantigens. We identified and cloned more than 150 KRAS T cell receptors (TCRs), with the strongest TCRs having similar potency to clinically active benchmark TCRs. T cells generated through this process were able to slow tumor growth in vitro and in vivo. The approach could be used as the basis for the development of an ex vivo primed therapeutic or to discover a library of TCRs against a broad range of KRAS neoantigens.
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Pan D, Li X, Qiao X, Wang Q. Immunosuppressive tumor microenvironment in pancreatic cancer: mechanisms and therapeutic targets. Front Immunol 2025; 16:1582305. [PMID: 40443678 PMCID: PMC12119487 DOI: 10.3389/fimmu.2025.1582305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 04/17/2025] [Indexed: 06/02/2025] Open
Abstract
Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. Conventional interventions including surgery, radiotherapy, and chemotherapy provide only modest survival benefits, underscoring an urgent need for more effective therapies. Although immunotherapy has revolutionized the management of several solid tumors, its clinical benefit in pancreatic cancer has so far been disappointing. Mounting evidence indicates that a highly immunosuppressive tumor microenvironment (TME), dominated by tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), drives immune evasion, tumor progression, metastasis, and chemoresistance through complex cytokine and chemokine networks. This review summarizes current knowledge of these immunosuppressive mechanisms and provides emerging strategies aimed at re-educating or depleting these cellular constituents to enhance the efficacy of immunotherapy in pancreatic cancer.
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Affiliation(s)
- Da Pan
- Department of Gastroenterology, Wenzhou Central Hospital, Wenzhou, China
- Department of Gastroenterology, The Dingli Clinical College of Wenzhou Medical University, Wenzhou, China
| | - Xinyue Li
- First College for Clinical Medicine, Xuzhou Medical University, Jiangsu, Xuzhou, China
| | - Xiao Qiao
- Department of Gastroenterology, The Affiliated Huaian Hospital of Xuzhou Medical University, Huaian, China
| | - Qiqi Wang
- Department of Gastroenterology, Wenzhou Central Hospital, Wenzhou, China
- Department of Gastroenterology, The Dingli Clinical College of Wenzhou Medical University, Wenzhou, China
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Toriyama K, Masago K, Shibata N, Haneda M, Kuwahara T, Natsume S, Kobayashi S, Fujita Y, Sasaki E, Yamao K, Kawashima H, Shimizu Y, Hara K, Yatabe Y, Hosoda W. Clinicopathological and molecular characterization of KRAS wild-type pancreatic ductal adenocarcinomas reveals precursor lesions with oncogenic mutations and fusions in RAS pathway genes. J Pathol 2025. [PMID: 40317966 DOI: 10.1002/path.6432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 03/07/2025] [Accepted: 03/26/2025] [Indexed: 05/07/2025]
Abstract
Pancreatic ductal adenocarcinomas (PDACs) with wild-type KRAS constitute a small fraction of PDACs, and these tumors were recently shown to harbor frequent actionable oncogenic mutations and fusions. However, the clinicopathological features of KRAS wild-type PDAC have not been well studied. Additionally, precancerous lesions occurring in patients with KRAS wild-type PDACs have rarely been characterized. Here, we investigated the clinicopathological characteristics and outcomes of 75 patients with KRAS wild-type PDAC. Molecular analyses were performed in 40 patients using targeted DNA and whole-exome sequencing and targeted RNA sequencing. We demonstrated that patients with metastatic PDAC with wild-type KRAS were younger (median 59.5 years) than those with mutated KRAS (median 67 years, p < 0.000055). The wild-type KRAS status was not a significant prognostic factor for metastatic disease. Molecularly, genes in the RAS pathway are frequently mutated or rearranged (46%, 16/35), including mutations in BRAF, NRAS, HRAS, EGFR, MAP2K1, FGFR1, FGFR3 and ERBB4 and fusions of FGFR2 (FGFR2::CCDC147, FGFR2::CAT, FGFR2::TXLNA), ALK (STRN::ALK, EML4::ALK), and BRAF (TRIP11::BRAF). Mismatch repair deficiency was identified in 10% (4/39) of patients. Potentially actionable alterations were identified frequently in KRAS wild-type PDACs (30%, 12/40), in which nontubular-type carcinomas were significantly enriched with actionable alterations compared with tubular adenocarcinomas [67% (6/9) versus 16% (5/31); p = 0.007]. Finally, we investigated the precursors of PDACs in 13 pancreatectomy specimens from patients with KRAS wild-type PDAC. We identified three pancreatic intraepithelial neoplasias (PanINs) and two intraductal papillary mucinous neoplasms (IPMNs) harboring oncogenic fusions of ALK and BRAF and driver mutations in BRAF and AKT1. This study suggests that in the context of unmutated KRAS, PDAC is driven by alternative oncogenic mutations or fusions of RAS pathway genes, which may be introduced during the early phase of tumorigenesis. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Kazuhiro Toriyama
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Katsuhiro Masago
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
| | - Noriko Shibata
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
| | - Masataka Haneda
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
| | | | - Seiji Natsume
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan
| | - Shota Kobayashi
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
| | - Yasuko Fujita
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
| | - Eiichi Sasaki
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
| | - Kenji Yamao
- Department of Gastroenterology, Narita Memorial Hospital, Toyohashi, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan
| | - Kazuo Hara
- Department of Gastroenterology, Aichi Cancer Center, Nagoya, Japan
| | - Yasushi Yatabe
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Waki Hosoda
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
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Eikenboom EL, Nasar N, Seier K, Gönen M, Spaander MCW, O'Reilly EM, Jarnagin WR, Drebin J, D'Angelica MI, Kingham TP, Balachandran VP, Soares KC, Wagner A, Wei AC. Survival of Patients with Resected Microsatellite Instability-High, Mismatch Repair Deficient, and Lynch Syndrome-Associated Pancreatic Ductal Adenocarcinomas. Ann Surg Oncol 2025; 32:3568-3577. [PMID: 39656390 DOI: 10.1245/s10434-024-16621-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 11/19/2024] [Indexed: 04/24/2025]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease due to its aggressiveness, late-stage diagnosis, and limited treatment options. Microsatellite instability-high (MSI-H) cancers are susceptible to immune checkpoint inhibitors. Survival outcomes for patients with MSI-H PDAC are unknown as the disease is rare. METHODS This study included patients with PDACs surgically resected from 1990 to 2023, and those with germline or sporadic pathogenic variants in DNA mismatch repair genes were identified. The study matched MSI-H, mismatch repair-deficient (MMRd), and Lynch syndrome (LS)-associated PDAC cases (on age, gender, and year of surgery) with microsatellite-stable (MSS), mismatch repair-proficient, or non-LS-associated PDAC cases in a 1:2 ratio. A generalized estimating equation Cox model with a robust sandwich estimator was used to compare overall survival (OS) in the matched cohorts. RESULTS Of 936 cases, 18 were included. Eight cases were MSI-H/MMRd, two were MSI/IHC-indeterminate, seven were MSS, and one was not tested for MSI. Nine patients had LS (MLH1 [n = 1], MSH2 [n = 4], MSH6 [n = 1], PMS2 [n = 3]), and nine patients had sporadic pathogenic variants in DNA MMR genes (MLH1 [n = 4], MSH6 [n = 5]). After matching to 36 control patients, the MSI-H/MMRd/LS PDACs had a significantly better OS (hazard ratio [HR], 0.36 [95% confidence interval [CI], 0.18-0.73; p = 0.005]; 5-year OS: MSI-H 77% [95% CI 58-100%] vs. MSS 27% [95% CI 15-51%]). CONCLUSION Before routine use of immune checkpoint inhibitors, the patients with MSI-H, MMRd, and LS-associated PDACs displayed significantly better survival than the patients with MSS, MMR-proficient, non-LS-associated PDACs. It is expected that survival for this cohort will further improve with increased availability of immunotherapy.
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Affiliation(s)
- Ellis L Eikenboom
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Clinical Genetics, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Naaz Nasar
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kenneth Seier
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mithat Gönen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Manon C W Spaander
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - William R Jarnagin
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jeffrey Drebin
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael I D'Angelica
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - T Peter Kingham
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vinod P Balachandran
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kevin C Soares
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anja Wagner
- Department of Clinical Genetics, Erasmus Medical Center Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Alice C Wei
- Hepato-Pancreato-Biliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Kryklyva V, Pflüger MJ, Ouchene H, Volleberg-Gorissen H, Mensenkamp AR, Jonker MA, van de Water C, Nagtegaal ID, Ligtenberg MJL, Brosens LAA. Germline Pathogenic Variants in Patients with Pancreatic Ductal Adenocarcinoma and Extra-Pancreatic Malignancies: A Nationwide Database Analysis. Mod Pathol 2025; 38:100709. [PMID: 39793706 DOI: 10.1016/j.modpat.2025.100709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 11/11/2024] [Accepted: 12/19/2024] [Indexed: 01/13/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Approximately 10% of affected individuals have an inherited component. Deleterious germline variants increase the lifetime risk for PDAC and are often associated with an elevated risk for extra-pancreatic malignancies. In this study, we aimed to determine the prevalence and impact of germline pathogenic variants (gPVs) in patients with PDAC and extra-pancreatic malignancies. Using tissue samples and longitudinal data from a nationwide pathology database, we identified patients with PDAC and a set of 7 extra-pancreatic malignancies to investigate the presence of gPVs in 25 cancer susceptibility genes with targeted next-generation sequencing. Of 473 patients with PDAC and at least 1 extra-pancreatic malignancy, 75 (16%) had gPVs. These were predominantly in ATM (n = 22), CDKN2A (n = 14), BRCA2 (n = 10), or CHEK2 (n = 10) genes. The combination of PDAC and ovarian carcinoma carried the highest prevalence of gPVs (4 of 10; 40%), followed by PDAC and melanoma (15 of 53; 28%), and PDAC and gastric cancer (2 of 9; 22%). Patients with PDAC and certain extra-pancreatic malignancies carry a higher burden of gPVs than unselected PDAC cohorts. This is a group that very likely benefits from genetic testing because germline status can have important diagnostic and therapeutic implications for affected individuals and their family members.
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Affiliation(s)
- Valentyna Kryklyva
- Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Michael J Pflüger
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery CCM|CVK, Charité - Universitätsmedizin Berlin, Germany; Department of Pathology, Graduate School of Life Sciences, Utrecht University, Utrecht, The Netherlands
| | - Hicham Ouchene
- Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hanneke Volleberg-Gorissen
- Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Arjen R Mensenkamp
- Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marianne A Jonker
- Department for Health Evidence, Section Biostatistics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Carlijn van de Water
- Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Iris D Nagtegaal
- Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Marjolijn J L Ligtenberg
- Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lodewijk A A Brosens
- Department of Pathology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
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9
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Doi T, Ishikawa T, Moriguchi M, Itoh Y. Current status of cancer genome medicine for pancreatic ductal adenocarcinoma. Jpn J Clin Oncol 2025; 55:443-452. [PMID: 39893577 DOI: 10.1093/jjco/hyaf012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 01/17/2025] [Indexed: 02/04/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis; however, advancements in cancer genome profiling using next-generation sequencing have provided new perspectives. KRAS mutations are the most frequently observed genomic alterations in patients with PDAC. However, until recently, it was not considered a viable therapeutic target. Although KRAS G12C mutations for which targeted therapies are already available are infrequent in PDAC, treatments targeting KRAS G12D and pan-KRAS are still under development. Similarly, new treatment methods for KRAS, such as chimeric antigen receptor T-cell therapy, have been developed. Several other potential therapeutic targets have been identified for KRAS wild-type PDAC. For instance, immune checkpoint inhibitors have demonstrated efficacy in PDAC treatment with microsatellite instability-high/deficient mismatch repair and tumor mutation burden-high profiles. However, for other PDAC cases with low immunogenicity, combination therapies that enhance the effectiveness of immune checkpoint inhibitors are being considered. Additionally, homologous recombination repair deficiencies, including BRCA1/2 mutations, are prevalent in PDAC and serve as important biomarkers for therapies involving poly (adenosine diphosphate-ribose) polymerase inhibitors and platinum-based therapies. Currently, olaparib is available for maintenance therapy of BRCA1/2 mutation-positive PDAC. Further therapeutic developments are ongoing for genetic abnormalities involving BRAF V600E and the fusion genes RET, NTRK, NRG, ALK, FGFR2, and ROS1. Overcoming advanced PDAC remains a formidable challenge; however, this review outlines the latest therapeutic strategies that are expected to lead to significant advancements.
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Affiliation(s)
- Toshifumi Doi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
- Cancer Genome Medical Center, University Hospital, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Takeshi Ishikawa
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
- Cancer Genome Medical Center, University Hospital, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
- Department of Medical Oncology Unit, University Hospital, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Michihisa Moriguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
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10
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Stoop TF, Javed AA, Oba A, Koerkamp BG, Seufferlein T, Wilmink JW, Besselink MG. Pancreatic cancer. Lancet 2025; 405:1182-1202. [PMID: 40187844 DOI: 10.1016/s0140-6736(25)00261-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 01/31/2025] [Accepted: 02/05/2025] [Indexed: 04/07/2025]
Abstract
Pancreatic cancer is frequently a lethal disease with an aggressive tumour biology often presenting with non-specific symptoms. Median survival is approximately 4 months with a 5-year survival of 13%. Surveillance is recommended in individuals with familial pancreatic cancer, specific mutations, and high-risk intraductal papillary mucinous neoplasm, as they are at high risk of developing pancreatic cancer. Chemotherapy combined with surgical resection remains the cornerstone of treatment. However, only a small subset of patients are candidates for surgery. Multi-agent chemotherapy has improved survival in the palliative setting for patients with metastatic disease, as (neo)adjuvant and induction therapy have in patients with borderline resectable and locally advanced pancreatic. Given that pancreatic cancer is predicted to become the second leading cause of cancer-related death by 2030, novel therapies are urgently needed.
