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Hossain MT, Hossain MA. Targeting PI3K in cancer treatment: A comprehensive review with insights from clinical outcomes. Eur J Pharmacol 2025; 996:177432. [PMID: 40020984 DOI: 10.1016/j.ejphar.2025.177432] [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: 11/16/2024] [Revised: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 03/03/2025]
Abstract
The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cancer, including cell growth, survival, metabolism, and metastasis. Its major role in tumor growth makes it a key target for cancer therapeutics, offering significant potential to slow tumor progression and enhance patient outcomes. Gain-of-function mutations, gene amplifications, and the loss of regulatory proteins like PTEN are frequently observed in malignancies, contributing to tumor development and resistance to conventional treatments such as chemotherapy and hormone therapy. As a result, PI3K inhibitors have received a lot of interest in cancer research. Several kinds of small-molecule PI3K inhibitors have been developed, including pan-PI3K inhibitors, isoform-specific inhibitors, and dual PI3K/mTOR inhibitors, each targeting a distinct component of the pathway. Some PI3K inhibitors such as idelalisib, copanlisib, duvelisib, alpelisib, and umbralisib have received FDA-approval, and are effective in the treatment of breast cancer and hematologic malignancies. Despite promising results in preclinical and clinical trials, the overall clinical success of PI3K inhibitors has been mixed. While some patients may get substantial advantages, a considerable number of them acquire resistance as a result of feedback activation of alternative pathways, adaptive tumor responses, and treatment-emergent mutations. The resistance mechanisms provide barriers to the sustained efficacy of PI3K-targeted treatments. This study reviews recent advancements in PI3K inhibitors, covering their clinical status, mechanism of action, resistance mechanisms, and strategies to overcome resistance.
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Affiliation(s)
- Md Takdir Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh.
| | - Md Arafat Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh.
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Jin G, Liu S, Zheng K, Cheng X, Chai R, Ye W, Wei W, Li Y, Huang A, Li G, Yi H, Kang Y. Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapy. Mol Metab 2025; 96:102151. [PMID: 40239741 PMCID: PMC12051152 DOI: 10.1016/j.molmet.2025.102151] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/27/2025] [Accepted: 04/06/2025] [Indexed: 04/18/2025] Open
Abstract
OBJECTIVES The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pivotal target in cancer treatment, driving substantial investigation into PI3K inhibitors (PI3Ki). However, the common on-target adverse effect of hyperglycemia presents a substantial challenge to their clinical application. There is an urgent need to discover an anti-hyperglycemic agent that maintains the efficacy of PI3Ki. METHODS We conducted a comprehensive study to explore the interaction between exogenous hyperinsulinemia and PI3Ki in SKOV3 and OVCAR3 ovarian cancer cell lines. We used Western blotting, CCK-8, and EdU assays to determine the effect of this interaction on cell proliferation. In addition, we evaluated the anti-hyperglycemic effects of dorzagliatin in a PI3Ki-induced hyperglycemic mice model. Cell line-derived xenograft (CDX) models were employed to evaluate the in vivo tumor growth inhibitory effects of combining dorzagliatin with PI3Ki. RESULTS Western blot analysis demonstrated that insulin activated the AKT/INSR/mTOR pathway, reversing PI3Ki-induced p-AKT inhibition. Insulin also attenuated the anti-proliferative effects of PI3Ki. In the hyperglycemic mouse model, dorzagliatin significantly reduced blood glucose levels compared to controls. The combination therapy group (Dorzagliatin + PI3Ki) in CDX models showed a marked reduction in tumor volume. Dorzagliatin not only mitigated hyperglycemia but also enhanced the anti-tumor effects of PI3Ki. A clinical trial (NCT06117566) in cervical cancer patients supported these findings, showing that dorzagliatin stabilized blood glucose levels, facilitated body weight recovery, and achieved a confirmed partial response (PR). CONCLUSIONS Dorzagliatin shows promise for managing PI3Ki-associated hyperglycemia, thereby enhancing its therapeutic efficacy. The activation of liver glycogen kinase and insulin regulation may be key mechanisms underlying its therapeutic benefits.
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Affiliation(s)
- Guanqin Jin
- Clinical Research Center, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Shihuang Liu
- Department of Gynecologic Oncology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, China; Fujian Province Key Clinical Specialty for Gynecology, Fujian Key Laboratory of Women and Children's Critical Diseases Research, National Key Gynecology Clinical Specialty Construction Institution of China, Fuzhou, 350001, China
| | - Kewei Zheng
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Xiaobo Cheng
- Clinical Research Center, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Ranran Chai
- Clinical Research Center, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Wei Ye
- Department of translational medicine, Shanghai Jiatan Pharmatech CO. LTD, Shanghai, 201203, China
| | - Wei Wei
- Department of translational medicine, Shanghai Jiatan Pharmatech CO. LTD, Shanghai, 201203, China
| | - Yongguo Li
- Department of translational medicine, Shanghai Jiatan Pharmatech CO. LTD, Shanghai, 201203, China
| | - Ai Huang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China
| | - Guiling Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China.
| | - Huan Yi
- Department of Gynecologic Oncology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, China; Fujian Province Key Clinical Specialty for Gynecology, Fujian Key Laboratory of Women and Children's Critical Diseases Research, National Key Gynecology Clinical Specialty Construction Institution of China, Fuzhou, 350001, China.
| | - Yu Kang
- Clinical Research Center, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
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Sheng Z, Beck P, Gabby M, Habte-Mariam S, Mitkos K. Molecular Basis of Oncogenic PI3K Proteins. Cancers (Basel) 2024; 17:77. [PMID: 39796708 PMCID: PMC11720314 DOI: 10.3390/cancers17010077] [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: 11/05/2024] [Revised: 12/20/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
The dysregulation of phosphatidylinositol 3-kinase (PI3K) signaling plays a pivotal role in driving neoplastic transformation by promoting uncontrolled cell survival and proliferation. This oncogenic activity is primarily caused by mutations that are frequently found in PI3K genes and constitutively activate the PI3K signaling pathway. However, tumorigenesis can also arise from nonmutated PI3K proteins adopting unique active conformations, further complicating the understanding of PI3K-driven cancers. Recent structural studies have illuminated the functional divergence among highly homologous PI3K proteins, revealing how subtle structural alterations significantly impact their activity and contribute to tumorigenesis. In this review, we summarize current knowledge of Class I PI3K proteins and aim to unravel the complex mechanism underlying their oncogenic traits. These insights will not only enhance our understanding of PI3K-mediated oncogenesis but also pave the way for the design of novel PI3K-based therapies to combat cancers driven by this signaling pathway.
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Affiliation(s)
- Zhi Sheng
- Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA
- Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
- Department of Neurosurgery, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA
- School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
- Faculty of Health Science, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
| | - Patrick Beck
- Division of General Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Maegan Gabby
- Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA
| | | | - Katherine Mitkos
- Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USA
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Aslam R, Richards CE, Fay J, Hudson L, Workman J, Lee CL, Murphy A, O’Neill B, Toomey S, Hennessy BT. Synergistic Effects of the Combination of Alpelisib (PI3K Inhibitor) and Ribociclib (CDK4/6 Inhibitor) in Preclinical Colorectal Cancer Models. Int J Mol Sci 2024; 25:13264. [PMID: 39769028 PMCID: PMC11676898 DOI: 10.3390/ijms252413264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/04/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
The CDK4/6 inhibitor Ribociclib has shown limited efficacy as a monotherapy in colorectal cancer (CRC). However, combining Ribociclib with targeted therapies could present a viable strategy for treating CRC. This study evaluated the combination of Ribociclib and the PI3K inhibitor Alpelisib across four distinct cell lines representing different mutational statuses (PIK3CA/KRAS wild-type, KRAS-mutated, PIK3CA-mutated, and PIK3CA/KRAS-mutated). We analyzed the drugs' impact on key proteins involved in the PI3K pathway, cell cycle regulation, and apoptosis. The combination of Alpelisib and Ribociclib demonstrated a synergistic anti-proliferative effect across all cell lines, leading to a simultaneous decrease in pRB, pAKT, and p-S6 levels, and a more comprehensive suppression of the PI3K/AKT/mTOR pathway. Additionally, there was an upregulation of the apoptotic marker, p-BCL2, in cells treated with the combination compared to controls. In vivo studies using Caco-2, LS1034, and SNUC4 xenografts revealed a significant reduction in tumour growth with the combination therapy compared to single-agent treatments. These findings suggest that combining Alpelisib and Ribociclib could be a promising therapeutic approach for CRC, warranting further clinical exploration.
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Affiliation(s)
- Razia Aslam
- Medical Oncology Group, Department of Medicine, RCSI University of Medicine and Health Sciences, D09 YD60 Dublin, Ireland; (R.A.); (C.E.R.)
- Beaumont RCSI Cancer Centre, D09 YD60 Dublin, Ireland
- Department of Medical Oncology, St James’s Hospital, D08 NHY1 Dublin, Ireland
| | - Cathy E. Richards
- Medical Oncology Group, Department of Medicine, RCSI University of Medicine and Health Sciences, D09 YD60 Dublin, Ireland; (R.A.); (C.E.R.)
- Beaumont RCSI Cancer Centre, D09 YD60 Dublin, Ireland
| | - Joanna Fay
- RCSI Biobank, RCSI University of Medicine and Health Sciences, D09 YD60 Dublin, Ireland
- Department of Pathology, RCSI University of Medicine and Health Science, D09 YD60 Dublin, Ireland
| | - Lance Hudson
- Department of Surgery, RCSI University of Medicine and Health Science, D09 YD60 Dublin, Ireland;
| | - Julie Workman
- Medical Oncology Group, Department of Medicine, RCSI University of Medicine and Health Sciences, D09 YD60 Dublin, Ireland; (R.A.); (C.E.R.)
| | - Cha Len Lee
- Medical Oncology Group, Department of Medicine, RCSI University of Medicine and Health Sciences, D09 YD60 Dublin, Ireland; (R.A.); (C.E.R.)
| | - Adrian Murphy
- Beaumont RCSI Cancer Centre, D09 YD60 Dublin, Ireland
- Department of Medical Oncology, Beaumont Hospital, D09 YD60 Dublin, Ireland
| | - Brian O’Neill
- Department of Radiation Oncology, St. Luke’s Radiation Oncology Centre, Beaumont Hospital, D09 YD60 Dublin, Ireland
| | - Sinead Toomey
- Medical Oncology Group, Department of Medicine, RCSI University of Medicine and Health Sciences, D09 YD60 Dublin, Ireland; (R.A.); (C.E.R.)
- Beaumont RCSI Cancer Centre, D09 YD60 Dublin, Ireland
| | - Bryan T. Hennessy
- Medical Oncology Group, Department of Medicine, RCSI University of Medicine and Health Sciences, D09 YD60 Dublin, Ireland; (R.A.); (C.E.R.)