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Affiliation(s)
- Thomas F Stoop
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, Netherlands; Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Ammar A Javed
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, Netherlands; Cancer Center Amsterdam, Amsterdam, Netherlands; Division of Surgical Oncology, Department of Surgery, New York University Medical Center, New York, NY, USA
| | - Atsushi Oba
- Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan; Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Division of Surgical Oncology, Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Thomas Seufferlein
- Department of International Medicine I, Ulm University Hospital, Ulm, Germany
| | - Johanna W Wilmink
- Department of Medical Oncology, Amsterdam, Netherlands; Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Marc G Besselink
- Amsterdam UMC, location University of Amsterdam, Department of Surgery, Amsterdam, Netherlands; Cancer Center Amsterdam, Amsterdam, Netherlands.
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11
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Bye BA, Jack JL, Pierce A, Walsh RM, Eades AE, Chalise P, Olou A, VanSaun MN. Combined Omipalisib and MAPK Inhibition Suppress PDAC Growth. Cancers (Basel) 2025; 17:1152. [PMID: 40227649 PMCID: PMC11987824 DOI: 10.3390/cancers17071152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Revised: 03/14/2025] [Accepted: 03/26/2025] [Indexed: 04/15/2025] Open
Abstract
Background: Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS, as well as downstream MAPK pathway effectors, have shown limited clinical success. While KRAS canonically drives MAPK signaling via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling. Methods: Our therapeutic study targeted the PI3K pathway with the drug Omipalisib (p110α/β/δ/γ and mTORC1/2 inhibitor) in combination with two different MAPK pathway inhibitors: Trametinib (MEK1/2 inhibitor) or SHP099-HCL (SHP099; SHP2 inhibitor). Western blot analysis demonstrated that the application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT). Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MAPK and PI3K-AKT, and effectively suppress PDAC growth. Results: In vitro studies demonstrated that, in several cell lines, both Omipalisib/Trametinib and Omipalisib/SHP099 combination therapeutic strategies were more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. In vivo oral administration of combined Omipalisib/Trametinib treatment was significantly more effective than Omipalisib/SHP099 in reducing implanted tumor growth, and the Omipalisib/Trametinib treatment more effectively reduced tumor progression and prolonged survival in an aggressive genetically engineered mouse model of PDAC than either Omipalisib or Trametinib alone. Conclusions: Altogether, our data support a rationale for a dual treatment strategy targeting both PI3K and MAPK pathways in pancreatic cancers.
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Affiliation(s)
- Bailey A. Bye
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
| | - Jarrid L. Jack
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
| | - Alexandra Pierce
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
| | - Richard McKinnon Walsh
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
| | - Austin E. Eades
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
| | - Prabhakar Chalise
- Department of Biostatistics and Data Science, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
| | - Appolinaire Olou
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
| | - Michael N. VanSaun
- Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
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12
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Vigié T, Perrier A, Chanez B, De Martino J, Favre L, Coulet F, Bachet JB, Guillerm E, Mas L. Prolonged response to osimertinib in three patients with refractory metastatic pancreatic adenocarcinomas with EGFR exon 19 deletion: a case report and literature review. Ther Adv Med Oncol 2025; 17:17588359241312078. [PMID: 40162000 PMCID: PMC11954516 DOI: 10.1177/17588359241312078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 12/19/2024] [Indexed: 04/02/2025] Open
Abstract
Pancreatic cancer is a rising cause of cancer death. Therapeutic options are scarce and of limited efficacy. Up to 26% of patients with metastatic pancreatic cancer could benefit from targeted therapies. We report here for the first time the case of three patients with metastatic pancreatic ductal adenocarcinoma (PDAC) without KRAS alteration for whom an activating mutation in exon 19 of the epidermal growth factor receptor (EGFR) gene was found through mainstreaming NGS. The EGFR variant was confirmed on multiple tumor samples and by circulating tumor DNA (ctDNA) analysis in two patients. The three patients were treated with osimertinib with early molecular, biologic, and morpho-metabolic responses. At the last follow-up, one patient had an ongoing response after 17 months, and disease control had been maintained for 8 and 6 months in the other two. Known resistance mechanisms were observed on ctDNA analysis at progression. These observations demonstrate the benefit of osimertinib for treating EGFR-mutated PDAC and highlight the interest in investigating rare molecular alterations, especially in patients without KRAS alterations.
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Affiliation(s)
- Timothée Vigié
- Hepato-Gastroenterology and Digestive Oncology Department, Sorbonne University, Pitié Salpêtrière Hospital, AP-HP, Paris, France
| | - Alexandre Perrier
- Genetics Medical Department, Sorbonne University, Pitié Salpêtrière Hospital, AP-HP, Paris, France
| | - Brice Chanez
- Medical Oncology Department, Institut Paoli-Calmettes, Marseille, France
| | - Julien De Martino
- Department of Hepato-Biliary and Pancreatic Surgery and Liver Transplantation, Sorbonne University, AP-HP, Pitié Salpêtrière Hospital, Paris, France
| | - Loëtitia Favre
- Genetics Medical Department, Sorbonne University, Pitié Salpêtrière Hospital, AP-HP, Paris, France
| | - Florence Coulet
- Genetics Medical Department, Sorbonne University, Pitié Salpêtrière Hospital, AP-HP, Paris, France
| | - Jean-Baptiste Bachet
- Hepato-Gastroenterology and Digestive Oncology Department, Sorbonne University, Pitié Salpêtrière Hospital, AP-HP, Paris, France
| | - Erell Guillerm
- Genetics Medical Department, Sorbonne University, Pitié Salpêtrière Hospital, AP-HP, Paris, France
| | - Léo Mas
- Hepato-Gastroenterology and Digestive Oncology Department, Sorbonne University, Pitié Salpêtrière Hospital, AP-HP, 47-83 Boulevard de l’Hôpital, Paris 75013, France
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13
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Dbouk M, Davis BG, Peller M, Sloan E, Hollander T, Reyes-Genere JP, Bazarbashi A, Ismail MK, Lang G, Kushnir V, Early D, Ballentine S, Dai SC, Kouanda A, Das KK. EUS-guided fine-needle biopsy sampling of solid pancreatic masses with and without rapid onsite evaluation for commercial next-generation genomic profiling. Gastrointest Endosc 2025:S0016-5107(25)01378-1. [PMID: 40122217 DOI: 10.1016/j.gie.2025.03.1208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 02/11/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND AND AIMS Although EUS-guided fine-needle biopsy sampling (EUS-FNB) of solid pancreatic lesions with or without the use of rapid onsite evaluation (ROSE) provides a high diagnostic yield, the utility of ROSE for commercial genomic analysis is unclear. METHODS A multicenter retrospective review was conducted of consecutive patients where genomic analysis was requested from EUS-FNB of solid pancreatic lesions, performed with 22-gauge fine-needle biopsy (FNB) needles. Data were collected at 2 academic centers, one that routinely uses ROSE to assess adequacy for all EUS-FNB cases (University of California San Francisco, n = 44) and one that does not use ROSE (Washington University, n = 186). RESULTS The cohort consisted of 230 patients (mean age, 67.3 ± 9.8 years; 52.6% women). There were no significant differences between patient and tumor characteristics or locations in the 2 groups. Adverse events were uncommon and similar between the groups (1.6% vs 0%). Adequacy for genomic evaluation was high and similar between those cases without and with ROSE (159/186 [85.5%] vs 39/44 [88.6%], P = .8). Genomic analysis resulted in potentially actionable mutations in a similar number of cases without and with ROSE (18.3% vs 15.9%, P = .82). However, compared with FNB sampling without ROSE, FNB sampling with ROSE required more than double the procedure time (mean, 21.1 ± 10 minutes vs 49.7 ± 20.6 minutes; P < .001) and a significantly higher number of median needle passes (3 [IQR, 2-3] vs 4 [IQR, 3-4], P < .001). CONCLUSIONS Although EUS-FNB with ROSE did not have a significantly different adequacy for commercial genomic analysis compared with EUS-FNB without ROSE, it required significantly more procedure time and needle passes.
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Affiliation(s)
- Mohamad Dbouk
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Brenton G Davis
- Division of Gastroenterology, University of California San Francisco, San Francisco, California, USA
| | - Matthew Peller
- Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Erika Sloan
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Thomas Hollander
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Juan Pablo Reyes-Genere
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Ahmad Bazarbashi
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Mohammad K Ismail
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Gabriel Lang
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Vladimir Kushnir
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Dayna Early
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Samuel Ballentine
- Department of Pathology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Sun-Chuan Dai
- Division of Gastroenterology, University of California San Francisco, San Francisco, California, USA
| | - Abdul Kouanda
- Division of Gastroenterology, University of California San Francisco, San Francisco, California, USA
| | - Koushik K Das
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA.
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14
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Sun X, Teper Y, Sinnett-Smith J, Markarian M, Hines OJ, Li G, Eibl G, Rozengurt E. Stress and Obesity Signaling Converge on CREB Phosphorylation to Promote Pancreatic Cancer. Mol Cancer Res 2025; 23:236-249. [PMID: 39642318 PMCID: PMC11875952 DOI: 10.1158/1541-7786.mcr-24-0785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/22/2024] [Accepted: 12/04/2024] [Indexed: 12/08/2024]
Abstract
One of the deadliest types of cancer is pancreatic ductal adenocarcinoma (PDAC). Chronic stress and obesity are recognized as risk factors for PDAC. We hypothesized that the combination of stress and obesity strongly promotes pancreatic cancer development and growth. Here, we show that the stress mediator norepinephrine and the β-adrenergic receptor agonist isoproterenol rapidly stimulate cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation at Ser133 in human PDAC cells. Exposure to the nonselective β-adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551, blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. Stimulation of PDAC cells with neurotensin, a neuropeptide implicated in obesity and PDAC, also stimulated CREB phosphorylation at Ser133. Mechanistically, norepinephrine induced CREB phosphorylation at Ser133 via PKA, whereas neurotensin promoted CREB phosphorylation predominantly through protein kinase D. Our results indicate that CREB is a point of signal convergence that mediates proliferation in PDAC cells and raised the possibility that stress and diet cooperate in promoting PDAC in vivo. To test this notion, mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, calorie diet that promotes early PDAC development were subjected to social isolation stress. We show that social isolation stress induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia) in KC mice subjected to an obesogenic high fat, calorie diet. Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer.
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Affiliation(s)
- Xiaoying Sun
- Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - Yaroslav Teper
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - James Sinnett-Smith
- Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - Mineh Markarian
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - O Joe Hines
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - Gang Li
- Department of Biostatistics, School of Public Health, University of California, Los Angeles, CA 90095
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - Enrique Rozengurt
- Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
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15
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Matsubayashi H, Kiyozumi Y, Ono H. Genetic medicine of familial and hereditary pancreatic cancer: Recent update in the era of precision cancer medicine. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2025; 32:212-227. [PMID: 39814596 DOI: 10.1002/jhbp.12112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
In Japan, 5 years have passed since the initiation of precision cancer medicine, and recent data accumulation in familial pancreatic cancer (FPC) and hereditary pancreatic cancer is outstanding. Multigene germline panel tests (MGPTs) have revealed that 7%-18% of patients with pancreatic cancer (PC) harbor pathogenic germline variants (PGVs), almost equal to the levels of breast, ovarian, endometrial, and colorectal cancers, with a higher incidence in FPC (14%-26%). The majority of PGVs seen in PC patients are clinically actionable and associated with homologous recombination (HR) pathways (6%-10%, particularly BRCA1/2 in 5%-6%), and the clinical guidelines recommend or propose genetic testing for all PC patients. Consensus guidelines have been established for most of the hereditary syndromes associated with PC risks, and surveillances of the pancreas and other at-risk organs are recommended for PGV carriers. Hereditary breast and ovarian cancer (HBOC) is the commonest hereditary cancer syndrome that has moderately increasing life-time risks of PC (3%-7% in Western countries); however, recent Japanese research demonstrated a higher risk level (BRCA1: 16%, BRCA2: 14%). Moreover, recent evidence has suggested a risk linkage between PC and ovarian cancer in HBOC pedigrees. High scores of homologous recombination deficiency suggest biallelic dysfunction of BRCA or other HR-related genes, and the likely effectiveness of platinum agents and PARP inhibitors against PCs. Remote counseling and testing are possible option in the future genetic medicine. As PC ranks in the second commonest target of precision cancer medicine in Japan, we must treat the patients and manage their at-risk relatives efficiently.
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Affiliation(s)
- Hiroyuki Matsubayashi
- Division of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka, Japan
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yoshimi Kiyozumi
- Division of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hiroyuki Ono
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan
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16
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Cai Q, Meng X, Sun J, Gagan J, Aggarwal A, Khanshour AM, Bhanvadia R, Xu J, Mohanty SK, Shah RB. Prostate Ductal Adenocarcinoma Revisited: Clinicopathological and Genomic Characterization Identifies Heterogenous Group of Diseases with Implications for Patient Management. Mod Pathol 2025; 38:100743. [PMID: 40015646 DOI: 10.1016/j.modpat.2025.100743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 02/15/2025] [Accepted: 02/16/2025] [Indexed: 03/01/2025]
Abstract
Prostate ductal adenocarcinoma (PDA) is an aggressive subtype of prostate adenocarcinoma (PA). It can be found either in the peripheral zone, typically associated with acinar PA, or centrally in or around the verumontanum as a urethral polyp. Whether centrally occurring PDAs are biologically and genetically different compared with peripheral PDA remains unknown. Thirty-five PDAs diagnosed on resection specimens were categorized into 3 groups based on PDA location (central [urethra] involvement only [PDA-C], both central and peripheral involvement [PDA-C&P], peripheral involvement only [PDA-P]) and analyzed for clinicopathological, genomic characteristics, and outcomes. Targeted next-generation DNA and RNA sequencing with full exon coverage of 1425 cancer-related genes was performed on 2 PDA-C, 8 PDA-C&P, and 12 PDA-P with a grossly dissectible population of viable PDA. In 11 PDA-P, the same patients' ductal and associated acinar components were sequenced separately. Of 35 PDAs, 2 (6%), 11 (31%), and 22 (63%) were PDA-C, PDA-C&P, and PDA-P, respectively. PDA-C&P compared with PDA-P presented with larger tumor size (median 45 mm vs 25 mm), % ductal component (100% vs 30%), ≥ pT3 disease (100% vs 64%), visceral metastasis (36% vs 0%), and cancer-specific mortality (27% vs 0%) (P < .05) and enrichment for at least 1 DNA damage and repair (DDR)-related gene alterations (BRCA2, ATM, CDK12, ERCC2) (63% vs 8%), and PI3K pathway alterations (37% vs none). PDA-Ps were enriched in FOXA1 alterations compared with PDA-C&P (75% vs 25%) including 5 (56%) having FOXA1 mutation in only ductal components. TMPRSS2::ERG fusion was present in only 1 patient with PDA-P in both ductal and acinar components. One patient with PDA-C and 3 with PDA-C&P exhibited novel gene fusion ACPP::FGFR2 and NF1::ADAP, FGFR2::POC1B, and RB1:TTTY3, respectively. In 2 patients with PDA-C, PDA was eradicated in transurethral resection with no residual disease in follow-up radical prostatectomy. PDA-C lacked alterations in DDR genes. Our findings suggest that PDAs are clinically and genetically heterogeneous diseases. Understanding the heterogeneity of PDA is critically important in determining its biological potential and facilitating optimal patient management.
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Affiliation(s)
- Qi Cai
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Xiaosong Meng
- Department of Urology, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jing Sun
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jeffrey Gagan
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Aditi Aggarwal
- Department of Anatomic Pathology, CORE Diagnostics, Gurgaon, India
| | - Anas M Khanshour
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Raj Bhanvadia
- Department of Urology, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jing Xu
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sambit K Mohanty
- Department of Anatomic Pathology, CORE Diagnostics, Gurgaon, India
| | - Rajal B Shah
- Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas.
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17
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Lena J, Alamé M, Italiano A, Soubeyran I, Blouin L, Khalifa E, Cousin S, Pernot S, Palmieri LJ. Extensive molecular profiling of KRAS wild-type as compared to KRAS mutated pancreatic ductal adenocarcinoma on 318 patients. Eur J Cancer 2025; 216:115197. [PMID: 39729677 DOI: 10.1016/j.ejca.2024.115197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/15/2024] [Accepted: 12/18/2024] [Indexed: 12/29/2024]
Abstract
PURPOSE Molecular profiling is increasingly implemented to guide treatment of advanced pancreatic ductal adenocarcinoma (PDAC), especially when for clinical trials enrollment. This study aimed to describe actionable alterations detected in KRAS mutated (KRASm) versus KRAS wild-type (KRASwt) PDAC, the latter group being considered enriched in molecular alterations. METHODS This prospective monocentric study included patients with locally advanced or metastatic PDAC who underwent next-generation sequencing (NGS) on liquid biopsy and/or tissue samples between 2015 and 2023, as part of the BIP academic study (NCT02534649). Actionable alterations were classified using the ESCAT (ESMO Scale for Clinical Actionability of molecular Targets). RESULTS A total of 378 patients with a PDAC underwent NGS: 73 on tissue samples, 162 on liquid biopsies, and 143 on both tissue and liquid. Liquid biopsies had a 59.3 % performance (181 informative samples out of 305). Among 318 informative NGS samples, 273 (86 %) were KRASm, and 45 (14 %) were KRASwt. Median overall survival (OS) was 19.35 in KRASwt patients and 16.89 months for KRASm patients (HR 0.67, 95 %CI (0.49-0.90), p = 0.02). ESCAT alterations were found in 15.7 % of total population, with 31.1 % in KRASwt tumors and 13.2 % in KRASm tumors. BRCA1/2 mutations were identified in 7.5 % of the population, and one NTRK fusion was found in a KRASwt PDAC. The molecular tumor board considered 71 patients (22.3 %) eligible for early-phase trials, with 14 treated with matched therapy. CONCLUSION Although actionable mutations were more frequent in KRASwt tumors, 13.2 % of KRASm PDAC harbored ESCAT alterations, emphasizing the importance of molecular profiling regardless of KRAS status.
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Affiliation(s)
- Jeanne Lena
- Department of Medicine, Institut Bergonié, Bordeaux, France
| | - Mélissa Alamé
- Department of Pathology, Institut Bergonié, Bordeaux, France
| | - Antoine Italiano
- Department of Medicine, Institut Bergonié, Bordeaux, France; Faculty of Medicine, University of Bordeaux, France
| | | | - Laura Blouin
- Department of Pathology, Institut Bergonié, Bordeaux, France
| | | | - Sophie Cousin
- Department of Medicine, Institut Bergonié, Bordeaux, France
| | - Simon Pernot
- Department of Medicine, Institut Bergonié, Bordeaux, France
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18
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Ko SW, Jo IH, Yoon SB. Feasibility and clinical utility of endoscopic ultrasound-guided tissue acquisition for comprehensive genomic profiling in pancreatic cancer: A systematic review and meta-analysis. Pancreatology 2025; 25:89-97. [PMID: 39732591 DOI: 10.1016/j.pan.2024.12.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 11/09/2024] [Accepted: 12/21/2024] [Indexed: 12/30/2024]
Abstract
BACKGROUND Endoscopic ultrasound-guided tissue acquisition (EUS-TA) has become essential for diagnosing pancreatic ductal adenocarcinoma (PDAC) and is increasingly utilized for comprehensive genome profiling (CGP) to advance precision medicine. This systematic review and meta-analysis assess the feasibility and clinical utility of EUS-TA samples for CGP in PDAC. METHODS We conducted a thorough systematic literature search in PubMed, EMBASE, and the Cochrane Library up to October 2023. Key outcomes included sequencing success rates, detection rates of four major driver genes and actionable genes, and concordance rates with other sample types or methodologies. RESULTS A total of 23 studies met the inclusion criteria. The pooled sequencing success rate was 83.9 % [95 % confidence interval (CI): 75.8-89.7 %]. No significant difference was observed in sequencing success rates between fine needle aspiration and biopsy (odds ratio 1.77, 95 % CI 0.70-4.47). Meta-regression analysis revealed that the minimum DNA requirement for CGP significantly influenced sequencing success rates. The pooled mutation rate for K-ras was 86.4 % (95 % CI 83.6-88.8), while potentially actionable mutations had a pooled rate of 17.7 % (95 % CI 12.8-23.8). The concordance rate between CGP results from EUS-guided samples and surgical specimens was 81.6 % (95 % CI 68.2-90.1). CONCLUSION Comprehensive genomic profiling of PDAC using EUS-TA-derived samples demonstrated feasibility in clinical settings. Approximately 18 % of patients undergoing CGP exhibited potentially actionable mutations, highlighting the potential for personalized therapeutic approaches.
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Affiliation(s)
- Sung Woo Ko
- Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Ik Hyun Jo
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea
| | - Seung Bae Yoon
- Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
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19
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Mouawad A, Habib S, Boutros M, Attieh F, Kourie HR. How to find a needle in a haystack: a systematic review on targeting KRAS wild-type pancreatic cancer. Future Oncol 2024; 20:3539-3547. [PMID: 38861291 PMCID: PMC11776852 DOI: 10.1080/14796694.2024.2355078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 05/10/2024] [Indexed: 06/12/2024] Open
Abstract
Aim: Pancreatic adenocarcinoma is a very aggressive type of cancer, in which targeted therapies have not yet been fully utilized. KRAS wild-type pancreatic adenocarcinoma tumors are associated with different genomic alterations in comparison to KRAS mutated pancreatic adenocarcinoma. Objective: This systematic review aims to provide a one-stop summary of all these alterations, their proposed targeted treatment and their effect on disease progression. Methods: An electronic search strategy was elaborated in the PubMed database between 2020 and January 2024. Results: 21 studies were included, and we found that the most frequent targetable genomic alterations in KRAS wild-type pancreatic adenocarcinoma were BRAF, EGFR, FGFR, MSI-H/dMMR, Her2/ERBB2 amplification, BRCA1/2 and other HRDs, and gene fusions like ALK, NTRK and NRG1.
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Affiliation(s)
- Antoine Mouawad
- Université Saint-Joseph de Beyrouth, Beyrouth, 11-5076, Lebanon
| | - Sofia Habib
- Université Saint-Joseph de Beyrouth, Beyrouth, 11-5076, Lebanon
| | - Marc Boutros
- Université Saint-Joseph de Beyrouth, Beyrouth, 11-5076, Lebanon
| | - Fouad Attieh
- Université Saint-Joseph de Beyrouth, Beyrouth, 11-5076, Lebanon
| | - Hampig Raphaël Kourie
- Department of Hematology-Oncology, Université Saint-Joseph de Beyrouth, Beyrouth, 11-5076, Lebanon
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20
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Diab M. New Therapeutic Targets in RAS Wild-type Pancreatic Cancer. Curr Treat Options Oncol 2024; 25:1556-1562. [PMID: 39546212 DOI: 10.1007/s11864-024-01242-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2024] [Indexed: 11/17/2024]
Abstract
OPINION STATEMENT The landscape of treatment of advanced PDAC is witnessing significant changes. This is in part due to the advent of molecular profiling, which has highlighted molecularly-distinct subsets of pts, especially those with KRAS wild-type disease. We now know that these pts harbor genomic alterations that not only serve as molecular drivers but also pose as therapeutically relevant markers. In the absence of strong evidence to support the use of targeted therapy in the front-line setting, we continue to offer chemotherapy for treatment-naïve pts. However, an argument can be made for the front-line use of targeted therapy in pts who are not fit for chemotherapy or who are not interested in it. The challenge is ensuring that molecular profiling is done in a timely fashion to prevent significant delays in therapy. In our practice, we offer molecular testing to all pts with a new diagnosis of advanced PDAC. We prefer the utility of targeted therapy in the second line and beyond for pts who have an actionable target, over the use of further chemotherapy, as targeted therapy appears to confer deep and durable responses and longer survival. For pts with MSI-H or MMRd disease, the use of immunotherapy is indicated, although it has to be noted that MSI-H/MMRd PDAC performed worse that other MSI-H/MMRd cancers treated with immunotherapy. Therefore, in the presence of MSI-H/MMRd and an additional actionable target, we prefer treating with targeted therapy and reserving immunotherapy for later lines. Pt preference has to be taken into consideration at all times though.
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Affiliation(s)
- Maria Diab
- Clinical Assistant Professor, Michigan State University/Henry Ford Health Sciences, 2800 W Grand Blvd, Detroit, MI, 48202, USA.
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21
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Cheng K, Li X, Lv W, Zhao G, Zhou R, Chang C, Yang H, Li R, Li Z, Chen Y, Yi C, Yan O, Xiao C, Zhang Y, Xiong J, Huang Z, Shao W, You X, Guo W, He D, Ling W, Wang R, Tian B, Zhao C, Cao D. Spatial interactions of immune cells as potential predictors to efficacy of toripalimab plus chemotherapy in locally advanced or metastatic pancreatic ductal adenocarcinoma: a phase Ib/II trial. Signal Transduct Target Ther 2024; 9:321. [PMID: 39582060 PMCID: PMC11586424 DOI: 10.1038/s41392-024-02031-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/10/2024] [Accepted: 10/23/2024] [Indexed: 11/26/2024] Open
Abstract
Advanced pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Immunotherapy alone offers limited efficacy, but it is still unknown whether its combination with chemotherapy could offer synergistic anti-tumor effects. This phase Ib/II study evaluated the safety and efficacy of combining toripalimab with the gemcitabine plus nab-paclitaxel (GnP) regimen as first-line treatment for locally advanced or metastatic PDAC and explored predictive biomarkers (ChiCTR2000032293). The primary endpoints were safety and overall survival (OS). The secondary outcomes were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Immune-related biomarkers including programmed death-ligand 1 (PD-L1) expression, genetic status, cytokine levels, and spatial features of the tumor immune microenviroment (TIME) were investigated. Neither serious treatment-related adverse events nor grade 4 immune-related adverse events were reported. Among the 72 patients, the median OS was 8.9 months, 12-month OS rate was 31.9%, with median PFS of 5.6 months, ORR of 33.3%, and DCR of 90.3%. Higher PD-L1 expression, without liver metastases were associated with higher ORR, however these factors could not effectively distinguish responders and non-responders. Importantly, dendritic cells - T helper cells - cytotoxic T lymphocytes (DC-Th-CTL) enriched immune niche and their spatial interactions were dominant predictors of response based on TIME analysis using a cyclic multiplex tissue staining assay, with an area under the curve value of 0.8. Overall, GnP plus toripalimab exhibited good safety and differentiated efficacy in selected population, and the spatial interactions of DC-Th-CTL represent promising predictors to efficacy of immunochemotherapy in locally advanced or metastatic PDAC.