- Beaumont RCSI Cancer Centre, D09 YD60 Dublin, Ireland
- Department of Medical Oncology, Beaumont Hospital, D09 YD60 Dublin, Ireland
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File DM, Abdou Y, Force J, Moore DT, Anders CK, Reeder-Hayes K, Carey LA, Muss HB, Perou CM, Marcom PK, Dees EC. A Phase I Trial of Alpelisib Combined With Capecitabine in Patients With HER2-Negative Metastatic Breast Cancer. Clin Breast Cancer 2024; 24:683-690. [PMID: 39217059 PMCID: PMC11840667 DOI: 10.1016/j.clbc.2024.08.001] [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: 04/02/2024] [Revised: 07/14/2024] [Accepted: 08/02/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Alpelisib is an oral α-specific class I PI3K inhibitor approved in combination with fulvestrant for the treatment of PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. The tolerability of this drug with the oral chemotherapy capecitabine is unknown. PATIENTS AND METHODS This phase I trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of alpelisib (250 mg or 300 mg daily for 3-weeks) with capecitabine (1000 mg/m2 twice daily for 2-weeks followed by a 1-week rest period) in patients with metastatic HER2-negative breast cancer, regardless of PIK3CA mutation status. RESULTS Eighteen patients were treated with alpelisib-capecitabine. Half of the patients had HR+ breast cancer, and 16 had prior systemic therapy for metastatic disease. The MTD of alpelisib was 250 mg daily in combination with capecitabine 1000 mg/m2 twice daily. DLTs included hyperglycemia, QTc prolongation, fatigue, and chest pain. The most common grade 3 adverse event (AE) was hyperglycemia (28%). No grade 4 AEs were observed. Three patients discontinued therapy due to an AE. One-third of patients required dose reduction of both alpelisib and capecitabine. Four patients experienced a partial response and 8 patients experienced stable disease. The median progression-free survival was 9.7 months (95% CI 2.8-13.5 months) and median overall survival was 18.2 months (95% CI 7.2-35.2 months). Twelve patients had PIK3CA mutation testing completed, of these 2 had known or likely deleterious PIK3CA mutation. CONCLUSION This study provides safety data for an oral combination therapy of alpelisib-capecitabine and defines tolerable doses for further study.
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Affiliation(s)
- Danielle M File
- Department of Medical Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Yara Abdou
- Department of Medical Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Lineberger Comprehensive Cancer Center, Chapel Hill, NC.
| | - Jeremy Force
- Department of Medicine, Duke University, Durham, NC; Duke Cancer Institute, Durham, NC
| | | | - Carey K Anders
- Department of Medicine, Duke University, Durham, NC; Duke Cancer Institute, Durham, NC
| | - Katherine Reeder-Hayes
- Department of Medical Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Lineberger Comprehensive Cancer Center, Chapel Hill, NC
| | - Lisa A Carey
- Department of Medical Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Lineberger Comprehensive Cancer Center, Chapel Hill, NC
| | - Hyman B Muss
- Department of Medical Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Lineberger Comprehensive Cancer Center, Chapel Hill, NC
| | - Charles M Perou
- Department of Medical Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Department of Genetics, The University of North Carolina, Chapel Hill, NC
| | - P Kelly Marcom
- Department of Medicine, Duke University, Durham, NC; Duke Cancer Institute, Durham, NC
| | - E Claire Dees
- Department of Medical Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Lineberger Comprehensive Cancer Center, Chapel Hill, NC
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Asiri A, Al Qarni A, Bakillah A. The Interlinking Metabolic Association between Type 2 Diabetes Mellitus and Cancer: Molecular Mechanisms and Therapeutic Insights. Diagnostics (Basel) 2024; 14:2132. [PMID: 39410536 PMCID: PMC11475808 DOI: 10.3390/diagnostics14192132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 09/15/2024] [Accepted: 09/16/2024] [Indexed: 10/20/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) and cancer share common risk factors including obesity, inflammation, hyperglycemia, and hyperinsulinemia. High insulin levels activate the PI3K/Akt/mTOR signaling pathway promoting cancer cell growth, survival, proliferation, metastasis, and anti-apoptosis. The inhibition of the PI3K/Akt/mTOR signaling pathway for cancer remains a promising therapy; however, drug resistance poses a major problem in clinical settings resulting in limited efficacy of agents; thus, combination treatments with therapeutic inhibitors may solve the resistance to such agents. Understanding the metabolic link between diabetes and cancer can assist in improving the therapeutic strategies used for the management of cancer patients with diabetes and vice versa. This review provides an overview of shared molecular mechanisms between diabetes and cancer as well as discusses established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management.
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Affiliation(s)
- Abutaleb Asiri
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Ali Al Qarni
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Ahmed Bakillah
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
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Pretzell I, Desuki A, Bleckmann A, Loges S, Reinacher-Schick A, Westphalen CB, Lange S. What Do German Molecular Tumor Boards Recommend in Patients with PIK3CA-Mutated Tumors? Launch and First Results from the German Transsectoral Molecular Tumor Board Exchange Platform Deutschland. Oncol Res Treat 2024; 47:410-419. [PMID: 38714183 DOI: 10.1159/000539217] [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: 02/03/2024] [Accepted: 04/26/2024] [Indexed: 05/09/2024]
Abstract
INTRODUCTION Comprehensive molecular tumor profiling is widely used in the management of patients with cancer. Molecular tumor boards devise treatment strategies based on testing results. In this setting, the Transsectoral Molecular Tumor Board exchange platform Deutschland (TEAM-D) aims to drive peer-to-peer exchange to connect experts in the field. METHODS During the first virtual TEAM-D meeting, participants from 16 German universities and 5 nonacademic institutions discussed five cases with PIK3CA hotspot mutations. Furthermore, an illustrative case vignette was presented. RESULTS Overall, German caregivers show restraint in administering off-label PIK3CA inhibitor and favor clinical trials in this setting. CONCLUSION In the setting of precision oncology, TEAM-D enables virtual case discussion across the different sectors of the German healthcare system. Based on the example of PIK3CA hotspot mutations, TEAM-D demonstrated the value of integrating knowledge from different healthcare professionals.
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Affiliation(s)
- Ina Pretzell
- West German Cancer Center, University Hospital Essen, Essen, Germany
| | - Alexander Desuki
- University Cancer Center Mainz, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Annalen Bleckmann
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
- West German Cancer Center, University Hospital Muenster, Muenster, Germany
| | - Sonja Loges
- Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Anke Reinacher-Schick
- Department of Hematology and Oncology, St. Josef Hospital, Ruhr University, Bochum, Germany
| | - C Benedikt Westphalen
- Comprehensive Cancer Center Munich and Department of Medicine III, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- German Cancer Consortium (DKTK), partner site Munich, Munich, Germany
| | - Sebastian Lange
- TUM School of Medicine and Health, Department of Clinical Medicine - Clinical Department for Internal Medicine II, University Medical Center, Technical University of Munich, Munich, Germany
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Stanland LJ, Ang HX, Hoj JP, Chu Y, Tan P, Wood KC, Luftig MA. CBF-Beta Mitigates PI3K-Alpha-Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer. Mol Cancer Res 2023; 21:1148-1162. [PMID: 37493631 PMCID: PMC10811747 DOI: 10.1158/1541-7786.mcr-23-0034] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 05/03/2023] [Accepted: 07/05/2023] [Indexed: 07/27/2023]
Abstract
PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, and survival. Some 4%-25% of gastric cancers display activating PIK3CA mutations, including 80% of Epstein-Barr virus-associated GCs. Small molecules, including pan-PI3K and dual PI3K/mTOR inhibitors, have shown moderate success clinically, due to broad on-target/off-tissue effects. Thus, isoform-specific and mutant selective inhibitors have been of significant interest. However, drug resistance is a problem and has affected success of new drugs. There has been a concerted effort to define mechanisms of resistance and identify potent combinations in many tumor types, though gastric cancer is comparatively understudied. In this study, we identified modulators of the response to the PI3Kα-specific inhibitor, BYL719, in PIK3CA-mutant GCs. We found that loss of NEDD9 or inhibition of BCL-XL conferred hypersensitivity to BYL719, through increased cell-cycle arrest and cell death, respectively. In addition, we discovered that loss of CBFB conferred resistance to BYL719. CBFB loss led to upregulation of the protein kinase PIM1, which can phosphorylate and activate several overlapping downstream substrates as AKT thereby maintaining pathway activity in the presence of PI3Kα inhibition. The addition of a pan-PIM inhibitor re-sensitized resistant cells to BYL719. Our data provide clear mechanistic insights into PI3Kα inhibitor response in PIK3CA-mutant gastric tumors and can inform future work as mutant-selective inhibitors are in development for diverse tumor types. IMPLICATIONS Loss of either NEDD9 or BCL-XL confers hypersensitivity to PI3K-alpha inhibition whereas loss of CBFB confers resistance through a CBFB/PIM1 signaling axis.
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Affiliation(s)
- Lyla J. Stanland
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine; Durham, NC, USA
| | - Hazel X. Ang
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine; Durham, NC, USA
| | - Jacob P. Hoj
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine; Durham, NC, USA
| | | | - Patrick Tan
- Duke-NUS Medical School Singapore; Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research; Singapore
| | - Kris C. Wood
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine; Durham, NC, USA
| | - Micah A. Luftig
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine; Durham, NC, USA
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Li YR, Fang Y, Lyu Z, Zhu Y, Yang L. Exploring the dynamic interplay between cancer stem cells and the tumor microenvironment: implications for novel therapeutic strategies. J Transl Med 2023; 21:686. [PMID: 37784157 PMCID: PMC10546755 DOI: 10.1186/s12967-023-04575-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 09/28/2023] [Indexed: 10/04/2023] Open
Abstract
Cancer stem cells (CSCs) have emerged as key contributors to tumor initiation, growth, and metastasis. In addition, CSCs play a significant role in inducing immune evasion, thereby compromising the effectiveness of cancer treatments. The reciprocal communication between CSCs and the tumor microenvironment (TME) is observed, with the TME providing a supportive niche for CSC survival and self-renewal, while CSCs, in turn, influence the polarization and persistence of the TME, promoting an immunosuppressive state. Consequently, these interactions hinder the efficacy of current cancer therapies, necessitating the exploration of novel therapeutic approaches to modulate the TME and target CSCs. In this review, we highlight the intricate strategies employed by CSCs to evade immune surveillance and develop resistance to therapies. Furthermore, we examine the dynamic interplay between CSCs and the TME, shedding light on how this interaction impacts cancer progression. Moreover, we provide an overview of advanced therapeutic strategies that specifically target CSCs and the TME, which hold promise for future clinical and translational studies in cancer treatment.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
| | - Ying Fang
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Zibai Lyu
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Yichen Zhu
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Lili Yang
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
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Glaviano A, Foo ASC, Lam HY, Yap KCH, Jacot W, Jones RH, Eng H, Nair MG, Makvandi P, Geoerger B, Kulke MH, Baird RD, Prabhu JS, Carbone D, Pecoraro C, Teh DBL, Sethi G, Cavalieri V, Lin KH, Javidi-Sharifi NR, Toska E, Davids MS, Brown JR, Diana P, Stebbing J, Fruman DA, Kumar AP. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer 2023; 22:138. [PMID: 37596643 PMCID: PMC10436543 DOI: 10.1186/s12943-023-01827-6] [Citation(s) in RCA: 677] [Impact Index Per Article: 338.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 07/18/2023] [Indexed: 08/20/2023] Open
Abstract
The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.