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Affiliation(s)
- Ke Cheng
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoying Li
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wanrui Lv
- Department of Oncology, Meishan City People's Hospital, Meishan, Sichuan, China
| | - Gang Zhao
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ruihan Zhou
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center, West China Hospital, Chengdu, Sichuan, China
| | - Chen Chang
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Heqi Yang
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ruizhen Li
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhiping Li
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ye Chen
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Cheng Yi
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ouying Yan
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chaoxin Xiao
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center, West China Hospital, Chengdu, Sichuan, China
| | - Yi Zhang
- Pancreatic Division, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of General Surgery, ChengDu ShangJing NanFu Hospital, Chengdu, Sichuan, China
| | - Junjie Xiong
- Pancreatic Division, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zixin Huang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Radiology, West China Tianfu Hospital, Sichuan University, Chengdu, Sichuan, China
| | | | - Xin You
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wenhao Guo
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Du He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wenwu Ling
- Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Rui Wang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bole Tian
- Pancreatic Division, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Chengjian Zhao
- State Key Laboratory of Biotherapy and Cancer Center, Sichuan University and Collaborative Innovation Center, West China Hospital, Chengdu, Sichuan, China.
| | - Dan Cao
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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22
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Zhang X, Xu Y, Shi L, Chen X, Hu M, Zhang M, Nie M, Liu X. FGF6 inhibits oral squamous cell carcinoma progression by regulating PI3K/AKT and MAPK pathways. Sci Rep 2024; 14:26877. [PMID: 39506091 PMCID: PMC11542074 DOI: 10.1038/s41598-024-78552-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 10/31/2024] [Indexed: 11/08/2024] Open
Abstract
To explore diagnostic and prognostic biomarkers in the progression of oral squamous cell carcinoma (OSCC) and to reveal their regulatory mechanisms in key pathways. A RayBiotech protein chip was used to screen differentially expressed serum proteins in OSCC, oral leukoplakia (OLK), and healthy participants. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to determine the pathways enriched by characteristic differential proteins. Immunohistochemical analysis and western blotting were used to verify the expression of characteristic differential proteins and key regulatory factors in human tissues and in a nude mouse model. Fibroblast growth factor 6 (FGF6) was identified as a key differential protein and was weakly expressed in OSCC tissues. The mitogen-activated protein kinases (MAPK) and PI3K-AKT pathways were identified as key signaling pathways. The results showed that pERK, Cyclin D1, pAKT, and BCL2 were highly expressed in OSCC, Caspase9 was lowly expressed in OSCC. With an increase in FGF6 expression in nude mice, the expression of FGFR4, pERK, Cyclin D1, pAKT, BCL2, GPX4, and ACSL4 increased, and the expression of Caspase9 decreased. FGF6 may change the expression of apoptosis-related proteins and proliferation factors by binding to FGFR4 in the PI3K-AKT/MAPK pathway and may inhibit the ferroptosis of OSCC, thereby possibly participating in the process of inhibiting OSCC.
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Affiliation(s)
- Xuan Zhang
- Department of Oral Basic Medicine, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
- Oral & Maxillofacial Reconstruction and Regeneration of Luzhou Key Laboratory, Southwest Medical University, Sichuan, 646000, China
| | - Yingjiao Xu
- Oral & Maxillofacial Reconstruction and Regeneration of Luzhou Key Laboratory, Southwest Medical University, Sichuan, 646000, China
- Department of Periodontics & Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Lijuan Shi
- Oral & Maxillofacial Reconstruction and Regeneration of Luzhou Key Laboratory, Southwest Medical University, Sichuan, 646000, China
- Department of Periodontics & Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Xiao Chen
- Department of Stomatology Technology, School of Medical Technology, Sichuan College of Traditional Medcine, Mianyang, 621000, China
- Department of Orthodontics, Mianyang Stomatological Hospital, Mianyang, 621000, China
| | - Miaoling Hu
- Oral & Maxillofacial Reconstruction and Regeneration of Luzhou Key Laboratory, Southwest Medical University, Sichuan, 646000, China
- Department of Periodontics & Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Mengxue Zhang
- Oral & Maxillofacial Reconstruction and Regeneration of Luzhou Key Laboratory, Southwest Medical University, Sichuan, 646000, China
- Department of Periodontics & Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Minhai Nie
- Oral & Maxillofacial Reconstruction and Regeneration of Luzhou Key Laboratory, Southwest Medical University, Sichuan, 646000, China.
- Department of Periodontics & Oral Mucosal Diseases, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
| | - Xuqian Liu
- Department of Oral Basic Medicine, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
- Oral & Maxillofacial Reconstruction and Regeneration of Luzhou Key Laboratory, Southwest Medical University, Sichuan, 646000, China.
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23
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Doi T, Ishikawa T, Sakakida T, Itani J, Sone D, Morita R, Kataoka S, Miyake H, Seko Y, Yamaguchi K, Moriguchi M, Sogame Y, Konishi H, Murashima K, Iwasaku M, Takayama K, Itoh Y. Real-world genome profiling in Japanese patients with pancreatic ductal adenocarcinoma focusing on HRD implications. Cancer Sci 2024; 115:3729-3739. [PMID: 39315592 PMCID: PMC11531956 DOI: 10.1111/cas.16329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 08/13/2024] [Accepted: 08/16/2024] [Indexed: 09/25/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges due to its high mortality, making it a critical area of research. This retrospective observational study aimed to analyze real-world data from comprehensive genome profiling (CGP) of Japanese patients with PDAC, mainly focusing on differences in gene detection rates among panels and the implications for homologous recombination deficiency (HRD) status. This study enrolled 2568 patients with PDAC who had undergone CGP between June 2019 and December 2021 using data from the nationwide Center for Cancer Genomics and Advanced Therapeutics database. Two types of CGP assays (tissue and liquid biopsies) were compared and a higher detection rate of genetic abnormalities in tissue specimens was revealed. HRD-related gene alterations were detected in 23% of patients, with BRCA1/2 mutations accounting for 0.9% and 2.9% of patients, respectively. Treatment outcome analysis indicated that patients with BRCA1/2 mutations had a longer time to treatment discontinuation with FOLFIRINOX than gemcitabine plus nab-paclitaxel as first-line therapy (9.3 vs. 5.6 months, p = 0.028). However, no significant differences were observed in the treatment response among the other HRD-related genes. Logistic regression analysis identified younger age and family history of breast, prostate, and ovarian cancers as predictive factors for HRD-related gene alterations. Despite the lack of progression-free survival data and the inability to discriminate between germline and somatic mutations, this study provides valuable insights into the clinical implications of CGP in Japanese patients with PDAC. Further research is warranted to optimize panel selection and elucidate the efficacy of platinum-based therapies depending on the HRD status.
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Affiliation(s)
- Toshifumi Doi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
- Cancer Genome Medical CenterUniversity Hospital, Kyoto Prefectural University of MedicineKyotoJapan
| | - Takeshi Ishikawa
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
- Cancer Genome Medical CenterUniversity Hospital, Kyoto Prefectural University of MedicineKyotoJapan
- Department of Medical Oncology UnitUniversity Hospital, Kyoto Prefectural University of MedicineKyotoJapan
| | - Tomoki Sakakida
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
- Cancer Genome Medical CenterUniversity Hospital, Kyoto Prefectural University of MedicineKyotoJapan
| | - Junichiro Itani
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
- Cancer Genome Medical CenterUniversity Hospital, Kyoto Prefectural University of MedicineKyotoJapan
| | - Daiki Sone
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
- Cancer Genome Medical CenterUniversity Hospital, Kyoto Prefectural University of MedicineKyotoJapan
| | - Ryuichi Morita
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
- Cancer Genome Medical CenterUniversity Hospital, Kyoto Prefectural University of MedicineKyotoJapan
| | - Seita Kataoka
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Hayato Miyake
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Yuya Seko
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Kanji Yamaguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Michihisa Moriguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Yoshio Sogame
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Hideyuki Konishi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Kyoko Murashima
- Cancer Genome Medical CenterUniversity Hospital, Kyoto Prefectural University of MedicineKyotoJapan
| | - Masahiro Iwasaku
- Cancer Genome Medical CenterUniversity Hospital, Kyoto Prefectural University of MedicineKyotoJapan
- Department of Pulmonary Medicine, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Koichi Takayama
- Cancer Genome Medical CenterUniversity Hospital, Kyoto Prefectural University of MedicineKyotoJapan
- Department of Medical Oncology UnitUniversity Hospital, Kyoto Prefectural University of MedicineKyotoJapan
- Department of Pulmonary Medicine, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
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24
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Connelly CF, Towne WS, Desai N, Smithgall MC, Cimic A, Baskota SU. Cytologic testing for mismatch repair deficiency/microsatellite instability and NTRK gene fusion is not routinely indicated in primary pancreaticobiliary carcinoma cell block material. J Am Soc Cytopathol 2024; 13:413-419. [PMID: 39341739 DOI: 10.1016/j.jasc.2024.08.130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/26/2024] [Accepted: 08/26/2024] [Indexed: 10/01/2024]
Abstract
INTRODUCTION Pancreaticobiliary carcinomas rarely harbor targetable genetic alterations, including microsatellite instability (MSI) or neurotrophic tyrosine receptor kinase (NTRK) gene fusions. As these malignancies are typically present at an advanced stage and have suboptimal response to chemotherapy, the discovery of an actionable genomic alteration provides an additional avenue of treatment for chemotherapy-refractory cases. MATERIALS AND METHODS In this study, we evaluate 319 cases of pancreaticobiliary carcinoma diagnosed on fine-needle aspiration biopsy or biliary brushing for DNA mismatch repair (MMR) protein deficiency and pan-TRK overexpression by immunohistochemistry (IHC) and compare these results to MSI and NTRK gene fusion molecular testing. RESULTS AND CONCLUSION Although we find a high concordance between MMR protein IHC and MSI molecular testing in the evaluation of MMR deficiency and between pan-TRK IHC and NTRK fusion testing by next-generation sequencing, the low prevalence of either of these genetic alterations in our cohort casts doubt on the value of screening cases of pancreaticobiliary carcinoma for MMR protein deficiency and NTRK fusions.
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Affiliation(s)
- Courtney F Connelly
- Department of Pathology and Cell Biology, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, New York
| | - William S Towne
- Department of Pathology, St. Luke's University Health Network, Bethlehem, Pennsylvania
| | - Niyati Desai
- Department of Pathology and Cell Biology, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, New York
| | - Marie C Smithgall
- Department of Pathology and Cell Biology, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, New York
| | - Adela Cimic
- Department of Pathology and Cell Biology, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, New York
| | - Swikrity U Baskota
- Department of Pathology and Laboratory Medicine, University of California Irvine Health School of Medicine, Sacramento, California.
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25
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Paranal RM, Wood LD, Klein AP, Roberts NJ. Understanding familial risk of pancreatic ductal adenocarcinoma. Fam Cancer 2024; 23:419-428. [PMID: 38609521 PMCID: PMC11660179 DOI: 10.1007/s10689-024-00383-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 03/24/2024] [Indexed: 04/14/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is the result of an accumulation of sequential genetic alterations. These genetic alterations can either be inherited, such as pathogenic germline variants that are associated with an increased risk of cancer, or acquired, such as somatic mutations that occur during the lifetime of an individual. Understanding the genetic basis of inherited risk of PDAC is essential to advancing patient care and outcomes through improved clinical surveillance, early detection initiatives, and targeted therapies. In this review we discuss factors associated with an increased risk of PDAC, the prevalence of genetic variants associated with an increased risk in patients with PDAC, estimates of PDAC risk in carriers of pathogenic germline variants in genes associated with an increased risk of PDAC. The role of common variants in pancreatic cancer risk will also be discussed.
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Affiliation(s)
- Raymond M Paranal
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Human Genetics Predoctoral Training Program, the McKusick-Nathans Department of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura D Wood
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alison P Klein
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, MD, USA.
| | - Nicholas J Roberts
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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26
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Dubrovsky G, Ross A, Jalali P, Lotze M. Liquid Biopsy in Pancreatic Ductal Adenocarcinoma: A Review of Methods and Applications. Int J Mol Sci 2024; 25:11013. [PMID: 39456796 PMCID: PMC11507494 DOI: 10.3390/ijms252011013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/08/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a malignancy with one of the highest mortality rates. One limitation in the diagnosis and treatment of PDAC is the lack of an early and universal biomarker. Extensive research performed recently to develop new assays which could fit this role is available. In this review, we will discuss the current landscape of liquid biopsy in patients with PDAC. Specifically, we will review the various methods of liquid biopsy, focusing on circulating tumor DNA (ctDNA) and exosomes and future opportunities for improvement using artificial intelligence or machine learning to analyze results from a multi-omic approach. We will also consider applications which have been evaluated, including the utility of liquid biopsy for screening and staging patients at diagnosis as well as before and after surgery. We will also examine the potential for liquid biopsy to monitor patient treatment response in the setting of clinical trial development.
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Affiliation(s)
- Genia Dubrovsky
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; (G.D.); (A.R.)
- Pittsburgh VA Medical Center, Pittsburgh, PA 15240, USA
| | - Alison Ross
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; (G.D.); (A.R.)
| | - Pooya Jalali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Centre, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran
| | - Michael Lotze
- Departments of Surgery, Immunology, and Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
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27
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Yang D, Sun X, Moniruzzaman R, Wang H, Citu C, Zhao Z, Wistuba II, Wang H, Maitra A, Chen Y. Loss of p53 and SMAD4 induces adenosquamous subtype pancreatic cancer in the absence of an oncogenic KRAS mutation. Cell Rep Med 2024; 5:101711. [PMID: 39232498 PMCID: PMC11525027 DOI: 10.1016/j.xcrm.2024.101711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 06/18/2024] [Accepted: 08/09/2024] [Indexed: 09/06/2024]
Abstract
Pancreatic cancer is associated with an oncogenic KRAS mutation in approximately 90% of cases. However, a non-negligible proportion of pancreatic cancer cases harbor wild-type KRAS (KRAS-WT). This study establishes genetically engineered mouse models that develop spontaneous pancreatic cancer in the context of KRAS-WT. The Trp53loxP/loxP;Smad4loxP/loxP;Pdx1-Cre (PPSSC) mouse model harbors KRAS-WT and loss of Trp53/Smad4. The Trp53loxP/loxP;Tgfbr2loxP/loxP;Pdx1-Cre (PPTTC) mouse model harbors KRAS-WT and loss of Trp53/Tgfbr2. We identify that either Trp53/Smad4 loss or Trp53/Tgfbr2 loss can induce spontaneous pancreatic tumor formation in the absence of an oncogenic KRAS mutation. The Trp53/Smad4 loss and Trp53/Tgfbr2 loss mouse models exhibit distinct pancreatic tumor histological features, as compared to oncogenic KRAS-driven mouse models. Furthermore, KRAS-WT pancreatic tumors with Trp53/Smad4 loss reveal unique histological features of pancreatic adenosquamous carcinoma (PASC). Single-cell RNA sequencing (scRNA-seq) analysis reveals the distinct tumor immune microenvironment landscape of KRAS-WT (PPSSC) pancreatic tumors as compared with that of oncogenic KRAS-driven pancreatic tumors.
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Affiliation(s)
- Daowei Yang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xinlei Sun
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rohan Moniruzzaman
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Hua Wang
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Citu Citu
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Zhongming Zhao
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Huamin Wang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Anirban Maitra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yang Chen
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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28
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Stein L, Murugesan K, Reeser JW, Risch Z, Wing MR, Paruchuri A, Samorodnitsky E, Hoskins EL, Dao T, Smith A, Le D, Babcook MA, Chang YS, Avenarius MR, Imam M, Freud AG, Roychowdhury S. FGFR2-fusions define a clinically actionable molecular subset of pancreatic cancer. NPJ Precis Oncol 2024; 8:207. [PMID: 39289482 PMCID: PMC11408739 DOI: 10.1038/s41698-024-00683-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 08/28/2024] [Indexed: 09/19/2024] Open
Abstract
Genomic alterations in fibroblast growth factor receptor (FGFR) genes are present in a small number of metastatic pancreatic ductal adenocarcinomas (PDAC) and may represent an emerging subgroup of patients likely to benefit from FGFR targeted therapies. Here we present four FGFR2 fusion-positive metastatic PDAC patients who exhibited durable responses or disease control to FGFR kinase inhibitors. Utilizing our custom FGFR focused cell-free DNA assay, FGFR-Dx, we serially monitored variant allele fractions of FGFR2 fusions during FGFR inhibitor treatment and observed dynamic changes correlating with clinical responses. Genomic analysis of 30,229 comprehensively profiled pancreatic cancers revealed FGFR1-3 fusions in 245 cases, an incidence of 0.81%. FGFR fusions were generally mutually exclusive from other known oncogenes. Our findings provide clinical evidence for identifying and treating FGFR2 fusion-positive PDAC patients with FGFR targeted therapy.
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Affiliation(s)
- Leah Stein
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
- Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA
| | | | - Julie W Reeser
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
| | - Zachary Risch
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
| | - Michele R Wing
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
| | - Anoosha Paruchuri
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
| | - Eric Samorodnitsky
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
| | - Emily L Hoskins
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
- Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA
| | - Thuy Dao
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
| | - Amy Smith
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
| | - Dat Le
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
| | - Melissa A Babcook
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
| | - Yi Seok Chang
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
| | - Matthew R Avenarius
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | | | - Aharon G Freud
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA
- Department of Pathology, The Ohio State University, Columbus, OH, USA
| | - Sameek Roychowdhury
- Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, USA.
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
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Orsi G, Carconi C, Ghiorzo P, Carrera P, Pastorino L, Presi S, Chiaravalli M, Barbieri E, Giordano G, Sciallero S, Puccini A, Salvatore L, Cortesi L, Macchini M, Natalicchio MI, Allavena E, Pirrone C, Archibugi L, Dalmasso B, Bruno W, Tortora G, Landriscina M, Capurso G, Cascinu S, Falconi M, Reni M. Germline pathogenic variants of cancer predisposition genes in a multicentre Italian cohort of pancreatic cancer patients. Eur J Cancer 2024; 208:114226. [PMID: 39029294 DOI: 10.1016/j.ejca.2024.114226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 06/30/2024] [Accepted: 07/07/2024] [Indexed: 07/21/2024]
Abstract
BACKGROUND AND AIM Germline BRCA1-2 test is routinely recommended in Pancreatic Cancer (PC) patients, due to its clinical-epidemiological relevance. Data on the prevalence of germline pathogenic variants (gPV) in other cancer predisposition and DNA Damage Repair (DDR) system-related genes in unselected PC cases are sparce in Italy. We assessed this prevalence in a multicentre cohort, to derive recommendations for PC patients. METHODS Clinical data of 1200 consecutive PC patients, of any age and stage, tested with a multigene germline panel were collected. A descriptive analysis of gPV frequency and clinical variables was performed both in 1092 patients tested for an 18 genes core-panel (CP-18 cohort) and in 869 patients screened only for CDKN2A. RESULTS 11.5 % (126/1092) of CP-18 cohort patients harbored a gPV in ≥ 1 gene. Highest gPV frequencies were detected in ATM (3.1 %), BRCA2 (2.9 %), BRCA1 (1.6 %), CHEK2 (1.1 %). Patients harboring any CP-18 gene and BRCA1-2 gPV were younger and with a higher rate of personal (PH) or family history (FH) of cancer when compared to no gPV patients. The risk of having a gPV was ≥ 7 % in all subgroups of patients, including those aged > 73, with tumor stage I-III and negative FH/PH. CDKN2A gPV were detected in 2.6 % (23/869) of patients. CONCLUSIONS A remarkable prevalence of gPV in cancer predisposition and DDR genes is reported in this large multicentre cohort of consecutive and unselected PC patients. Therefore, we recommend multigene germline testing (at least including BRCA1-2, ATM, CDKN2A, PALB2) for all PC patients, irrespective of age, stage, PH/FH.
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Affiliation(s)
- Giulia Orsi
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Catia Carconi
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Paola Ghiorzo
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa, Italy; Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Paola Carrera
- Unit of Genomics for Human Disease Diagnosis, Laboratory of Clinical Genomics, IRCCS San Raffaele Scientific Institute, Milan, Italy; Laboratory of Clinical Molecular Genetics, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Lorenza Pastorino
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa, Italy; Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Silvia Presi
- Unit of Genomics for Human Disease Diagnosis, Laboratory of Clinical Genomics, IRCCS San Raffaele Scientific Institute, Milan, Italy; Laboratory of Clinical Molecular Genetics, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Marta Chiaravalli
- Oncologia medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy
| | - Elena Barbieri
- SS Genetica Oncologica, SC Oncologia Medica, AOU Policlinico, Modena, Italy
| | - Guido Giordano
- Unit of Medical Oncology and Biomolecular Therapy, Policlinico Ospedaliero-Universitario, Foggia, Italy; Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Stefania Sciallero
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Alberto Puccini
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, MI, Italy
| | - Lisa Salvatore
- Oncologia medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy
| | - Laura Cortesi
- SS Genetica Oncologica, SC Oncologia Medica, AOU Policlinico, Modena, Italy
| | - Marina Macchini
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Maria Iole Natalicchio
- SSVD Biologia Molecolare Oncologica-PMMP, Genetica Oncologica e Farmacogenetica, Ambulatorio Tumori Eredo-Familiari, Policlinico Ospedaliero-Universitario, Foggia, Italy
| | - Eleonora Allavena
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa, Italy; Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Chiara Pirrone
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa, Italy; Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Livia Archibugi
- Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Bruna Dalmasso
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - William Bruno
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa, Italy; Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Giampaolo Tortora
- Oncologia medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy
| | - Matteo Landriscina
- Unit of Medical Oncology and Biomolecular Therapy, Policlinico Ospedaliero-Universitario, Foggia, Italy; Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gabriele Capurso
- Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Massimo Falconi
- Pancreatic and Transplant Surgery Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Michele Reni
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
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30
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Elhariri A, Patel J, Mahadevia H, Albelal D, Ahmed AK, Jones JC, Borad MJ, Babiker H. Identifying Actionable Alterations in KRAS Wild-Type Pancreatic Cancer. Target Oncol 2024; 19:679-689. [PMID: 39123077 DOI: 10.1007/s11523-024-01088-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2024] [Indexed: 08/12/2024]
Abstract
The 5-year relative survival rate for pancreatic cancer is currently the lowest among all cancer types with a dismal 13%. A Kirsten rat sarcoma virus (KRAS) gene mutation is present in approximately 90% of patients with pancreatic cancer; however, KRAS-specific drugs are not yet widely used in clinical practice for pancreatic cancer, specifically the KRASG12D variant. Advances in genomic testing revealed an opportunity to detect genetic alterations in a subset of patients with no KRAS mutation termed KRAS wild-type. Patients with KRAS wild-type tumors have a propensity to express driver alterations, hence paving the way for utilizing a targeted therapy approach either via clinical trials or standard-of-care drugs. These alterations include fusions, amplifications, translocations, rearrangements and microsatellite instability-high tumors and can be as high as 11% in some studies. Here, we discuss some of the most notable alterations in KRAS wild-type and highlight promising clinical trials.
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Affiliation(s)
- Ahmed Elhariri
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA
| | - Jaydeepbhai Patel
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA
| | - Himil Mahadevia
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA
| | - Douaa Albelal
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA
| | - Ahmed K Ahmed
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA
| | - Jeremy C Jones
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA
| | - Mitesh J Borad
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Arizona, Phoenix, AZ, USA
| | - Hani Babiker
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA.
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Zou S, Zhang L, Jiang C, Li F, Yang Y, Deng X, Zhang J, Chen H, Jiang L, Cheng X, Deng L, Lin L, Shen B, Wen C, Zhan Q. Driver mutation subtypes involve with differentiated immunophenotypes influencing pancreatic cancer outcomes. Cancer Lett 2024; 599:217134. [PMID: 39094824 DOI: 10.1016/j.canlet.2024.217134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 07/03/2024] [Accepted: 07/23/2024] [Indexed: 08/04/2024]
Abstract
Despite many studies focusing on the prognostic biomarkers in pancreatic adenocarcinomas (PAADs), there is ill-informed about the relationships between their genomic features and immune characteristics. Herein, we deeply investigated the involvement of major driver mutation subtypes with immunophenotypes impacting PAAD outcomes. Based on public data analyses of RNA expression-based immune subtypes in PAAD, in contrast to KRAS G12D & TP53 co-mutant patients with poor outcomes, the best immune subtype C3 (inflammatory) characterized by high Th1/Th2 ratio was relatively enriched in KRASnon-G12DTP53wt patients with better survival, whereas the inferior subtype C2 (IFN-γ dominant) with low Th1/Th2 ratio was more common in the former than in the latter. Moreover, contrary to the highly immunosuppressive microenvironment (high Treg, high ratio of Treg to tumor-specific CD4+ T cell) in KRASG12DTP53mut patients, KRASG12VTP53wt individuals exhibited an inflamed context profiled by multiplex immunohistochemistry. It could be responsible for their outstanding survival advantage over others in postsurgical PAAD patients receiving adjuvant chemotherapy as shown by our cohort. Together, KRASG12VTP53wt may be a promising biomarker for prognostic evaluation and screening certain candidates with PAAD to get desirable survival benefit from adjuvant chemotherapy.
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Affiliation(s)
- Siyi Zou
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, PR China; Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Lei Zhang
- Genecast Biotechnology Co., Ltd, 88 Danshan Road, Xidong Chuangrong Building, Suite C 1310-1318, Xishan District, Wuxi City, Jiangsu, 214104, PR China
| | - Cen Jiang
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, PR China
| | - Fanlu Li
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, PR China; Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Ying Yang
- Genecast Biotechnology Co., Ltd, 88 Danshan Road, Xidong Chuangrong Building, Suite C 1310-1318, Xishan District, Wuxi City, Jiangsu, 214104, PR China
| | - Xiaxing Deng
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, PR China; Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Jiao Zhang
- Genecast Biotechnology Co., Ltd, 88 Danshan Road, Xidong Chuangrong Building, Suite C 1310-1318, Xishan District, Wuxi City, Jiangsu, 214104, PR China
| | - Hao Chen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, PR China; Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Lingxi Jiang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, PR China; Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Xueyan Cheng
- Genecast Biotechnology Co., Ltd, 88 Danshan Road, Xidong Chuangrong Building, Suite C 1310-1318, Xishan District, Wuxi City, Jiangsu, 214104, PR China
| | - Lisha Deng
- Genecast Biotechnology Co., Ltd, 88 Danshan Road, Xidong Chuangrong Building, Suite C 1310-1318, Xishan District, Wuxi City, Jiangsu, 214104, PR China
| | - Lin Lin
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, PR China.
| | - Baiyong Shen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, PR China; Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
| | - Chenlei Wen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, PR China; Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
| | - Qian Zhan
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin Er Road, Shanghai, 200025, PR China; Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
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Tiong J, Nguyen P, Sritharan M, Lundy J, Shen H, Kumar B, Swan M, Jenkins B, Croagh D. Evaluation of Needles in Endoscopic Ultrasound-Guided Tissue Acquisition of Pancreatic Cancer for Genetic Yield and Quality. Cureus 2024; 16:e68431. [PMID: 39360054 PMCID: PMC11445693 DOI: 10.7759/cureus.68431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/01/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Endoscopic ultrasound-guided fine needle biopsy (FNB) is the gold standard in tissue acquisition of pancreatic ductal adenocarcinoma (PDAC). There is a paucity of evidence of the impact of needle type or size on the genetic yield and quality. METHODS Patients 18 years and older with PDAC who underwent FNB were retrospectively identified from a single database from 2016 to 2021. Genetic quantity is measured in micrograms (µg) and quality defined by RNA or DNA integrity number (RIN and DIN). FNB needles examined were Acquire 22 gauge (Boston Scientific, Marlborough, MA, USA) and ProCore 22 and 20 gauges (Cook Medical, Bloomington, IN, USA). RESULTS Two hundred seventy-seven patients were identified. ProCore 20G needle procured higher RNA quantity (4125.8µg, IQR: 2003.8, 5954.8, p = 0.012) compared to ProCore 22G (2050µg IQR: 966.4, 3181.6) and Acquire 22G (2310.6µg, IQR: 1439.3, 4312). Median DNA quantity was 3340.5µg (Acquire 22G), 2610.4µg (ProCore 22G) and 3499.7µg (ProCore 20G) (p = 0.763). Median DIN was 7.3 (Acquire 22G and ProCore 22G) and 7.4 (ProCore 20G) (p = 0.449). Median RIN was 3.0 (Acquire 22G and ProCore 22G) and 2.7 (ProCore 20G) (p = 0.886). CONCLUSION ProCore 20G was associated with higher quantity of RNA. There were no differences in the quality acquired by different needles.