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Affiliation(s)
- Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Aaron S C Foo
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore
| | - Hiu Y Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - Kenneth C H Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - William Jacot
- Department of Medical Oncology, Institut du Cancer de Montpellier, Inserm U1194, Montpellier University, Montpellier, France
| | - Robert H Jones
- Cardiff University and Velindre Cancer Centre, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Huiyan Eng
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Madhumathy G Nair
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, 560034, India
| | - Pooyan Makvandi
- The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, 324000, Zhejiang, China
| | - Birgit Geoerger
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Inserm U1015, Université Paris-Saclay, Paris, France
| | - Matthew H Kulke
- Section of Hematology and Medical Oncology, Boston University and Boston Medical Center, Boston, MA, USA
| | - Richard D Baird
- Cancer Research UK Cambridge Centre, Hills Road, Cambridge, CB2 0QQ, UK
| | - Jyothi S Prabhu
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, 560034, India
| | - Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Camilla Pecoraro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Daniel B L Teh
- Departments of Ophthalmology and Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, and Neurobiology Programme, National University of Singapore, Singapore, Singapore
| | - Gautam Sethi
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Vincenzo Cavalieri
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Kevin H Lin
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - Eneda Toska
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA
| | - Matthew S Davids
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jennifer R Brown
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Justin Stebbing
- Division of Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
| | - David A Fruman
- Department of Molecular Biology and Biochemistry, University of California, 216 Sprague Hall, Irvine, CA, USA
| | - Alan P Kumar
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
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11
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Ji Y, Tan E, Hengelage T, Quinlan M, Hendriks BS. Exploratory Food Effect Assessment in Patients in Early Clinical Development of Oncology Drugs. Clin Pharmacol Ther 2023; 114:288-302. [PMID: 37078098 DOI: 10.1002/cpt.2911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 04/12/2023] [Indexed: 04/21/2023]
Abstract
Instructions for administration with regard to food are a key aspect of how patients experience oral drugs. Through potential effects on pharmacokinetics, the food condition can influence safety and efficacy, and thereby is one of many dimensions of dose optimization. Regulatory guidance from major health authorities advocates for the early investigation of food effect (FE) in clinical development. In oncology, exploratory FE (eFE) evaluation is often incorporated into the first-in-human (FIH) studies in patients to inform food condition of later clinical studies. However, the design aspects of such exploratory assessments are generally under-reported and barely described, and yet complex, due to uniqueness of FIH study design and drug development process in oncology. Herein, we review literature of eFE assessment study design in oncology in patients, and present the Novartis experience in the design, execution, and impact of eFE in FIH oncology studies from 2014 to 2021. Based on this, we propose a roadmap for eFE assessment in early clinical drug development for oncology drugs in patients, including a framework for common study design options with a focus on study- and patient-level timing for typical scenarios. We also provide a broad spectrum of decision-making factors which should be evaluated to drive the design and implementation of eFE assessment, spanning from clinical development strategy, FIH study design, to compound-specific features.
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Affiliation(s)
- Yan Ji
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | - Eugene Tan
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | | | - Michelle Quinlan
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | - Bart S Hendriks
- Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA
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12
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Pant S, Hamilton E, Ulahannan SV, Strauss JF, Braiteh FS, Huang M, Liaw DCH. Phase 1b study of pan‐AKT inhibitor vevorisertib alone or with paclitaxel or fulvestrant in
PIK3CA
/
AKT
/
PTEN
‐mutated advanced solid tumors. Cancer 2023; 129:1919-1929. [DOI: 10.1002/cncr.34733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/13/2023] [Accepted: 02/01/2023] [Indexed: 03/29/2023]
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13
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Ye Y, Huang Z, Zhang M, Li J, Zhang Y, Lou C. Synergistic therapeutic potential of alpelisib in cancers (excluding breast cancer): Preclinical and clinical evidences. Biomed Pharmacother 2023; 159:114183. [PMID: 36641927 DOI: 10.1016/j.biopha.2022.114183] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/19/2022] [Accepted: 12/28/2022] [Indexed: 01/15/2023] Open
Abstract
The phosphoinositide 3-kinase (PI3K) signaling pathway is well-known for its important role in cancer growth, proliferation and migration. The activation of PI3K pathway is always connected with endocrine resistance and poor prognosis in cancers. Alpelisib, a selective inhibitor of PI3K, has been demonstrated to be effective in combination with endocrine therapy in HR+ PIK3CA-mutated advanced breast cancer in preclinical and clinical trials. Recently, the synergistic effects of alpelisib combined with targeted agents have been widely reported in PIK3CA-mutated cancer cells, such as breast, head and neck squamous cell carcinoma (HNSCC), cervical, liver, pancreatic and lung cancer. However, previous reviews mainly focused on the pharmacological activities of alpelisib in breast cancer. The synergistic therapeutic potential of alpelisib in other cancers has not yet been well reviewed. In this review, an extensive study of related literatures (published until December 20, 2022) regarding the anti-cancer functions and synergistic effects of alpelisib was carried out through the databases. Useful information was extracted. We summarized the preclinical and clinical studies of alpelisib in combination with targeted anti-cancer agents in cancer treatment (excluding breast cancer). The combinations of alpelisib and other targeted agents significantly improved the therapeutic efficacy both in preclinical and clinical studies. Unfortunately, synergistic therapies still could not effectively avoid the possible toxicities and adverse events during treatment. Finally, some prospects for the combination studies in cancer treatment were provided in the paper. Taken together, this review provided valuable information for alpelisib in preclinical and clinical applications.
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Affiliation(s)
- Yuhao Ye
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Zhiyu Huang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Maoqing Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Jiayue Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Yiqiong Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Chenghua Lou
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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14
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Mansur A, Radovanovic I. Vascular malformations: An overview of their molecular pathways, detection of mutational profiles and subsequent targets for drug therapy. Front Neurol 2023; 14:1099328. [PMID: 36846125 PMCID: PMC9950274 DOI: 10.3389/fneur.2023.1099328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/25/2023] [Indexed: 02/12/2023] Open
Abstract
Vascular malformations are anomalies in vascular development that portend a significant risk of hemorrhage, morbidity and mortality. Conventional treatments with surgery, radiosurgery and/or endovascular approaches are often insufficient for cure, thereby presenting an ongoing challenge for physicians and their patients. In the last two decades, we have learned that each type of vascular malformation harbors inherited germline and somatic mutations in two well-known cellular pathways that are also implicated in cancer biology: the PI3K/AKT/mTOR and RAS/RAF/MEK pathways. This knowledge has led to recent efforts in: (1) identifying reliable mechanisms to detect a patient's mutational burden in a minimally-invasive manner, and then (2) understand how cancer drugs that target these mutations can be repurposed for vascular malformation care. The idea of precision medicine for vascular pathologies is growing in potential and will be critical in expanding the clinician's therapeutic armamentarium.
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Affiliation(s)
- Ann Mansur
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, School of Graduate Studies, University of Toronto, Toronto, ON, Canada
| | - Ivan Radovanovic
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
- Krembil Brain Institute, University Health Network, Toronto, ON, Canada
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15
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Royer B, Kaderbhaï CG, Schmitt A. Pharmacokinetics and Pharmacodynamic of Alpelisib. Clin Pharmacokinet 2023; 62:45-53. [PMID: 36633813 DOI: 10.1007/s40262-022-01195-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2022] [Indexed: 01/13/2023]
Abstract
Advanced breast cancers are frequently hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative. Some of them harbor a mutation in PIK3CA, a gene encoding the PI3K catalytic subunit α of phosphatidyl-inositol 3-kinase (PI3K), which confers resistance to hormone therapy. Alpelisib is the first oral selective p110 [Formula: see text] PI3K inhibitor approved by FDA and EMA, in association with fulvestrant, based on PFS improvement as compared to fulvestrant alone. The aim of this review is to summarize and critically review the key aspects of alpelisib pharmacokinetics (PK) and pharmacodynamics (PD). Preclinical data have shown that alpelisib IC50 was 50 times lower for the α enzyme than for the β, δ and γ PI3K enzymes, leading to a decrease in intra-tumoral AKT phosphorylation. The PK properties of alpelisib are somehow favorable, with a rapid and important absorption, a limited CYP P450-mediated metabolism and a predominant biliary excretion, with a half-life of 17.5 ± 5.9 h. Only limited drug-drug interactions are expected and there is no need for dose adaptation in mild and moderate renal impaired and mild to severe hepatic impaired patients. Pharmacokinetic/pharmacodynamic relationships were evidenced during drug development for exposure/efficacy, but also exposure/safety. Main adverse events are hyperglycemia, rash, and diarrhea. The first, if not fully contra-indicated in (pre-)diabetic patients, warrants a close follow up when treatment is started and a potential dose reduction when needed. Because of its safety profile, alpelisib require stringent patient selection and close follow-up.
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Affiliation(s)
- Bernard Royer
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.,Laboratoire de Pharmacologie Clinique et Toxicologie, CHU Besançon, Besançon, France
| | | | - Antonin Schmitt
- Pharmacy Department, Centre Georges-François Leclerc, 1 rue Pr Marion, 21079, Dijon Cedex, France. .,INSERM U1231, University of Burgundy Franche-Comté, Dijon, France.
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16
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Abbasian MH, Ardekani AM, Sobhani N, Roudi R. The Role of Genomics and Proteomics in Lung Cancer Early Detection and Treatment. Cancers (Basel) 2022; 14:5144. [PMID: 36291929 PMCID: PMC9600051 DOI: 10.3390/cancers14205144] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/10/2022] [Accepted: 10/18/2022] [Indexed: 08/17/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related death worldwide, with non-small-cell lung cancer (NSCLC) being the primary type. Unfortunately, it is often diagnosed at advanced stages, when therapy leaves patients with a dismal prognosis. Despite the advances in genomics and proteomics in the past decade, leading to progress in developing tools for early diagnosis, targeted therapies have shown promising results; however, the 5-year survival of NSCLC patients is only about 15%. Low-dose computed tomography or chest X-ray are the main types of screening tools. Lung cancer patients without specific, actionable mutations are currently treated with conventional therapies, such as platinum-based chemotherapy; however, resistances and relapses often occur in these patients. More noninvasive, inexpensive, and safer diagnostic methods based on novel biomarkers for NSCLC are of paramount importance. In the current review, we summarize genomic and proteomic biomarkers utilized for the early detection and treatment of NSCLC. We further discuss future opportunities to improve biomarkers for early detection and the effective treatment of NSCLC.
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Affiliation(s)
- Mohammad Hadi Abbasian
- Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran 1497716316, Iran
| | - Ali M. Ardekani
- Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran 1497716316, Iran
| | - Navid Sobhani
- Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX 77030, USA
| | - Raheleh Roudi
- Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA
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17
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Mortazavi M, Moosavi F, Martini M, Giovannetti E, Firuzi O. Prospects of targeting PI3K/AKT/mTOR pathway in pancreatic cancer. Crit Rev Oncol Hematol 2022; 176:103749. [PMID: 35728737 DOI: 10.1016/j.critrevonc.2022.103749] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/11/2022] [Accepted: 06/16/2022] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses among all malignancies. PI3K/AKT/mTOR signaling pathway, a main downstream effector of KRAS is involved in the regulation of key hallmarks of cancer. We here report that whole-genome analyses demonstrate the frequent involvement of aberrant activations of PI3K/AKT/mTOR pathway components in PDAC patients and critically evaluate preclinical and clinical evidence on the application of PI3K/AKT/mTOR pathway targeting agents. Combinations of these agents with chemotherapeutics or other targeted therapies, including the modulators of cyclin-dependent kinases, receptor tyrosine kinases and RAF/MEK/ERK pathway are also examined. Although human genetic studies and preclinical pharmacological investigations have provided strong evidence on the role of PI3K/AKT/mTOR pathway in PDAC, clinical studies in general have not been as promising. Patient stratification seems to be the key missing point and with the advent of biomarker-guided clinical trials, targeting PI3K/AKT/mTOR pathway could provide valuable assets for treatment of pancreatic cancer patients.
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Affiliation(s)
- Motahareh Mortazavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Moosavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Miriam Martini
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, the Netherlands; Cancer Pharmacology Lab, Fondazine Pisana per la Scienza, Pisa, Italy
| | - Omidreza Firuzi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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18
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PI3K Inhibitor Eruptions: an Overview of Diagnostic and Management Strategies for the Inpatient Dermatologist. CURRENT DERMATOLOGY REPORTS 2022. [DOI: 10.1007/s13671-022-00365-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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19
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Reculé F, Agüero R, Chaparro X, Fischer C, Hasbún T. Orbital Vascular Malformation: Successful Outcome in Two Patients Treated With Rapamycin. Dermatol Ther 2022; 35:e15655. [PMID: 35726592 DOI: 10.1111/dth.15655] [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: 01/28/2022] [Revised: 05/19/2022] [Accepted: 06/19/2022] [Indexed: 11/30/2022]
Abstract
Combined vascular malformations are complex vascular anomalies that have high morbidity and therefore, therapeutic strategies are hard to establish. In this report, we aim to present two pediatric cases of ocular combined vascular malformations successfully treated with Rapamycin. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Francisca Reculé
- Departamento de Cirugía y Servicio de Dermatología, Clínica Alemana de Santiago - Facultad de Medicina Universidad del Desarrollo
| | - Rosario Agüero
- Facultad de Medicina Clínica Alemana - Universidad del Desarrollo
| | - Ximena Chaparro
- Departamento de Cirugía y Servicio de Dermatología, Clínica Alemana de Santiago - Facultad de Medicina Universidad del Desarrollo.,Servicio de Dermatología, Hospital Exequiel González Cortés, Santiago, Chile
| | - Cecilia Fischer
- Servicio de Dermatología, Hospital Exequiel González Cortés, Santiago, Chile
| | - Trinidad Hasbún
- Departamento de Cirugía y Servicio de Dermatología, Clínica Alemana de Santiago - Facultad de Medicina Universidad del Desarrollo.,Servicio de Dermatología, Hospital Exequiel González Cortés, Santiago, Chile
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20
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Zhu J, Li K, Xu L, Cai Y, Chen Y, Zhao X, Li H, Huang G, Jin J. Discovery of novel selective PI3Kγ inhibitors through combining machine learning-based virtual screening with multiple protein structures and bio-evaluation. J Adv Res 2022; 36:1-13. [PMID: 35127160 PMCID: PMC8800018 DOI: 10.1016/j.jare.2021.04.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 04/09/2021] [Accepted: 04/16/2021] [Indexed: 01/10/2023] Open
Abstract
Introduction Phosphoinositide 3-kinase gamma (PI3Kγ) has been regarded as a promising drug target for the treatment of various diseases, and the diverse physiological roles of class I PI3K isoforms (α, β, δ, and γ) highlight the importance of isoform selectivity in the development of PI3Kγ inhibitors. However, the high structural conservation among the PI3K family makes it a big challenge to develop selective PI3Kγ inhibitors. Objectives A novel machine learning-based virtual screening with multiple PI3Kγ protein structures was developed to discover novel PI3Kγ inhibitors. Methods A large chemical database was screened using the virtual screening model, the top-ranked compounds were then subjected to a series of bio-evaluations, which led to the discovery of JN-KI3. The selective inhibition mechanism of JN-KI3 against PI3Kγ was uncovered by a theoretical study. Results 49 hits were identified through virtual screening, and the cell-free enzymatic studies found that JN-KI3 selectively inhibited PI3Kγ at a concentration as low as 3,873 nM but had no inhibitory effect on Class IA PI3Ks, leading to the selective cytotoxicity on hematologic cancer cells. Meanwhile, JN-KI3 potently blocked the PI3K signaling, finally led to distinct apoptosis of hematologic cell lines at a low concentration. Lastly, the key residues of PI3Kγ and the structural characteristics of JN-KI3, which both would influence γ isoform-selective inhibition, were highlighted by systematic theoretical studies. Conclusion The developed virtual screening model strongly manifests the robustness to find novel PI3Kγ inhibitors. JN-KI3 displays a specific cytotoxicity on hematologic tumor cells, and significantly promotes apoptosis associated with the inhibition of the PI3K signaling, which depicts PI3Kγ as a potential target for the hematologic tumor therapy. The theoretical results reveal that those key residues interacting with JN-KI3 are less common compared to most of the reported PI3Kγ inhibitors, indicating that JN-KI3 has novel structural characteristics as a selective PIK3γ inhibitor.
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Key Words
- ADMET, absorption, distribution, metabolism, excretion, and toxicity
- AKT, protein kinase B
- AUC, area under receiver operations characteristic curve
- Badapple, bioactivity data associative promiscuity pattern learning engine
- CADD, computer-aided drug design
- CDRA, confirmatory dose–response assays
- DMEM, Dulbecco’s Modified Eagle Medium
- DS3.5, discovery studio 3.5
- FBS, fetal bovine serum
- GPCR, G protein-coupled receptors
- H-bond, hydrogen bond
- Hematologic malignancies
- IMDM, Iscove’s Modified Dulbecco’s Medium
- Ionic, ionic interactions
- JN-KI3
- MD, molecular dynamics
- MM/GBSA, molecular mechanics/generalized born surface area
- Molecular dynamics simulation
- NBC, naive Bayesian classifier
- PAGE, polyacrylamide gel electrophoresis
- PAINS, pan-assay interference compounds
- PARP, poly ADP-ribose polymerase
- PDB, protein data bank
- PI3K, Phosphoinositide 3-kinase
- PI3Kγ
- PSA, primary screening assays
- REOS, rapid elimination of swill
- RMSD, root-mean-squared-deviation
- RMSF, root-mean-squared-fluctuation
- ROC, receiver operations characteristic
- RTK, receptor tyrosine kinases
- SD, standard deviation
- SMILES, simplified molecular input line entry specification
- SP, standard precision
- Selective inhibitor
- VS, virtual screening
- Virtual screening
- Water Bridge, hydrogen bonds through water molecular bridge
- XP, extra precision
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Affiliation(s)
- Jingyu Zhu
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Kan Li
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Lei Xu
- Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, China
| | - Yanfei Cai
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Yun Chen
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xinling Zhao
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Huazhong Li
- School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 21412 2, China
| | - Gang Huang
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Jian Jin
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu 214122, China
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21
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Goncalves MD, Farooki A. Management of Phosphatidylinositol-3-Kinase Inhibitor-Associated Hyperglycemia. Integr Cancer Ther 2022; 21:15347354211073163. [PMID: 35075945 PMCID: PMC8793384 DOI: 10.1177/15347354211073163] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 12/06/2021] [Accepted: 12/22/2021] [Indexed: 11/15/2022] Open
Abstract
Phosphatidylinositol-3-kinase (PI3K) pathway hyperactivation has been associated with the development of cancer and treatment resistance. PI3K inhibitors are now used to treat hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-), PIK3CA-mutated advanced breast cancer. Hyperglycemia, a frequently observed adverse event with PI3K inhibitors (PI3Ki), is regarded as an on-target effect because inhibition of the PI3K pathway has been shown to decrease glucose transport and increase glycogenolysis and gluconeogenesis. PI3Ki-induced hyperglycemia results in a compensatory increase in insulin release, which has been shown to reduce the efficacy of treatment by reactivating the PI3K pathway in preclinical models. Patients with an absolute or relative deficiency in insulin, and those with insulin resistance or pancreatic dysfunction, may experience exacerbated or prolonged hyperglycemia. Therefore, the effective management of PI3Ki-associated hyperglycemia depends on early identification of patients at risk, frequent monitoring to allow prompt recognition of hyperglycemia and its sequelae, and initiating appropriate management strategies. Risk factors for the development of hyperglycemia include older age (≥75 years), overweight/obese at baseline, and family history of diabetes. Consultation with an endocrinologist is recommended for patients considered high risk. The management of PI3Ki-induced hyperglycemia requires an integrative approach that combines diets low in carbohydrates and glucose-lowering medications. Medications that do not affect the PI3K pathway are preferred as the primary and secondary agents for the management of hyperglycemia. These include metformin, sodium-glucose co-transporter 2 inhibitors, thiazolidinediones, and α-glucosidase inhibitors. Insulin should only be considered as a last-line agent for PI3Ki-associated hyperglycemia due to its stimulatory effect of PI3K signaling. Clinical studies show that alpelisib-associated hyperglycemia is reversible and manageable, rarely leading to treatment discontinuation. Management of PI3Ki-associated hyperglycemia in patients with breast cancer should focus on the prevention of acute and subacute complications of hyperglycemia, allowing patients to remain on anticancer treatment longer.
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Affiliation(s)
| | - Azeez Farooki
- Memorial Sloan Kettering Cancer Center,
New York, NY, USA
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22
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Fagone E, Fruciano M, Gili E, Sambataro G, Vancheri C. Developing PI3K Inhibitors for Respiratory Diseases. Curr Top Microbiol Immunol 2022; 436:437-466. [DOI: 10.1007/978-3-031-06566-8_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Garland-Kledzik M, Scholer A, Ensenyat-Mendez M, Orozco JIJ, Khader A, Santamaria-Barria J, Fischer T, Pigazzi A, Marzese DM. Establishing Novel Molecular Subtypes of Appendiceal Cancer. Ann Surg Oncol 2021; 29:2118-2125. [PMID: 34718915 DOI: 10.1245/s10434-021-10945-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 09/24/2021] [Indexed: 01/03/2023]
Abstract
PURPOSE Appendiceal cancer is a rare disease process with complex treatment strategies. The objective of this study was to identify mutation-based genetic subtypes that may differ from the current histological classification, compare the genetic make-up of primaries and metastases, and find novel targetable alterations. METHODS The analyses involved the curation and normalization of gene mutation panels from appendiceal adenocarcinoma and mucinous adenocarcinoma (n = 196) stored in the AACR GENIE Database v6.0. Genes mutated in less than one patient and tumors profiled with incomplete mutation panels were excluded from the study. The optimal number of AC subtypes was established using the Nonnegative Matrix Factorization algorithm. Statistical comparisons of mutation frequencies were performed using Pearson's χ2 test. RESULTS AC patients were stratified into five mutation subtypes, based on a final set of 41 cancer-related genes. AC0 had no mutations. The most frequently mutated genes varied between the subtypes were: AC1: KRAS (91.9%) and GNAS (77.4%); AC2: KRAS (52.5%), APC (32.5%), and GNAS (30%); AC3: KMT2D (38.7%), TP53 (38.7%), KRAS (35.5%), EP300 (22.6%); and AC4: TP53 (97.2%), KRAS (77.8%), and SMAD4 (36.1%). Additionally, AC3 was less likely to be mucinous (22.6% vs. 50.0-74.2%, p < 0.001) and had a higher mutation frequency (3.6 vs. 0-3.1, p < 0.001). There were no significant differences between primary tumors and metastases in the 41 assessed genes (p = 0.35). CONCLUSIONS The characterization of these subtypes suggests a need for molecular approaches to complement anatomical and histopathological staging for AC. A prospective comparison of subtype prognosis and response to surgery and adjuvant treatment is needed to identify the clinical applications of the novel molecular subtypes.