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Affiliation(s)
| | - Phi Nguyen
- Department of Surgery, Monash Health, Melbourne, AUS
| | | | - Joanne Lundy
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, AUS
| | - Henry Shen
- Department of Surgery, Monash Health, Melbourne, AUS
| | - Beena Kumar
- Department of Anatomical Pathology, Monash Health, Melbourne, AUS
| | - Michael Swan
- Department of Gastroenterology, Monash Health, Melbourne, AUS
| | - Brendan Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, AUS
| | - Daniel Croagh
- Department of Surgery, Monash Health, Melbourne, AUS
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Zhong Y, Zhang H, Wang P, Zhao J, Ge Y, Sun Z, Wang Z, Li J, Hu S. Auger emitter in combination with Olaparib suppresses tumor growth via promoting antitumor immune responses in pancreatic cancer. Invest New Drugs 2024; 42:442-453. [PMID: 38941055 DOI: 10.1007/s10637-024-01454-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 06/18/2024] [Indexed: 06/29/2024]
Abstract
The present study aimed to clarify the hypothesis that auger emitter 125I particles in combination with PARP inhibitor Olaparib could inhibit pancreatic cancer progression by promoting antitumor immune response. Pancreatic cancer cell line (Panc02) and mice subcutaneously inoculated with Panc02 cells were employed for the in vitro and in vivo experiments, respectively, followed by 125I and Olaparib administrations. The apoptosis and CRT exposure of Panc02 cells were detected using flow cytometry assay. QRT-PCR, immunofluorescence, immunohistochemical analysis, and western blot were employed to examine mRNA and protein expression. Experimental results showed that 125I combined with Olaparib induced immunogenic cell death and affected antigen presentation in pancreatic cancer. 125I in combination with Olaparib influenced T cells and dendritic cells by up-regulating CD4, CD8, CD69, Caspase3, CD86, granzyme B, CD80, and type I interferon (IFN)-γ and down-regulating Ki67 in vivo. The combination also activated the cyclic GMP-AMP synthase stimulator of IFN genes (Sting) pathway in Panc02 cells. Moreover, Sting knockdown alleviated the effect of the combination of 125I and Olaparib on pancreatic cancer progression. In summary, 125I in combination with Olaparib inhibited pancreatic cancer progression through promoting antitumor immune responses, which may provide a potential treatment for pancreatic cancer.
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Affiliation(s)
- Yanqi Zhong
- Department of Radiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, Jiangsu, 214000, China
| | - Heng Zhang
- Department of Radiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, Jiangsu, 214000, China
| | - Peng Wang
- Department of Radiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, Jiangsu, 214000, China
| | - Jing Zhao
- Department of Radiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, Jiangsu, 214000, China
| | - Yuxi Ge
- Department of Radiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, Jiangsu, 214000, China
| | - Zongqiong Sun
- Department of Radiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, Jiangsu, 214000, China
| | - Zi Wang
- Department of Radiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, Jiangsu, 214000, China
| | - Jie Li
- Department of Radiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, Jiangsu, 214000, China.
| | - Shudong Hu
- Department of Radiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, Jiangsu, 214000, China.
- Institute of Translational Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China.
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Yao Y, Lv H, Zhang M, Li Y, Herman JG, Brock MV, Gao A, Wang Q, Fuks F, Zhang L, Guo M. Epigenetic silencing of BEND4, a novel DNA damage repair gene, is a synthetic lethal marker for ATM inhibitor in pancreatic cancer. Front Med 2024; 18:721-734. [PMID: 38926248 DOI: 10.1007/s11684-023-1053-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 12/04/2023] [Indexed: 06/28/2024]
Abstract
Synthetic lethality is a novel model for cancer therapy. To understand the function and mechanism of BEN domain-containing protein 4 (BEND4) in pancreatic cancer, eight cell lines and a total of 492 cases of pancreatic neoplasia samples were included in this study. Methylation-specific polymerase chain reaction, CRISPR/Cas9, immunoprecipitation assay, comet assay, and xenograft mouse model were used. BEND4 is a new member of the BEN domain family. The expression of BEND4 is regulated by promoter region methylation. It is methylated in 58.1% (176/303) of pancreatic ductal adenocarcinoma (PDAC), 33.3% (14/42) of intraductal papillary mucinous neoplasm, 31.0% (13/42) of pancreatic neuroendocrine tumor, 14.3% (3/21) of mucinous cystic neoplasm, 4.3% (2/47) of solid pseudopapillary neoplasm, and 2.7% (1/37) of serous cystic neoplasm. BEND4 methylation is significantly associated with late-onset PDAC (> 50 years, P < 0.01) and tumor differentiation (P < 0.0001), and methylation of BEND4 is an independent poor prognostic marker (P < 0.01) in PDAC. Furthermore, BEND4 plays tumor-suppressive roles in vitro and in vivo. Mechanistically, BEND4 involves non-homologous end joining signaling by interacting with Ku80 and promotes DNA damage repair. Loss of BEND4 increased the sensitivity of PDAC cells to ATM inhibitor. Collectively, the present study revealed an uncharacterized tumor suppressor BEND4 and indicated that methylation of BEND4 may serve as a potential synthetic lethal marker for ATM inhibitor in PDAC treatment.
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Affiliation(s)
- Yuanxin Yao
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Honghui Lv
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Meiying Zhang
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Yuan Li
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
- Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, China
| | - James G Herman
- UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Malcolm V Brock
- Department of surgery, School of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA
| | - Aiai Gao
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Qian Wang
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Francois Fuks
- Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Universite Libre de Bruxelles (ULB), Brussels, 1070, Belgium
| | - Lirong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Mingzhou Guo
- Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
- National Key Laboratory of Kidney Diseases, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
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Mosele MF, Westphalen CB, Stenzinger A, Barlesi F, Bayle A, Bièche I, Bonastre J, Castro E, Dienstmann R, Krämer A, Czarnecka AM, Meric-Bernstam F, Michiels S, Miller R, Normanno N, Reis-Filho J, Remon J, Robson M, Rouleau E, Scarpa A, Serrano C, Mateo J, André F. Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group. Ann Oncol 2024; 35:588-606. [PMID: 38834388 DOI: 10.1016/j.annonc.2024.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice. METHODS The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility. RESULTS As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available. CONCLUSION Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer.
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Affiliation(s)
- M F Mosele
- INSERM U981, Gustave Roussy, Villejuif; Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - C B Westphalen
- Comprehensive Cancer Center Munich & Department of Medicine III, University Hospital, LMU Munich, Munich
| | - A Stenzinger
- Institute of Pathology, University Hospital Heidelberg and Center for Personalized Medicine (ZPM), Heidelberg, Germany
| | - F Barlesi
- INSERM U981, Gustave Roussy, Villejuif; Department of Cancer Medicine, Gustave Roussy, Villejuif, France; Faculty of Medicine, Université Paris-Saclay, Kremlin Bicêtre
| | - A Bayle
- Faculty of Medicine, Université Paris-Saclay, Kremlin Bicêtre; Drug Development Department (DITEP), Gustave Roussy, Villejuif; Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif; Service de Biostatistique et Epidémiologie, Gustave Roussy, Villejuif
| | - I Bièche
- Department of Genetics, Institut Curie, INSERM U1016, Université Paris Cité, Paris, France
| | - J Bonastre
- Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif; Service de Biostatistique et Epidémiologie, Gustave Roussy, Villejuif
| | - E Castro
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid
| | - R Dienstmann
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona; University of Vic-Central University of Catalonia, Vic, Spain; Oncoclínicas, São Paulo, Brazil
| | - A Krämer
- Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Heidelberg; Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
| | - A M Czarnecka
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw; Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - F Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - S Michiels
- Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif; Service de Biostatistique et Epidémiologie, Gustave Roussy, Villejuif
| | - R Miller
- Department of Medical Oncology, University College London, London; Department of Medical Oncology, St Bartholomew's Hospital, London, UK
| | - N Normanno
- Scientific Directorate, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - J Reis-Filho
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York
| | - J Remon
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - M Robson
- Breast Medicine and Clinical Genetics Services, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
| | - E Rouleau
- Tumor Genetics Service, Medical Biology and Pathology Department, Gustave Roussy, Villejuif, France
| | - A Scarpa
- Section of Pathology, Department of Diagnostics and Public Health, University of Verona-School of Medicine, Verona, Italy
| | - C Serrano
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona
| | - J Mateo
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona
| | - F André
- INSERM U981, Gustave Roussy, Villejuif; Department of Cancer Medicine, Gustave Roussy, Villejuif, France; Faculty of Medicine, Université Paris-Saclay, Kremlin Bicêtre.
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Norgard RJ, Budhani P, O'Brien SA, Xia Y, Egan JN, Flynn B, Tagore JR, Seco J, Peet GW, Mikucka A, Wasti R, Chan LC, Hinkel M, Martinez-Morilla S, Pignatelli J, Trapani F, Corse E, Feng D, Kostyrko K, Hofmann MH, Liu K, Kashyap AS. Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response. CANCER RESEARCH COMMUNICATIONS 2024; 4:1548-1560. [PMID: 38727236 PMCID: PMC11191876 DOI: 10.1158/2767-9764.crc-24-0172] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 06/23/2024]
Abstract
KRAS inhibitors have demonstrated exciting preclinical and clinical responses, although resistance occurs rapidly. Here, we investigate the effects of KRAS-targeting therapies on the tumor microenvironment using a library of KrasG12D, p53-mutant, murine pancreatic ductal adenocarcinoma-derived cell lines (KPCY) to leverage immune-oncology combination strategies for long-term tumor efficacy. Our findings show that SOS1 and MEK inhibitors (SOS1i+MEKi) suppressed tumor growth in syngeneic models and increased intratumoral CD8+ T cells without durable responses. Single-cell RNA sequencing revealed an increase in inflammatory cancer-associated fibroblasts (iCAF), M2 macrophages, and a decreased dendritic cell (DC) quality that ultimately resulted in a highly immunosuppressive microenvironment driven by IL6+ iCAFs. Agonist CD40 treatment was effective to revert macrophage polarization and overcome the lack of mature antigen-presenting DCs after SOS1i+MEKi therapy. Treatment increased the overall survival of KPCY tumor-bearing mice. The addition of checkpoint blockade to SOS1i+MEKi combination resulted in tumor-free mice with established immune memory. Our data suggest that KRAS inhibition affects myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong antitumor effects. SIGNIFICANCE Combination of SOS1 and MEK inhibitors increase T cell infiltration while blunting pro-immune myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong anti-tumor effects.
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Affiliation(s)
- Robert J. Norgard
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Pratha Budhani
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Sarah A. O'Brien
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Youli Xia
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Jessica N. Egan
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Brianna Flynn
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Joshua R. Tagore
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Joseph Seco
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Gregory W. Peet
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Ania Mikucka
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Ruby Wasti
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Li-Chuan Chan
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Melanie Hinkel
- Late Stage Cancer Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Sandra Martinez-Morilla
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Jeanine Pignatelli
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Francesca Trapani
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Emily Corse
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Di Feng
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Kaja Kostyrko
- Late Stage Cancer Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Marco H. Hofmann
- Cancer Pharmacology and Disease Positioning Department, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Kang Liu
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Abhishek S. Kashyap
- Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
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Sharma B, Twelker K, Nguyen C, Ellis S, Bhatia ND, Kuschner Z, Agriantonis A, Agriantonis G, Arnold M, Dave J, Mestre J, Shafaee Z, Arora S, Ghanta H, Whittington J. Bile Acids in Pancreatic Carcinogenesis. Metabolites 2024; 14:348. [PMID: 39057671 PMCID: PMC11278541 DOI: 10.3390/metabo14070348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/10/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Pancreatic cancer (PC) is a dangerous digestive tract tumor that is becoming increasingly common and fatal. The most common form of PC is pancreatic ductal adenocarcinoma (PDAC). Bile acids (BAs) are closely linked to the growth and progression of PC. They can change the intestinal flora, increasing intestinal permeability and allowing gut microbes to enter the bloodstream, leading to chronic inflammation. High dietary lipids can increase BA secretion into the duodenum and fecal BA levels. BAs can cause genetic mutations, mitochondrial dysfunction, abnormal activation of intracellular trypsin, cytoskeletal damage, activation of NF-κB, acute pancreatitis, cell injury, and cell necrosis. They can act on different types of pancreatic cells and receptors, altering Ca2+ and iron levels, and related signals. Elevated levels of Ca2+ and iron are associated with cell necrosis and ferroptosis. Bile reflux into the pancreatic ducts can speed up the kinetics of epithelial cells, promoting the development of pancreatic intraductal papillary carcinoma. BAs can cause the enormous secretion of Glucagon-like peptide-1 (GLP-1), leading to the proliferation of pancreatic β-cells. Using Glucagon-like peptide-1 receptor agonist (GLP-1RA) increases the risk of pancreatitis and PC. Therefore, our objective was to explore various studies and thoroughly examine the role of BAs in PC.