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Affiliation(s)
| | - Anthony Scholer
- Department of Surgery, Saint John's Cancer Institute at Providence St. John's Health Center, Santa Monica, CA, USA
| | - Miquel Ensenyat-Mendez
- Cancer Epigenetic Laboratory, Health Research Institute of the Balearic Islands (IdISBa), Palma, Islas Baleares, Spain
| | - Javier I J Orozco
- Cancer Epigenetics Laboratory, Saint John's Cancer Institute at Providence St. John's Health Center, Santa Monica, CA, USA
| | - Adam Khader
- Department of Surgery, Saint John's Cancer Institute at Providence St. John's Health Center, Santa Monica, CA, USA
| | - Juan Santamaria-Barria
- Department of Surgery, Saint John's Cancer Institute at Providence St. John's Health Center, Santa Monica, CA, USA
| | - Trevan Fischer
- Department of Surgery, Saint John's Cancer Institute at Providence St. John's Health Center, Santa Monica, CA, USA
| | - Alessio Pigazzi
- Colon and Rectal Surgery, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA
| | - Diego M Marzese
- Cancer Epigenetic Laboratory, Health Research Institute of the Balearic Islands (IdISBa), Palma, Islas Baleares, Spain
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Aleksakhina SN, Imyanitov EN. Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives. Int J Mol Sci 2021; 22:ijms222010931. [PMID: 34681592 PMCID: PMC8536080 DOI: 10.3390/ijms222010931] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/11/2022] Open
Abstract
The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.
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Affiliation(s)
- Svetlana N. Aleksakhina
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 Saint-Petersburg, Russia;
- Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 Saint-Petersburg, Russia
| | - Evgeny N. Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 Saint-Petersburg, Russia;
- Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 Saint-Petersburg, Russia
- Correspondence: ; Tel.: +7-812-439-95-28
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25
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Chandrasekaran S, Funk CR, Kleber T, Paulos CM, Shanmugam M, Waller EK. Strategies to Overcome Failures in T-Cell Immunotherapies by Targeting PI3K-δ and -γ. Front Immunol 2021; 12:718621. [PMID: 34512641 PMCID: PMC8427697 DOI: 10.3389/fimmu.2021.718621] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/06/2021] [Indexed: 12/18/2022] Open
Abstract
PI3K-δ and PI3K-γ are critical regulators of T-cell differentiation, senescence, and metabolism. PI3K-δ and PI3K-γ signaling can contribute to T-cell inhibition via intrinsic mechanisms and regulation of suppressor cell populations, including regulatory T-cells and myeloid derived suppressor cells in the tumor. We examine an exciting new role for using selective inhibitors of the PI3K δ- and γ-isoforms as modulators of T-cell phenotype and function in immunotherapy. Herein we review the current literature on the implications of PI3K-δ and -γ inhibition in T-cell biology, discuss existing challenges in adoptive T-cell therapies and checkpoint blockade inhibitors, and highlight ongoing efforts and future directions to incorporate PI3K-δ and PI3K-γ as synergistic T-cell modulators in immunotherapy.
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Affiliation(s)
- Sanjay Chandrasekaran
- Department of Hematology and Medical Oncology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
| | - Christopher Ronald Funk
- Department of Hematology and Medical Oncology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
| | - Troy Kleber
- Department of Hematology and Medical Oncology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
| | - Chrystal M. Paulos
- Department of Surgery/Microbiology & Immunology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
| | - Mala Shanmugam
- Department of Hematology and Medical Oncology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
| | - Edmund K. Waller
- Department of Hematology and Medical Oncology, Winship Cancer Institute at Emory University, Atlanta, GA, United States
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Chen X, Zhabyeyev P, Azad AK, Vanhaesebroeck B, Grueter CE, Murray AG, Kassiri Z, Oudit GY. Pharmacological and cell-specific genetic PI3Kα inhibition worsens cardiac remodeling after myocardial infarction. J Mol Cell Cardiol 2021; 157:17-30. [PMID: 33887328 DOI: 10.1016/j.yjmcc.2021.04.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND PI3Kα (Phosphoinositide 3-kinase α) regulates multiple downstream signaling pathways controlling cell survival, growth, and proliferation and is an attractive therapeutic target in cancer and obesity. The clinically-approved PI3Kα inhibitor, BYL719, is in further clinical trials for cancer and overgrowth syndrome. However, the potential impact of PI3Kα inhibition on the heart and following myocardial infarction (MI) is unclear. We aim to determine whether PI3Kα inhibition affects cardiac physiology and post-MI remodeling and to elucidate the underlying molecular mechanisms. METHODS AND RESULTS Wildtype (WT) 12-wk old male mice receiving BYL719 (daily, p.o.) for 10 days showed reduction in left ventricular longitudinal strain with normal ejection fraction, weight loss, mild cardiac atrophy, body composition alteration, and prolonged QTC interval. RNASeq analysis showed gene expression changes in multiple pathways including extracellular matrix remodeling and signaling complexes. After MI, both p110α and phospho-Akt protein levels were increased in human and mouse hearts. Pharmacological PI3Kα inhibition aggravated cardiac dysfunction and resulted in adverse post-MI remodeling, with increased apoptosis, elevated inflammation, suppressed hypertrophy, decreased coronary blood vessel density, and inhibited Akt/GSK3β/eNOS signaling. Selective genetic ablation of PI3Kα in endothelial cells was associated with worsened post-MI cardiac function and reduced coronary blood vessel density. In vitro, BYL719 suppressed Akt/eNOS activation, cell viability, proliferation, and angiogenic sprouting in coronary and human umbilical vein endothelial cells. Cardiomyocyte-specific genetic PI3Kα ablation resulted in mild cardiac systolic dysfunction at baseline. After MI, cardiac function markedly deteriorated with increased mortality concordant with greater apoptosis and reduced hypertrophy. In isolated adult mouse cardiomyocytes, BYL719 decreased hypoxia-associated activation of Akt/GSK3β signaling and cell survival. CONCLUSIONS PI3Kα is required for cell survival (endothelial cells and cardiomyocytes) hypertrophic response, and angiogenesis to maintain cardiac function after MI. Therefore, PI3Kα inhibition that is used as anti-cancer treatment, can be cardiotoxic, especially after MI.
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Affiliation(s)
- Xueyi Chen
- Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada
| | - Pavel Zhabyeyev
- Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada
| | - Abul K Azad
- Department of Medicine, University of Alberta, Edmonton, Canada
| | | | - Chad E Grueter
- Division of Cardiovascular Medicine, Department of Internal Medicine, Francois M. Abboud Cardiovascular Research Center, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, USA
| | - Allan G Murray
- Department of Medicine, University of Alberta, Edmonton, Canada
| | - Zamaneh Kassiri
- Department of Physiology, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada
| | - Gavin Y Oudit
- Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
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27
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Badarni M, Prasad M, Golden A, Bhattacharya B, Levin L, Yegodayev KM, Dimitstein O, Joshua BZ, Cohen L, Khrameeva E, Kong D, Porgador A, Braiman A, Grandis JR, Rotblat B, Elkabets M. IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer. Cancers (Basel) 2021; 13:cancers13092250. [PMID: 34067117 PMCID: PMC8125641 DOI: 10.3390/cancers13092250] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary In the current study, we delineate the molecular mechanisms of acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib and taselisib, in human papillomavirus positive head and neck cell lines. By comparing RNA sequencing of isiPI3K-sensitive tumor cells and their corresponding isiPI3K-acquired-resistant tumor cells, we found that overexpression of insulin growth factor 2 (IGF2) is associated with the resistance phenotype. We further demonstrated by gain and loss of function studies that IGF2 plays a causative role in limiting the sensitivity of human papillomavirus-positive head and neck cell lines. Moreover, we show that blocking IGF2 stimulation activity, using an inhibitor of the IGF1 receptor (IGF1R), enhances isiPI3K efficacy and displays a synergistic anti-tumor effect in vitro and superior anti-tumor activity ex vivo and in vivo. Abstract Over 50% of human papilloma positive head-and-neck cancer (HNCHPV+) patients harbor genomic-alterations in PIK3CA, leading to hyperactivation of the phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) pathway. Nevertheless, despite PI3K pathway activation in HNCHPV+ tumors, the anti-tumor activities of PI3K pathway inhibitors are moderate, mostly due to the emergence of resistance. Thus, for potent and long-term tumor management, drugs blocking resistance mechanisms should be combined with PI3K inhibitors. Here, we delineate the molecular mechanisms of the acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib (BYL719) and taselisib (GDC0032), in HNCHPV+ cell lines. By comparing the transcriptional landscape of isiPI3K-sensitive tumor cells with that of their corresponding isiPI3K-acquired-resistant tumor cells, we found upregulation of insulin growth factor 2 (IGF2) in the resistant cells. Mechanistically, we show that upon isiPI3K treatment, isiPI3K-sensitive tumor cells upregulate the expression of IGF2 to induce cell proliferation via the activation of the IGF1 receptor (IGF1R). Stimulating tumor cells with recombinant IGF2 limited isiPI3K efficacy and released treated cells from S phase arrest. Knocking-down IGF2 with siRNA, or blocking IGF1R with AEW541, resulted in superior anti-tumor activity of isiPI3K in vitro and ex vivo. In vivo, the combination of isiPI3K and IGF1R inhibitor induced stable disease in mice bearing either tumors generated by the HNCHPV+ UM-SCC47 cell line or HPV+ patient-derived xenografts. These findings indicate that IGF2 and the IGF2/IGF1R pathway may constitute new targets for combination therapies to enhance the efficacy of PI3K inhibitors for the treatment of HNCHPV+.
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Affiliation(s)
- Mai Badarni
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (M.B.); (M.P.); (B.B.); (K.M.Y.); (L.C.); (A.P.); (A.B.)
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (O.D.); (B.-Z.J.)
| | - Manu Prasad
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (M.B.); (M.P.); (B.B.); (K.M.Y.); (L.C.); (A.P.); (A.B.)
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (O.D.); (B.-Z.J.)
| | - Artemiy Golden
- Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia; (A.G.); (E.K.)
| | - Baisali Bhattacharya
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (M.B.); (M.P.); (B.B.); (K.M.Y.); (L.C.); (A.P.); (A.B.)
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (O.D.); (B.-Z.J.)
| | - Liron Levin
- Bioinformatics Core Facility, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
- The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Ksenia M. Yegodayev
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (M.B.); (M.P.); (B.B.); (K.M.Y.); (L.C.); (A.P.); (A.B.)
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (O.D.); (B.-Z.J.)
| | - Orr Dimitstein
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (O.D.); (B.-Z.J.)
- Department of Otolaryngology—Head and Neck Surgery, Soroka University Medical Center, Beer-Sheva 84105, Israel
| | - Ben-Zion Joshua
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (O.D.); (B.-Z.J.)
- Department of Otorhinolaryngology and Head & Neck Surgery, Barzilay Medical Center, Ashkelon 7830604, Israel
| | - Limor Cohen
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (M.B.); (M.P.); (B.B.); (K.M.Y.); (L.C.); (A.P.); (A.B.)
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (O.D.); (B.-Z.J.)
| | - Ekaterina Khrameeva
- Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia; (A.G.); (E.K.)
| | - Dexin Kong
- School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China;
| | - Angel Porgador
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (M.B.); (M.P.); (B.B.); (K.M.Y.); (L.C.); (A.P.); (A.B.)
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (O.D.); (B.-Z.J.)
| | - Alex Braiman
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (M.B.); (M.P.); (B.B.); (K.M.Y.); (L.C.); (A.P.); (A.B.)
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (O.D.); (B.-Z.J.)
| | - Jennifer R. Grandis
- Department of Otolaryngology—Head and Neck Surgery, University of California San Francisco, San Francisco, CA 94143, USA;
| | - Barak Rotblat
- The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
- Department of Life Sciences, Faculty of Life Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
- Correspondence: (B.R.); (M.E.); Tel.: +972-(0)8-6428806 (B.R.); +972-86428846 (M.E.)
| | - Moshe Elkabets
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (M.B.); (M.P.); (B.B.); (K.M.Y.); (L.C.); (A.P.); (A.B.)
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (O.D.); (B.-Z.J.)
- Correspondence: (B.R.); (M.E.); Tel.: +972-(0)8-6428806 (B.R.); +972-86428846 (M.E.)
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Mishra R, Patel H, Alanazi S, Kilroy MK, Garrett JT. PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. Int J Mol Sci 2021; 22:3464. [PMID: 33801659 PMCID: PMC8037248 DOI: 10.3390/ijms22073464] [Citation(s) in RCA: 175] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/19/2021] [Accepted: 03/23/2021] [Indexed: 02/07/2023] Open
Abstract
The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.
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Affiliation(s)
| | | | | | | | - Joan T. Garrett
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267-0514, USA; (R.M.); (H.P.); (S.A.); (M.K.K.)
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Leenhardt F, Alexandre M, Jacot W. Alpelisib for the treatment of PIK3CA-mutated, hormone receptor-positive, HER2-negative metastatic breast cancer. Expert Opin Pharmacother 2021; 22:667-675. [PMID: 33622114 DOI: 10.1080/14656566.2021.1873952] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: Two-thirds of advanced breast cancers are hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-). Gene mutations in PIK3CA, encoding the PI3K catalytic subunit alpha of phosphatidyl-inositol 3-kinase (PI3K), are a frequent event in this population and are implicated in hormone therapy resistance. Alpelisib is a PI3K-alpha inhibitor and is the first PI3K inhibitor approved, in association with fulvestrant, by the FDA and EMA, based on improved progression-free survival (PFS) versus fulvestrant alone in a randomized phase III trial in HR+/HER2-, PIK3CA-mutated tumors following progression on/after HT.Areas covered: The scientific rationale, preclinical development, pharmacokinetics, and clinical efficacy/safety of alpelisib-fulvestrant are summarized. The role of alpelisib in the clinical setting is discussed, referencing current therapeutic options and clinical challenges associated with alpelisib's safety profile.Expert opinion: Alpelisib is an option for patients with HR+/HER2-, PIK3CA-mutated tumors whose disease progressed during/after aromatase inhibitor treatment. The PFS benefit appears clinically significant over fulvestrant alone, with a 7.9 months, non-significant, improvement in overall survival. Its safety profile requires strict patient selection, mainly based on baseline glycemic status, and close monitoring.
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Affiliation(s)
- Fanny Leenhardt
- Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, Montpellier, France.,Service Pharmacie, Institut du Cancer de Montpellier, Université de Montpellier, Montpellier, France.,Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Université de Montpellier, Montpellier, France
| | - Marie Alexandre
- Département d'Oncologie Médicale, Institut du Cancer de Montpellier, Université de Montpellier, Montpellier, France
| | - William Jacot
- Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Université de Montpellier, Montpellier, France.,Département d'Oncologie Médicale, Institut du Cancer de Montpellier, Université de Montpellier, Montpellier, France
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Seo SW, Kim JM, Han DG, Geum D, Yun H, Yoon IS. A sensitive HPLC-FLD method for the quantification of alpelisib, a novel phosphatidylinositol 3-kinase inhibitor, in rat plasma: Drug metabolism and pharmacokinetic evaluation in vitro and in vivo. J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1163:122508. [PMID: 33387858 DOI: 10.1016/j.jchromb.2020.122508] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 12/03/2020] [Accepted: 12/14/2020] [Indexed: 01/25/2023]
Abstract
Alpelisib, a novel phosphatidylinositol 3-kinase inhibitor, is an oral anticancer agent approved for the treatment of advanced or metastatic breast cancer. In this study, a sensitive bioanalytical method using high-performance liquid chromatography combined with a fluorescence detector (HPLC-FLD) was developed for the determination of alpelisib in rat plasma. This newly developed method was validated in terms of linearity (1-1,000 ng/mL), precision, accuracy, recovery, matrix effect, and stability according to the US Food and Drug Administration guideline and these parameters were within the acceptable limits. Alpelisib tended to be stable in plasma, urine, simulated intestinal fluid, and buffer with pH > 4.0 for 24 h, but in the pH 1.2 buffer and simulated gastric fluid for up to 4 h only. A study involving intravenous administration of alpelisib in rats showed that the dose-normalized area under the plasma concentration versus time curve (AUC) of alpelisib changed significantly as the dose increased from 1 to 10 mg/kg. Similarly, an oral rat study indicated that the dose-normalized AUC and the fraction of dose that remained in the gastrointestinal (GI) tract changed significantly as the dose increased from 0.5 to 10 mg/kg. These nonlinear (dose-dependent) pharmacokinetics of intravenous and oral alpelisib could be attributed to the saturation of ubiquitous metabolism among most tissues and/or GI absorption processes. To the best of our knowledge, this is the first study to investigate the in vivo nonlinear pharmacokinetics of alpelisib and its possible mechanisms, together with a new HPLC-FLD method to determine alpelisib in biological matrices.
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Affiliation(s)
- Seong-Wook Seo
- Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan, South Korea
| | - Ji-Min Kim
- Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan, South Korea
| | - Dong-Gyun Han
- Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan, South Korea
| | - Dongho Geum
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea
| | - Hwayoung Yun
- Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan, South Korea.
| | - In-Soo Yoon
- Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan, South Korea.
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Mavratzas A, Marmé F. Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations. Future Oncol 2021; 17:13-36. [DOI: 10.2217/fon-2020-0464] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Since the US FDA approval of everolimus/exemestane in July 2012, and of the first CDK 4/6 inhibitor, palbociclib, combined with endocrine treatment in February 2015, a third class of therapeutic compounds, the PI3K inhibitors, has been introduced to the arsenal of targeted therapies overcoming endocrine resistance in hormone receptor-positive metastatic breast cancer. Alpelisib (PIQRAY®) is the first of these novel agents yielding promising clinical results, giving an impetus to further development of tailored endocrine anticancer treatments. Herein, we review its pharmacodynamic and pharmacokinetic properties, safety and efficacy data, as well as Phase III SOLAR-1 trial, prompting FDA approval of alpelisib in hormone receptor-positive metastatic breast cancer harboring PIK3CA mutations. Furthermore, implications for clinical use and current research will also be discussed.
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Affiliation(s)
- Athanasios Mavratzas
- Department of Obstetrics & Gynecology Mannheim, Section of Conservative Gynecologic Oncology, Experimental & Translational Gynecologic Oncology, Medical Faculty Mannheim of University Heidelberg University Hospital, Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Frederik Marmé
- Department of Obstetrics & Gynecology Mannheim, Section of Conservative Gynecologic Oncology, Experimental & Translational Gynecologic Oncology, Medical Faculty Mannheim of University Heidelberg University Hospital, Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
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Zhu J, Li K, Yu L, Chen Y, Cai Y, Jin J, Hou T. Targeting phosphatidylinositol 3-kinase gamma (PI3Kγ): Discovery and development of its selective inhibitors. Med Res Rev 2020; 41:1599-1621. [PMID: 33300614 DOI: 10.1002/med.21770] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 10/13/2020] [Accepted: 11/29/2020] [Indexed: 12/11/2022]
Abstract
Phosphatidylinositol 3-kinase gamma (PI3Kγ) has been regarded as a promising drug target for the treatment of advanced solid tumors, leukemia, lymphoma, and inflammatory and autoimmune diseases. However, the high level of structural conservation among the members of the PI3K family and the diverse physiological roles of Class I PI3K isoforms (α, β, δ, and γ) highlight the importance of isoform selectivity in the development of PI3Kγ inhibitors. In this review, we provide an overview of the structural features of PI3Kγ that influence γ-isoform selectivity and discuss the structure-selectivity-activity relationship of existing clinical PI3Kγ inhibitors. Additionally, we summarize the experimental and computational techniques utilized to identify PI3Kγ inhibitors. The insights gained so far could be used to overcome the main challenges in development and accelerate the discovery of PI3Kγ-selective inhibitors.
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Affiliation(s)
- Jingyu Zhu
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu, China
| | - Kan Li
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu, China
| | - Li Yu
- School of Inspection and Testing Certification, Changzhou Vocational Institute of Engineering, Changzhou, Jiangsu, China
| | - Yun Chen
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu, China
| | - Yanfei Cai
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu, China
| | - Jian Jin
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi, Jiangsu, China
| | - Tingjun Hou
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
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Mendoza-Almanza G, Burciaga-Hernández L, Maldonado V, Melendez-Zajgla J, Olmos J. Role of platelets and breast cancer stem cells in metastasis. World J Stem Cells 2020; 12:1237-1254. [PMID: 33312396 PMCID: PMC7705471 DOI: 10.4252/wjsc.v12.i11.1237] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/23/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
The high mortality rate of breast cancer is mainly caused by the metastatic ability of cancer cells, resistance to chemotherapy and radiotherapy, and tumor regression capacity. In recent years, it has been shown that the presence of breast cancer stem cells is closely associated with the migration and metastatic ability of cancer cells, as well as with their resistance to chemotherapy and radiotherapy. The tumor microenvironment is one of the main molecular factors involved in cancer and metastatic processes development, in this sense it is interesting to study the role of platelets, one of the main communicator cells in the human body which are activated by the signals they receive from the microenvironment and can generate more than one response. Platelets can ingest and release RNA, proteins, cytokines and growth factors. After the platelets interact with the tumor microenvironment, they are called "tumor-educated platelets." Tumor-educated platelets transport material from the tumor microenvironment to sites adjacent to the tumor, thus helping to create microenvironments conducive for the development of primary and metastatic tumors. It has been observed that the clone capable of carrying out the metastatic process is a cancer cell with stem cell characteristics. Cancer stem cells go through a series of processes, including epithelial-mesenchymal transition, intravasation into blood vessels, movement through blood vessels, extravasation at the site of the establishment of a metastatic focus, and site colonization. Tumor-educated platelets support all these processes.