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Affiliation(s)
- Bharti Sharma
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Kate Twelker
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Cecilia Nguyen
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Scott Ellis
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Navin D. Bhatia
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Zachary Kuschner
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Andrew Agriantonis
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - George Agriantonis
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Monique Arnold
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Jasmine Dave
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Juan Mestre
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Zahra Shafaee
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Shalini Arora
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Hima Ghanta
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Jennifer Whittington
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
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Wang X, Breuer J, Garbe S, Giordano F, Brossart P, Feldmann G, Bisht S. Triple Blockade of Oncogenic RAS Signaling Using KRAS and MEK Inhibitors in Combination with Irradiation in Pancreatic Cancer. Int J Mol Sci 2024; 25:6249. [PMID: 38892436 PMCID: PMC11172716 DOI: 10.3390/ijms25116249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/27/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of human malignancies and carries an exceptionally poor prognosis. It is mostly driven by multiple oncogenic alterations, with the highest mutation frequency being observed in the KRAS gene, which is a key oncogenic driver of tumorogenesis and malignant progression in PDAC. However, KRAS remained undruggable for decades until the emergence of G12C mutation specific KRAS inhibitors. Despite this development, this therapeutic approach to target KRAS directly is not routinely used for PDAC patients, with the reasons being the rare presence of G12C mutation in PDAC with only 1-2% of occurring cases, modest therapeutic efficacy, activation of compensatory pathways leading to cell resistance, and absence of effective KRASG12D or pan-KRAS inhibitors. Additionally, indirect approaches to targeting KRAS through upstream and downstream regulators or effectors were also found to be either ineffective or known to cause major toxicities. For this reason, new and more effective treatment strategies that combine different therapeutic modalities aiming at achieving synergism and minimizing intrinsic or adaptive resistance mechanisms are required. In the current work presented here, pancreatic cancer cell lines with oncogenic KRAS G12C, G12D, or wild-type KRAS were treated with specific KRAS or SOS1/2 inhibitors, and therapeutic synergisms with concomitant MEK inhibition and irradiation were systematically evaluated by means of cell viability, 2D-clonogenic, 3D-anchorage independent soft agar, and bioluminescent ATP assays. Underlying pathophysiological mechanisms were examined by using Western blot analyses, apoptosis assay, and RAS activation assay.
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Affiliation(s)
- Xuan Wang
- Department of Internal Medicine 3, Center of Integrated Oncology (CIO-ABCD) Aachen-Bonn-Cologne-Düsseldorf, University Hospital of Bonn, Venusberg Campus-1, 53127 Bonn, Germany
| | - Johanna Breuer
- Institute of Molecular Medicine and Experimental Immunology, University Hospital of Bonn, Venusberg Campus-1, 53127 Bonn, Germany
| | - Stephan Garbe
- Department of Radiology and Radiation Oncology, University Hospital of Bonn, Venusberg Campus-1, 53127 Bonn, Germany
| | - Frank Giordano
- Department of Radiology and Radiation Oncology, University Hospital of Bonn, Venusberg Campus-1, 53127 Bonn, Germany
| | - Peter Brossart
- Department of Internal Medicine 3, Center of Integrated Oncology (CIO-ABCD) Aachen-Bonn-Cologne-Düsseldorf, University Hospital of Bonn, Venusberg Campus-1, 53127 Bonn, Germany
| | - Georg Feldmann
- Department of Internal Medicine 3, Center of Integrated Oncology (CIO-ABCD) Aachen-Bonn-Cologne-Düsseldorf, University Hospital of Bonn, Venusberg Campus-1, 53127 Bonn, Germany
| | - Savita Bisht
- Department of Internal Medicine 3, Center of Integrated Oncology (CIO-ABCD) Aachen-Bonn-Cologne-Düsseldorf, University Hospital of Bonn, Venusberg Campus-1, 53127 Bonn, Germany
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Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, Winters IP, Salman Z, Blaj C, Menard M, Brodbeck J, Chen Z, Wei X, Rosen MJ, Gindin Y, Lee BJ, Evans JW, Chang S, Wang Z, Seamon KJ, Parsons D, Cregg J, Marquez A, Tomlinson AC, Yano JK, Knox JE, Quintana E, Aguirre AJ, Arbour KC, Reed A, Gustafson WC, Gill AL, Koltun ES, Wildes D, Smith JA, Wang Z, Singh M. Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discov 2024; 14:994-1017. [PMID: 38593348 PMCID: PMC11149917 DOI: 10.1158/2159-8290.cd-24-0027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/09/2024] [Accepted: 03/19/2024] [Indexed: 04/11/2024]
Abstract
RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985). SIGNIFICANCE The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors. This article is featured in Selected Articles from This Issue, p. 897.
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Affiliation(s)
| | - Lingyan Jiang
- Revolution Medicines, Inc., Redwood City, California
| | | | - Yingyun Wang
- Revolution Medicines, Inc., Redwood City, California
| | | | - Ida Aronchik
- Revolution Medicines, Inc., Redwood City, California
| | - Ian P. Winters
- Revolution Medicines, Inc., Redwood City, California
- D2G Oncology, Inc., Mountain View, California
| | - Zeena Salman
- Revolution Medicines, Inc., Redwood City, California
| | - Cristina Blaj
- Revolution Medicines, Inc., Redwood City, California
| | - Marie Menard
- Revolution Medicines, Inc., Redwood City, California
| | - Jens Brodbeck
- Revolution Medicines, Inc., Redwood City, California
| | - Zhe Chen
- Revolution Medicines, Inc., Redwood City, California
| | - Xing Wei
- Revolution Medicines, Inc., Redwood City, California
| | | | | | - Bianca J. Lee
- Revolution Medicines, Inc., Redwood City, California
| | | | | | - Zhican Wang
- Revolution Medicines, Inc., Redwood City, California
| | | | - Dylan Parsons
- Revolution Medicines, Inc., Redwood City, California
| | - James Cregg
- Revolution Medicines, Inc., Redwood City, California
| | - Abby Marquez
- Revolution Medicines, Inc., Redwood City, California
| | | | - Jason K. Yano
- Revolution Medicines, Inc., Redwood City, California
| | - John E. Knox
- Revolution Medicines, Inc., Redwood City, California
| | - Elsa Quintana
- Revolution Medicines, Inc., Redwood City, California
| | - Andrew J. Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Kathryn C. Arbour
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Abby Reed
- The Christ Hospital Cancer Center, Cincinnati, Ohio
| | | | | | | | - David Wildes
- Revolution Medicines, Inc., Redwood City, California
| | | | | | - Mallika Singh
- Revolution Medicines, Inc., Redwood City, California
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Emelyanova M, Ikonnikova A, Pushkov A, Pudova E, Krasnov G, Popova A, Zhanin I, Khomich D, Abramov I, Tjulandin S, Gryadunov D, Pokataev I. Mutations in Mismatch Repair Genes and Microsatellite Instability Status in Pancreatic Cancer. Cancers (Basel) 2024; 16:2111. [PMID: 38893230 PMCID: PMC11171205 DOI: 10.3390/cancers16112111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/19/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
Patients with pancreatic cancer (PC) showing mismatch repair (MMR) deficiency may benefit from immunotherapy. Microsatellite instability (MSI) is a hallmark of MMR deficiency (MMR-D). Here, we estimated the prevalence of MSI in PC, investigated germline and somatic mutations in the three MMR genes (MLH1, MSH2, and MSH6), and assessed the relationship between MMR genes mutations and MSI status in PC. Clinical specimens from PC patients were analyzed using targeted next-generation sequencing, including paired normal and tumor specimens from 155 patients, tumor-only specimens from 86 patients, and normal-only specimens from 379 patients. The MSI status of 235 PCs was assessed via PCR. Pathogenic/likely pathogenic (P/LP) germline variants in the MMR genes were identified in 1.1% of patients, while somatic variants were found in 2.6% of patients. No MSI-H tumors were detected. One patient carried two variants (P (VAF = 0.57) and LP (VAF = 0.25)) simultaneously; however, their germline/somatic status remains unknown due to the investigation focusing solely on the tumor and MSI analysis was not performed for this patient. MSI is rare in PC, even in tumors with MMR genes mutations. Our findings underscore the importance of assessing tumor MMR-D status in PC patients with confirmed Lynch syndrome when deciding whether to prescribe immunotherapy.
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Affiliation(s)
- Marina Emelyanova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (A.I.); (E.P.); (G.K.); (D.K.); (I.A.); (D.G.)
| | - Anna Ikonnikova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (A.I.); (E.P.); (G.K.); (D.K.); (I.A.); (D.G.)
| | - Alexander Pushkov
- Federal State Autonomous Institution “National Medical Research Center for Children’s Health” of the Ministry of Health of the Russian Federation, Moscow 119991, Russia; (A.P.); (I.Z.)
| | - Elena Pudova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (A.I.); (E.P.); (G.K.); (D.K.); (I.A.); (D.G.)
| | - George Krasnov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (A.I.); (E.P.); (G.K.); (D.K.); (I.A.); (D.G.)
| | - Anna Popova
- N.N. Blokhin National Medical Research Center for Oncology, Ministry of Health of the Russian Federation, Moscow 115522, Russia; (A.P.); (S.T.); (I.P.)
| | - Ilya Zhanin
- Federal State Autonomous Institution “National Medical Research Center for Children’s Health” of the Ministry of Health of the Russian Federation, Moscow 119991, Russia; (A.P.); (I.Z.)
| | - Darya Khomich
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (A.I.); (E.P.); (G.K.); (D.K.); (I.A.); (D.G.)
| | - Ivan Abramov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (A.I.); (E.P.); (G.K.); (D.K.); (I.A.); (D.G.)
| | - Sergei Tjulandin
- N.N. Blokhin National Medical Research Center for Oncology, Ministry of Health of the Russian Federation, Moscow 115522, Russia; (A.P.); (S.T.); (I.P.)
| | - Dmitry Gryadunov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; (A.I.); (E.P.); (G.K.); (D.K.); (I.A.); (D.G.)
| | - Ilya Pokataev
- N.N. Blokhin National Medical Research Center for Oncology, Ministry of Health of the Russian Federation, Moscow 115522, Russia; (A.P.); (S.T.); (I.P.)
- City Clinical Cancer Hospital No 1, Moscow Department of Health, Moscow 129090, Russia
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Bingham V, Harewood L, McQuaid S, Craig SG, Revolta JF, Kim CS, Srivastava S, Quezada-Marín J, Humphries MP, Salto-Tellez M. Topographic analysis of pancreatic cancer by TMA and digital spatial profiling reveals biological complexity with potential therapeutic implications. Sci Rep 2024; 14:11361. [PMID: 38762572 PMCID: PMC11102543 DOI: 10.1038/s41598-024-62031-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 05/13/2024] [Indexed: 05/20/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies. Tissue microarrays (TMA) are an established method of high throughput biomarker interrogation in tissues but may not capture histological features of cancer with potential biological relevance. Topographic TMAs (T-TMAs) representing pathophysiological hallmarks of cancer were constructed from representative, retrospective PDAC diagnostic material, including 72 individual core tissue samples. The T-TMA was interrogated with tissue hybridization-based experiments to confirm the accuracy of the topographic sampling, expression of pro-tumourigenic and immune mediators of cancer, totalling more than 750 individual biomarker analyses. A custom designed Next Generation Sequencing (NGS) panel and a spatial distribution-specific transcriptomic evaluation were also employed. The morphological choice of the pathophysiological hallmarks of cancer was confirmed by protein-specific expression. Quantitative analysis identified topography-specific patterns of expression in the IDO/TGF-β axis; with a heterogeneous relationship of inflammation and desmoplasia across hallmark areas and a general but variable protein and gene expression of c-MET. NGS results highlighted underlying genetic heterogeneity within samples, which may have a confounding influence on the expression of a particular biomarker. T-TMAs, integrated with quantitative biomarker digital scoring, are useful tools to identify hallmark specific expression of biomarkers in pancreatic cancer.
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Affiliation(s)
- Victoria Bingham
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, BT9 7AE, UK
| | - Louise Harewood
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, BT9 7AE, UK
| | - Stephen McQuaid
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, BT9 7AE, UK
- Cellular Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - Stephanie G Craig
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, BT9 7AE, UK
| | - Julia F Revolta
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, BT9 7AE, UK
| | - Chang S Kim
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, BT9 7AE, UK
| | - Shambhavi Srivastava
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, BT9 7AE, UK
| | - Javier Quezada-Marín
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, BT9 7AE, UK
| | - Matthew P Humphries
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, BT9 7AE, UK.
- Leeds Teaching Hospitals NHS Trust, Leeds, LS9 7TF, UK.
- University of Leeds, St James' University Hospital, Leeds, UK.
| | - Manuel Salto-Tellez
- Precision Medicine Centre of Excellence, The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, BT9 7AE, UK.
- Cellular Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
- Division of Molecular Pathology, The Institute for Cancer Research, London, UK.
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Desai A, Xiao AH, Choi D, Toruner MD, Walden D, Halfdanarson TR, Alberts S, McWilliams RR, Mahipal A, Ahn D, Babiker H, Stybayeva G, Revzin A, Kizilbash S, Adjei A, Bekaii-Saab T, Mansfield AS, Carr RM, Ma WW. Molecular Characterization and Therapeutic Opportunities in KRAS Wildtype Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2024; 16:1861. [PMID: 38791940 PMCID: PMC11119482 DOI: 10.3390/cancers16101861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/01/2024] [Accepted: 05/03/2024] [Indexed: 05/26/2024] Open
Abstract
PURPOSE To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. RESULTS Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. CONCLUSIONS KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.