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Affiliation(s)
| | | | - Vilma Maldonado
- Laboratorio de Epigenética, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Melendez-Zajgla
- Génómica funcional del cáncer, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Olmos
- Biotecnología Marina, Centro de Investigación Científica y de Estudios Superiores de Ensenada, Ensenada 22860, Mexico
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Tran KB, Buchanan CM, Shepherd PR. Evolution of Molecular Targets in Melanoma Treatment. Curr Pharm Des 2020; 26:396-414. [PMID: 32000640 DOI: 10.2174/1381612826666200130091318] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 11/21/2019] [Indexed: 12/12/2022]
Abstract
Melanoma is the deadliest type of skin cancers, accounting for more than 80% of skin cancer mortality. Although melanoma was known very early in the history of medicine, treatment for this disease had remained largely the same until very recently. Previous treatment options, including removal surgery and systemic chemotherapy, offered little benefit in extending the survival of melanoma patients. However, the last decade has seen breakthroughs in melanoma treatment, which all emerged following new insight into the oncogenic signaling of melanoma. This paper reviewed the evolution of drug targets for melanoma treatment based on the emergence of novel findings in the molecular signaling of melanoma. One of the findings that are most influential in melanoma treatment is that more than 50% of melanoma tumors contain BRAF mutations. This is fundamental for the development of BRAF inhibitors, which is the first group of drugs that significantly improves the overall survival of melanoma patients compared to the traditional chemotherapeutic dacarbazine. More recently, findings of the role of immune checkpoint molecules such as CTLA-4 and PD1/PD-L1 in melanoma biology have led to the development of a new therapeutic category: immune checkpoint inhibitors, which, for the first time in the history of cancer treatment, produced a durable response in a subset of melanoma patients. However, as this paper discussed next, there is still an unmet need for melanoma treatment. A significant population of patients did not respond to either BRAF inhibitors or immune checkpoint inhibitors. Of those patients who gained an initial response from those therapies, a remarkable percentage would develop drug resistance even when MEK inhibitors were added to the treatment. Finally, this paper discusses some possible targets for melanoma treatment.
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Affiliation(s)
- Khanh B Tran
- Department of Molecular Medicine and Pathology, University of Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Christina M Buchanan
- Department of Molecular Medicine and Pathology, University of Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Peter R Shepherd
- Department of Molecular Medicine and Pathology, University of Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.,Auckland Cancer Society Research Centre, University of Auckland, New Zealand
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Shields M, Mo Q, Armitage M, Sharpe SC, Costa RLB. A systematic review and meta-analysis of selected toxicity endpoints of alpelisib. Oncotarget 2020; 11:3793-3799. [PMID: 33144920 PMCID: PMC7584237 DOI: 10.18632/oncotarget.27770] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 09/24/2020] [Indexed: 01/08/2023] Open
Abstract
Purpose: Alpelisib is a first-in-class α-specific phosphatidylinositol 3-kinase inhibitor approved for the treatment of patients with estrogen receptor–positive metastatic breast cancer. High absolute risk (AR) of relevant toxicities has been observed with this treatment. This meta-analysis aimed to improve the precision of the estimated AR of selected adverse events (AEs) associated with this new agent. Materials and Methods: A literature search was conducted in August 2019 to identify trials analyzing the anti-tumor efficacy and toxicity profile of alpelisib. Heterogeneity was assessed by using I2 statistics. Data were analyzed using random effect meta-analyses for AR. Eleven trials and 511 patients were included. Results: There was no evidence of heterogeneity between studies regarding the AR of most AEs except for all-grade weight loss and grade 3–4 stomatitis. The number of serious AEs was clearly reported in only one study, of which the most common was hyperglycemia; the most common all-grade AEs were hyperglycemia (59%), diarrhea (56%), nausea (44%), and rash (38%). Grade 3/4 hyperglycemia and rash occurred in 28% and 10% of patients, respectively. No treatment-associated deaths were observed, and 18% of patients had to stop treatment due to toxicities. Conclusions: Alpelisib is associated with clinically relevant AEs that can lead to treatment discontinuation. The most common AE was hyperglycemia. No treatment-related deaths were observed.
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Affiliation(s)
- Misty Shields
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Qianxing Mo
- Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Melissa Armitage
- Department of Pharmacy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Susan C Sharpe
- Moffitt Biomedical Library, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Ricardo L B Costa
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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Abstract
Vascular malformations are inborn errors of vascular morphogenesis and consist of localized networks of abnormal blood and/or lymphatic vessels with weak endothelial cell proliferation. They have historically been managed by surgery and sclerotherapy. Extensive insight into the genetic origin and molecular mechanism of development has been accumulated over the last 20 years. Since the discovery of the first somatic mutations in a vascular anomaly 10 years ago, it is now recognized that they are perhaps all caused by inherited or somatic mutations in genes that hyperactivate two major intracellular signaling pathways: the RAS/MAPK/ERK and/or the phosphatidylinositol 3 kinase (PIK3)/protein kinase B/mammalian target of rapamycin (mTOR) pathway. Several targeted molecular inhibitors of these pathways have been developed, mostly for the treatment of cancers that harbor mutations in the same pathways. The mTOR inhibitor sirolimus is the most studied compound for the treatment of venous, lymphatic, and complex malformations. Disease responses of vascular malformations to sirolimus have now been reported in several studies in terms of clinical changes, quality of life, functional and radiological outcomes, and safety. Other targeted treatment strategies, such as the PIK3CA inhibitor alpelisib for PIK3CA-mutated vascular malformations, are also emerging. Repurposing of cancer drugs has become a major focus in this rapidly evolving field.
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Lu YS, Lee KS, Chao TY, Tseng LM, Chitapanarux I, Chen SC, Liu CT, Sohn J, Kim JH, Chang YC, Yang Y, Shotelersuk K, Jung KH, Valenti R, Slader C, Gao M, Park YH. A Phase Ib Study of Alpelisib or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer. Clin Cancer Res 2020; 27:408-417. [PMID: 32718997 DOI: 10.1158/1078-0432.ccr-20-1008] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 06/25/2020] [Accepted: 07/19/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE This study reports the MTD, recommended phase 2 dose (RP2D), and preliminary efficacy of alpelisib or buparlisib used in combination with tamoxifen plus goserelin in premenopausal patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). PATIENTS AND METHODS This study enrolled premenopausal women with HR+, HER2- ABC. Patients received tamoxifen (20 mg once daily) and goserelin acetate (3.6 mg every 28 days) with either alpelisib (350 mg once daily; n = 16) or buparlisib (100 mg once daily; n = 13) in 28-day cycles until MTD was observed. RESULTS The criteria for MTD were not met for both alpelisib and buparlisib. The RP2D of alpelisib and buparlisib in combination with tamoxifen and goserelin were 350 mg and 100 mg, respectively. Both combinations met protocol-specified criteria for tolerability. The most common grade 3/4 treatment-emergent adverse events (TEAE) were hypokalemia (12.5%), hyperglycemia (6.3%), and rash (6.3%) for alpelisib and alanine aminotransferase increase (30.8%), aspartate aminotransferase increase (23.1%), and anxiety (15.4%) for buparlisib. TEAEs led to treatment discontinuation in 18.8% and 53.8% of alpelisib- and buparlisib-treated patients, respectively. Progression-free survival was 25.2 months in the alpelisib group and 20.6 months in the buparlisib group. CONCLUSIONS The RP2Ds of alpelisib and buparlisib were 350 mg and 100 mg, respectively. No unexpected safety findings were reported. Although an early-phase study, data suggest that alpelisib plus endocrine therapy may be a potentially efficacious treatment that warrants further evaluation for premenopausal patients with HR+, HER2- ABC.See related commentary by Clark et al., p. 371.
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Affiliation(s)
- Yen-Shen Lu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Keun Seok Lee
- Center for Breast Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Tsu-Yi Chao
- Division of Hematology/Oncology, Shuang Ho Hospital and Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan
| | - Ling-Ming Tseng
- Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Imjai Chitapanarux
- Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Shin-Cheh Chen
- Breast Surgery Division, Chang Gung Memorial Hospital, Linkou, Taoyouan City, Taiwan
| | - Chien-Ting Liu
- Division of Hematology and Oncology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan
| | - Joohyuk Sohn
- Division of Medical Oncology, Yonsei Cancer Center, Seoul, South Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
| | | | - Youngsen Yang
- Taichung Veterans General Hospital, Taichung, Taiwan
| | - Kanjana Shotelersuk
- Division of Therapeutic Radiology and Oncology, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kyung Hae Jung
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | | | | | | | - Yeon Hee Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul, South Korea.
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Dermatologic adverse events related to the PI3Kα inhibitor alpelisib (BYL719) in patients with breast cancer. Breast Cancer Res Treat 2020; 183:227-237. [PMID: 32613539 DOI: 10.1007/s10549-020-05726-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/02/2020] [Indexed: 12/17/2022]
Abstract
PURPOSE Rash develops in approximately 50% of patients receiving alpelisib for breast cancer, often requiring dose modifications. Here, we describe the clinicopathologic, laboratory, and management characteristics of alpelisib-related dermatologic adverse events (dAEs). METHODS A single center-retrospective analysis was conducted. Data were abstracted from electronic medical records. RESULTS A total of 102 patients (mean age 56 years, range 27-83) receiving alpelisib most frequently in combination with endocrine therapy (79, 77.5%) were included. We identified 41 (40.2%) patients with all-grade rash distributed primarily along the trunk (78%) and extremities (70%) that developed approximately within two weeks of treatment initiation (mean 12.8 ± 1.5 days) and lasted one-week (mean duration 7.1 ± 0.8 days). Of 29 patients with documented morphology of alpelisib-related dAEs, 26 (89.7%) had maculopapular rash. Histology showed perivascular and interface lymphocytic dermatitis. All-grade rash correlated with an increase in serum eosinophils from 2.7 to 4.4%, p < 0.05, and prophylaxis with non-sedating antihistamines (n = 43) was correlated with a reduction of grade 1/2 rash (OR 0.39, p = 0.09). Sixteen (84.2%) of 19 patients with grade 3 dAEs resulted in interruption of alpelisib, which were managed with antihistamines, topical and systemic corticosteroids. We did not observe rash recurrence in 12 (75%) patients who were re-challenged. CONCLUSIONS A maculopapular rash associated with increased blood eosinophils occurs frequently with alpelisib. While grade 3 rash leads to alpelisib therapy interruption, dermatologic improvement is evident with systemic corticosteroids; and most patients can continue oncologic treatment at a maintained or reduced dose upon re-challenge with alpelisib.