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Affiliation(s)
- Aakash Desai
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | | | - Daheui Choi
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA; (D.C.); (G.S.); (A.R.)
| | - Merih D. Toruner
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Daniel Walden
- Division of Hematology and Oncology, Mayo Clinic, Phoenix, AZ 85054, USA; (D.W.); (D.A.); (T.B.-S.)
| | - Thorvardur R. Halfdanarson
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Steven Alberts
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Robert R. McWilliams
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Amit Mahipal
- Department of Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA;
| | - Daniel Ahn
- Division of Hematology and Oncology, Mayo Clinic, Phoenix, AZ 85054, USA; (D.W.); (D.A.); (T.B.-S.)
| | - Hani Babiker
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL 32224, USA;
| | - Gulnaz Stybayeva
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA; (D.C.); (G.S.); (A.R.)
| | - Alexander Revzin
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55902, USA; (D.C.); (G.S.); (A.R.)
| | - Sani Kizilbash
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Alex Adjei
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Tanios Bekaii-Saab
- Division of Hematology and Oncology, Mayo Clinic, Phoenix, AZ 85054, USA; (D.W.); (D.A.); (T.B.-S.)
| | - Aaron S. Mansfield
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Ryan M. Carr
- Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA; (A.D.); (M.D.T.); (T.R.H.); (S.A.); (R.R.M.); (S.K.)
| | - Wen Wee Ma
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
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Gkountakos A, Singhi AD, Westphalen CB, Scarpa A, Luchini C. Fusion genes in pancreatic tumors. Trends Cancer 2024; 10:430-443. [PMID: 38378317 DOI: 10.1016/j.trecan.2024.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/19/2024] [Accepted: 01/23/2024] [Indexed: 02/22/2024]
Abstract
Gene fusions and rearrangements play a crucial role in tumor biology. They are rare events typically detected in KRAS wild-type (WT) pancreatic tumors. Their identification can inform clinical management by enabling precision oncology, as fusions involving BRAF, FGFR2, RET, NTRK, NRG1, and ALK represent actionable targets in KRAS-WT cancers, and serve diagnostic purposes since fusions involving PRKACA/B represent the diagnostic hallmark of intraductal oncocytic papillary neoplasms (IOPNs). Although they are rare, the therapeutic and diagnostic importance of these genomic events should not be underestimated, highlighting the need for quality-ensured molecular diagnostics in the management of cancer. Herein we review the existing literature on the role of fusion genes in pancreatic tumors and their clinical potential as effective biomarkers and therapeutic targets.
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Affiliation(s)
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - C Benedikt Westphalen
- Department of Medicine III and Comprehensive Cancer Centre (CCC), LMU University Hospital Munich and German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Aldo Scarpa
- ARC-Net Research Center, University of Verona, Verona, Italy; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.
| | - Claudio Luchini
- ARC-Net Research Center, University of Verona, Verona, Italy; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.
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George B, Kudryashova O, Kravets A, Thalji S, Malarkannan S, Kurzrock R, Chernyavskaya E, Gusakova M, Kravchenko D, Tychinin D, Savin E, Alekseeva L, Butusova A, Bagaev A, Shin N, Brown JH, Sethi I, Wang D, Taylor B, McFall T, Kamgar M, Hall WA, Erickson B, Christians KK, Evans DB, Tsai S. Transcriptomic-Based Microenvironment Classification Reveals Precision Medicine Strategies for Pancreatic Ductal Adenocarcinoma. Gastroenterology 2024; 166:859-871.e3. [PMID: 38280684 DOI: 10.1053/j.gastro.2024.01.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 12/11/2023] [Accepted: 01/18/2024] [Indexed: 01/29/2024]
Abstract
BACKGROUND & AIMS The complex tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) has hindered the development of reliable predictive biomarkers for targeted therapy and immunomodulatory strategies. A comprehensive characterization of the TME is necessary to advance precision therapeutics in PDAC. METHODS A transcriptomic profiling platform for TME classification based on functional gene signatures was applied to 14 publicly available PDAC datasets (n = 1657) and validated in a clinically annotated independent cohort of patients with PDAC (n = 79). Four distinct subtypes were identified using unsupervised clustering and assessed to evaluate predictive and prognostic utility. RESULTS TME classification using transcriptomic profiling identified 4 biologically distinct subtypes based on their TME immune composition: immune enriched (IE); immune enriched, fibrotic (IE/F); fibrotic (F); and immune depleted (D). The IE and IE/F subtypes demonstrated a more favorable prognosis and potential for response to immunotherapy compared with the F and D subtypes. Most lung metastases and liver metastases were subtypes IE and D, respectively, indicating the role of clonal phenotype and immune milieu in developing personalized therapeutic strategies. In addition, distinct TMEs with potential therapeutic implications were identified in treatment-naive primary tumors compared with tumors that underwent neoadjuvant therapy. CONCLUSIONS This novel approach defines a distinct subgroup of PADC patients that may benefit from immunotherapeutic strategies based on their TME subtype and provides a framework to select patients for prospective clinical trials investigating precision immunotherapy in PDAC. Further, the predictive utility and real-world clinical applicability espoused by this transcriptomic-based TME classification approach will accelerate the advancement of precision medicine in PDAC.
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Affiliation(s)
- Ben George
- LaBahn Pancreatic Cancer Program, Division of Hematology and Oncology, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin.
| | | | | | - Samih Thalji
- LaBahn Pancreatic Cancer Program, Department of Surgery, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
| | - Subramaniam Malarkannan
- Versiti Blood Research Institute, Department of Medicine, Microbiology & Molecular Genetics, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
| | - Razelle Kurzrock
- Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, Division of Hematology and Oncology, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
| | | | | | | | | | - Egor Savin
- BostonGene Corporation, Waltham, Massachusetts
| | | | | | | | - Nara Shin
- BostonGene Corporation, Waltham, Massachusetts
| | | | - Isha Sethi
- BostonGene Corporation, Waltham, Massachusetts
| | - Dandan Wang
- Versiti Blood Research Institute, Department of Medicine, Microbiology & Molecular Genetics, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
| | - Bradley Taylor
- Clinical and Translational Science Institute, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
| | - Thomas McFall
- LaBahn Pancreatic Cancer Program, Department of Biochemistry, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
| | - Mandana Kamgar
- LaBahn Pancreatic Cancer Program, Division of Hematology and Oncology, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
| | - William A Hall
- LaBahn Pancreatic Cancer Program, Department of Radiation Oncology, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
| | - Beth Erickson
- LaBahn Pancreatic Cancer Program, Department of Radiation Oncology, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
| | - Kathleen K Christians
- LaBahn Pancreatic Cancer Program, Department of Surgery, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
| | - Douglas B Evans
- LaBahn Pancreatic Cancer Program, Department of Surgery, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
| | - Susan Tsai
- LaBahn Pancreatic Cancer Program, Department of Surgery, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin
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Buchberg J, de Stricker K, Pfeiffer P, Mortensen MB, Detlefsen S. Mutational profiling of 103 unresectable pancreatic ductal adenocarcinomas using EUS-guided fine-needle biopsy. Endosc Ultrasound 2024; 13:154-164. [PMID: 39318643 PMCID: PMC11419524 DOI: 10.1097/eus.0000000000000072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 05/27/2024] [Indexed: 09/26/2024] Open
Abstract
Background and Objective Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers, with a 5-year survival rate of around 9%. Only 20% are candidates for surgery. Most unresectable patients undergo EUS-guided fine-needle biopsy (EUS-FNB) for diagnosis. Identification of targetable mutations using next-generation sequencing (NGS) is increasingly requested. Data on feasibility of EUS-FNB for NGS and knowledge regarding mutational profile of unresectable PDAC are scarce. We evaluated the "technical yield" of EUS-FNB for NGS in unresectable PDAC: relative fraction of diagnostic EUS-FNBs meeting technical criteria. We also investigated the "molecular yield": relative fraction of EUS-FNBs included in NGS containing sufficient DNA for detection of at least one mutation. Furthermore, we determined the relative frequency of cancer-associated mutations in unresectable PDAC. Patients and Methods Formalin-fixed and paraffin-embedded EUS-FNBs diagnostic of unresectable PDAC and fulfilling these criteria were included (n = 105): minimum 3-mm2 tissue, minimum of 2-mm2 tumor area, and minimum 20% relative tumor area. NGS was performed using Ion GeneStudio S5 Prime System and Oncomine™ Comprehensive Assay v.3 including 161 cancer-related genes. Results Technical yield was 48% (105/219) and molecular yield was 98% (103/105). Most frequently mutated genes were KRAS (89.3%) and TP53 (69.9%), followed by CDKN2A (24.3%), ARID1A (9.7%), SMAD4 (7.8%), TSC2 (7.8%), and CCND3 (6.8%). Conclusion EUS-FNB for NGS of unresectable PDAC is feasible. Our technical criteria for NGS, using leftovers in formalin-fixed and paraffin-embedded blocks after routine pathology diagnosis, were met by around half of EUS-FNBs. Almost all EUS-FNBs fulfilling the technical criteria yielded a successful NGS analysis.
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Affiliation(s)
- Julie Buchberg
- Department of Pathology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Karin de Stricker
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Per Pfeiffer
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Department of Oncology, Odense University Hospital, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
| | - Michael Bau Mortensen
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
- Department of Surgery, Upper GI and HPB Section, Odense University Hospital, Odense, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
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Ciulla C, Luchini C. Genomic determinants of biological aggressiveness and poor prognosis of pancreatic cancers: KRAS and beyond. Expert Rev Mol Diagn 2024; 24:355-362. [PMID: 38708441 DOI: 10.1080/14737159.2024.2348676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/24/2024] [Indexed: 05/07/2024]
Abstract
INTRODUCTION A marked histomolecular heterogeneity characterizes pancreatic cancer. Thus, different tumor histologies with divergent genomic profiles exist within the same category. AREAS COVERED Using data from PubMed, SCOPUS, and Embase (last search date: 04/04/2024), this expert-based, narrative review presents and discusses the essential molecular determinants of biological aggressiveness and poor prognosis in pancreatic cancer. First, KRAS mutation still represents one of the most critical difficulties in treating pancreatic cancers. In this district, it is mutated in > 90% of malignant tumors. Notably, actionable alterations for molecular-based therapies are typically lacking in KRAS-mutated pancreatic cancer. Furthermore, transcriptome-based studies clarified that the squamous phenotype is characterized by poorer prognosis and response to standard chemotherapy. We also discuss molecular biomarkers related to dismal prognosis in specific subsets of pancreatic cancer, such as SMAD4 in signet-ring cell carcinoma and TP53 in invasive cancers derived from intraductal tubulopapillary neoplasms. EXPERT OPINION The identification of the subgroups of pancreatic cancer with particularly unfavorable prognoses is a critical step for addressing specific research efforts. In addition to implementing and strengthening current precision oncology strategies, the decisive step for improving the survival of patients affected by pancreatic cancer must pass through targeting the KRAS gene.
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Affiliation(s)
- Calogero Ciulla
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- ARC-Net Research Center, University of Verona, Verona, Italy
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Okuno N, Hara K. Endoscopic ultrasound-guided tissue acquisition for comprehensive genomic profiling. J Med Ultrason (2001) 2024; 51:253-260. [PMID: 38281237 DOI: 10.1007/s10396-023-01403-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 11/18/2023] [Indexed: 01/30/2024]
Abstract
Advances in next-generation sequencing have made comprehensive genomic profiling (CGP) using tumor tissue specimens and liquid biopsy using blood samples feasible in routine clinical practice. In the context of pancreaticobiliary cancer, it is necessary to consider CGP in formulating individualized treatment strategies. Performing CGP with tumor tissue specimens requires a sufficient number of high-quality samples. EUS-guided tissue acquisition (EUS-TA) is expected to play a significant role in this regard, and endosonographers need to address this role. Here, we review the current status of EUS-TA for CGP focusing on pancreatic cancer and biliary tract cancer.
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Affiliation(s)
- Nozomi Okuno
- Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.
| | - Kazuo Hara
- Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan
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Newhook TE, Tsai S, Meric-Bernstam F. Precision Oncology in Hepatopancreatobiliary Cancer Surgery. Surg Oncol Clin N Am 2024; 33:343-367. [PMID: 38401914 DOI: 10.1016/j.soc.2023.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2024]
Abstract
Advances in technology have allowed for the characterization of tumors at the genomic, transcriptomic, and proteomic levels. There are well-established targets for biliary tract cancers, with exciting new targets emerging in pancreatic ductal adenocarcinoma and potential targets in hepatocellular carcinoma. Taken together, these data suggest an important role for molecular profiling for personalizing cancer therapy in advanced disease and need for design of novel neoadjuvant studies to leverage these novel therapeutics perioperatively in the surgical patient.
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Affiliation(s)
- Timothy E Newhook
- Department of Surgical Oncology, Division of Surgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Susan Tsai
- Division of Surgical Oncology, Department of Surgery, Ohio State University Comprehensive Cancer Center, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, FC8.3044, Houston, TX 77030, USA.
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Reshkin SJ, Cardone RA, Koltai T. Genetic Signature of Human Pancreatic Cancer and Personalized Targeting. Cells 2024; 13:602. [PMID: 38607041 PMCID: PMC11011857 DOI: 10.3390/cells13070602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/27/2024] [Accepted: 03/27/2024] [Indexed: 04/13/2024] Open
Abstract
Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.
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Affiliation(s)
- Stephan J. Reshkin
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Tomas Koltai
- Oncomed, Via Pier Capponi 6, 50132 Florence, Italy
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Halani V, Sharayah A, Beck B, Patolia S. "New Targets in Non-Small-Cell Lung Cancer"-RET, HER2, and KRAS. Am J Respir Crit Care Med 2024; 209:748-750. [PMID: 38190703 DOI: 10.1164/rccm.202208-1596rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 01/03/2024] [Indexed: 01/10/2024] Open
Affiliation(s)
- Varun Halani
- Pulmonary and Critical Care Fellowship, Division of Pulmonary, Critical Care and Sleep Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri
| | - Ahmad Sharayah
- Pulmonary and Critical Care Fellowship, Division of Pulmonary, Critical Care and Sleep Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri
| | - Bryan Beck
- Pulmonary and Critical Care Fellowship, Division of Pulmonary, Critical Care and Sleep Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri
| | - Setu Patolia
- Pulmonary and Critical Care Fellowship, Division of Pulmonary, Critical Care and Sleep Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri
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