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Parikh BA, Love-Gregory L, Duncavage EJ, Heusel JW. Identification of challenges and a framework for implementation of the AMP/ASCO/CAP classification guidelines for reporting somatic variants. Pract Lab Med 2020; 21:e00170. [PMID: 32548229 PMCID: PMC7286953 DOI: 10.1016/j.plabm.2020.e00170] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 04/30/2020] [Accepted: 05/18/2020] [Indexed: 01/08/2023] Open
Abstract
Objectives In 2017, AMP, ASCO and CAP jointly published the first formalized classification system for the interpretation and reporting of sequence variants in cancer. The challenges of incorporating new variant interpretation guidelines into existing, validated workflows have likely hampered adoption and implementation in labs with classification methods in place. Ambiguity in assigning clinical significance across guidelines is grounded in differential weighting of evidence used in variant assessment. Therefore, we undertook an internal process-improvement exercise to correlate the two classification schemes using historical laboratory data. Design and methods Existing clinical variant assignments from 40 consecutive oncology cases comprising 150 somatic variants were re-assessed according to the 2017 AMP/ASCO/CAP scheme. Approximately 50% of these were cancers of the gynecologic tract. Results Our laboratory-developed (GPS) classifications for 'actionable' variants and variants of uncertain clinical significance mapped consistently with the AMP/ASCO/CAP Tiers I-III. The majority of Level 1 variants were reclassified to Tier I (21/25; 84%) while all Level 2 and Level 4 variants were assigned to Tier II (9/9; 100%) and Tier III (17/17; 100%), respectively. The greatest variability was seen for GPS Level 3 variants, which was strongly influenced by TP53 interpretations. Ultimately, we found that most GPS Level 3 variants were classified as Tier III (77/99; 77.8%). Conclusions Our internally developed 5-level classifications mapped consistently with the proposed AMP/ASCO/CAP 4-Tiered system. As a result of this analysis, we can provide a framework for other labs considering a similar transition to the 2017 AMP/ASCO/CAP guidelines and a rationale for explaining specific discrepancies.
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Affiliation(s)
- Bijal A Parikh
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Latisha Love-Gregory
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Eric J Duncavage
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Jonathan W Heusel
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.,Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA
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Michmerhuizen NL, Owen JH, Heft Neal ME, Mann JE, Leonard E, Wang J, Zhai J, Jiang H, McHugh JB, Brenner JC, Prince MEP. Rationale for the advancement of PI3K pathway inhibitors for personalized chordoma therapy. J Neurooncol 2020; 147:25-35. [PMID: 32067197 DOI: 10.1007/s11060-020-03418-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 01/30/2020] [Indexed: 11/26/2022]
Abstract
PURPOSE Chordomas are rare and serious tumors with few effective treatments outside of aggressive surgery and radiation. Targeted therapies may present a more effective option for a subset of patients with lesions possessing certain genetic biomarkers. METHODS A small molecule inhibitor library was tested in patient-derived UM-Chor1 cells to identify targeted therapies with potential efficacy. Targeted exome sequencing of UM-Chor1 and UM-Chor2 cells was performed to investigate genetic aberrations in relevant pathways. Chordoma cell lines were treated with inhibitors of the phosphotidylinositol 3-kinase (PI3K), epidermal growth factor receptor (EGFR), and cyclin dependent kinase (CDK) pathways, and responses were determined using resazurin cell viability assays, Annexin V apoptosis assays, and western blotting. Pan-PI3K inhibitor BKM120 was also tested in five chordoma xenograft models. RESULTS Unbiased small molecule profiling nominated PI3K-AKT-mTOR pathway inhibitors as a promising therapy in chordoma, and genetic analyses of UM-Chor1 and UM-Chor2 cell lines revealed aberrations in PTEN, EGFR, and CDKN2A. Treatment of UM-Chor1 and UM-Chor2 with targeted PI3K, EGFR, and CDK inhibitors inhibited growth and proliferation and induced apoptosis more robustly than imatinib, a currently used chordoma therapy. Furthermore, BKM120 significantly inhibited tumor growth in a subset of the xenograft models tested. CONCLUSION Targeted therapies, especially those inhibiting PI3K, display promising effects in multiple chordoma cell line and xenograft models. Nevertheless, the limited effects of PI3K, EGFR, and CDK targeting agents in other models reveal the presence of resistance mechanisms, which motivates future research to both identify biomarkers of response and develop combination therapies.
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Affiliation(s)
- N L Michmerhuizen
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - J H Owen
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA
| | - M E Heft Neal
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA
| | - J E Mann
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - E Leonard
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA
| | - J Wang
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - J Zhai
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - H Jiang
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - J B McHugh
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - J C Brenner
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA.
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - M E P Prince
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, MI, 48109-0602, USA
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
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Zhang J, Wang Q, Wang Q, Cao J, Sun J, Zhu Z. Mechanisms of resistance to estrogen receptor modulators in ER+/HER2- advanced breast cancer. Cell Mol Life Sci 2020; 77:559-572. [PMID: 31471681 PMCID: PMC11105043 DOI: 10.1007/s00018-019-03281-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 08/08/2019] [Accepted: 08/12/2019] [Indexed: 02/07/2023]
Abstract
Endocrine therapy represents a mainstay adjuvant treatment of estrogen receptor-positive (ER+) breast cancer in clinical practice with an overall survival (OS) benefit. However, the emergence of resistance is inevitable over time and is present in one-third of the ER+ breast tumors. Several mechanisms of endocrine resistance in ER+/HER2- advanced breast cancers, through ERα itself, receptor tyrosine signaling, or cell cycle pathway, have been identified to be pivotal in endocrine therapy. The epigenetic alterations also contribute to ensuring tumor cells' escape from endocrine therapies. The strategy of combined hormone therapy with targeted pharmaceutical compounds has shown an improvement of progression-free survival or OS in clinical practice, including three different classes of drugs: CDK4/6 inhibitors, selective inhibitor of PI3Kα and mTOR inhibitors. Many therapeutic targets of cell cycle pathway and cell signaling and their combination strategies have recently entered clinical trials. This review focuses on Cyclin D-CDK4/6-RB axis, PI3K pathway and HDACs. Additionally, genomic evolution is complex in tumors exposed to hormonal therapy. We highlight the genomic alterations present in ESR1 and PIK3CA genes to elucidate adaptive mechanisms of endocrine resistance, and discuss how these mutations may inform novel combinations to improve clinical outcomes in the future.
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Affiliation(s)
- Jin Zhang
- Tianjin Key Laboratory of Protein Science, Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Qianying Wang
- Tianjin Key Laboratory of Protein Science, Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Qing Wang
- Tianjin Key Laboratory of Protein Science, Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jiangran Cao
- Tianjin Key Laboratory of Protein Science, Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jiafu Sun
- Tianjin Key Laboratory of Protein Science, Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Zhengmao Zhu
- Tianjin Key Laboratory of Protein Science, Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
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Huang TX, Guan XY, Fu L. Therapeutic targeting of the crosstalk between cancer-associated fibroblasts and cancer stem cells. Am J Cancer Res 2019; 9:1889-1904. [PMID: 31598393 PMCID: PMC6780671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 08/28/2019] [Indexed: 06/10/2023] Open
Abstract
Cancer-associated fibroblasts (CAFs) play critical roles in cancer progression and treatment failure. CAFs display extreme phenotypic heterogeneity and functional diversity. Some subpopulations of CAFs have the ability to reconstitute cancer stemness by promoting the expansion of cancer stem cells (CSCs) or by inducing the generation of CSCs from differentiated cancer cells. CAFs regulate cancer stemness in different types of solid tumors by activating a wide array of CSC-related signaling by secreting proteins and exosomes. As feedback, the CSCs can also induce the proliferation and further activation of CAFs to promote their CSC-supporting activities, thus completing the loop of CAF-CSC crosstalk. Current research on targeting CAF-CSC crosstalk could be classified into (i) specific depletion of CAF subpopulations that have CSC-supporting activities and (ii) targeting molecular signaling in CAF-CSC crosstalk, such as the IL6/STAT3, TGF-β/SDF-1/PI3K, WNT/β-catenin, HGF/cMET and SHH/Hh pathways. Strategies targeting CAF-CSC crosstalk may open new avenues for overcoming cancer progression and therapeutic resistance.
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Affiliation(s)
- Tu-Xiong Huang
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Shenzhen International Cancer Center, Shenzhen University School of MedicineShenzhen, China
| | - Xin-Yuan Guan
- Department of Clinical Oncology, The University of Hong KongHong Kong
| | - Li Fu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Shenzhen International Cancer Center, Shenzhen University School of MedicineShenzhen, China
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Liu JJ, Ho JY, Lee HW, Baik MW, Kim O, Choi YJ, Hur SY. Inhibition of Phosphatidylinositol 3-kinase (PI3K) Signaling Synergistically Potentiates Antitumor Efficacy of Paclitaxel and Overcomes Paclitaxel-Mediated Resistance in Cervical Cancer. Int J Mol Sci 2019; 20:E3383. [PMID: 31295843 PMCID: PMC6679163 DOI: 10.3390/ijms20143383] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 06/30/2019] [Accepted: 07/08/2019] [Indexed: 12/19/2022] Open
Abstract
Acquired paclitaxel (PTX) resistance limits its effectiveness and results in advanced cancer progression. This review investigated whether the inhibition of phosphatidylinositol 3-kinase (PI3K) signaling overcomes paclitaxel resistance in cervical cancer. It was established paclitaxel-resistant cell lines (PTX-R ME180/PTX-R HeLa) and determined the combination index for paclitaxel and PI3K inhibitors (BYL-719/ LY294002) by tetrazolium dye assay. Flow cytometry was used to detect the cell cycle and apoptosis. Migration and invasion were explored by wound healing and transwell assays. Genes related to multiple pathways were assessed by a western blot. It was found that the PI3K pathway was significantly activated in paclitaxel-resistant HeLa and ME180 cells compared to parental cells. PTX + PI3K inhibitor combined therapy showed a synergistic effect by strengthening paclitaxel-induced S and G2M arrest in PTX-R cell sublines by the inactivation of cyclin A1, cyclin B1, cyclin E, and Cdc2 expression. Moreover, combination therapy significantly enhanced drug sensitivity and apoptosis through the activation of Bax, and cleavage of poly-(ADP-ribose) polymerase compared with paclitaxel alone. In addition, PI3K inhibition also suppressed tumor migration and invasion by targeting β-catenin and matrix metalloproteinase-2/9. The authors suggest that the combination of a PI3K inhibitor with paclitaxel may enhance antitumor activity through a cascade of PI3K signaling events.
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Affiliation(s)
- Jing Jing Liu
- Department of Gynecology and Obstetrics, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Korea
- Cancer Research Institute, Department of Medical Life Science, and Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jung Yoon Ho
- Department of Gynecology and Obstetrics, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Korea
- Cancer Research Institute, Department of Medical Life Science, and Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Hye Won Lee
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06591, Korea
| | - Min Wha Baik
- Department of Gynecology and Obstetrics, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Korea
| | - Oyoung Kim
- Department of Gynecology and Obstetrics, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Korea
| | - Youn Jin Choi
- Department of Gynecology and Obstetrics, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Korea.
- Cancer Research Institute, Department of Medical Life Science, and Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
| | - Soo Young Hur
- Department of Gynecology and Obstetrics, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Korea.
- Cancer Research Institute, Department of Medical Life Science, and Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
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Ando Y, Iwasa S, Takahashi S, Saka H, Kakizume T, Natsume K, Suenaga N, Quadt C, Yamada Y. Phase I study of alpelisib (BYL719), an α-specific PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Sci 2019; 110:1021-1031. [PMID: 30588709 PMCID: PMC6398875 DOI: 10.1111/cas.13923] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 12/17/2018] [Accepted: 12/24/2018] [Indexed: 12/11/2022] Open
Abstract
This phase I study aimed to determine tolerability and preliminary efficacy of single‐agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28‐day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose‐limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all‐grade treatment‐suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression‐free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.
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Affiliation(s)
| | | | - Shunji Takahashi
- The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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