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Haggstrom L, Chan WY, Nagrial A, Chantrill LA, Sim HW, Yip D, Chin V. Chemotherapy and radiotherapy for advanced pancreatic cancer. Cochrane Database Syst Rev 2024; 12:CD011044. [PMID: 39635901 PMCID: PMC11619003 DOI: 10.1002/14651858.cd011044.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
BACKGROUND Pancreatic cancer (PC) is a lethal disease with few effective treatment options. Many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review synthesises all the randomised data available to help better inform patient and clinician decision-making. It updates the previous version of the review, published in 2018. OBJECTIVES To assess the effects of chemotherapy, radiotherapy, or both on overall survival, severe or life-threatening adverse events, and quality of life in people undergoing first-line treatment of advanced pancreatic cancer. SEARCH METHODS We searched for published and unpublished studies in CENTRAL, MEDLINE, Embase, and CANCERLIT, and handsearched various sources for additional studies. The latest search dates were in March and July 2023. SELECTION CRITERIA We included randomised controlled trials comparing chemotherapy, radiotherapy, or both with another intervention or best supportive care. Participants were required to have locally advanced, unresectable pancreatic cancer or metastatic pancreatic cancer not amenable to curative intent treatment. Histological confirmation was required. Trials were required to report overall survival. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We included 75 studies in the review and 51 in the meta-analysis (11,333 participants). We divided the studies into seven categories: any anti-cancer treatment versus best supportive care; various chemotherapy types versus gemcitabine; gemcitabine-based combinations versus gemcitabine alone; various chemotherapy combinations versus gemcitabine plus nab-paclitaxel; fluoropyrimidine-based studies; miscellaneous studies; and radiotherapy studies. In general, the included studies were at low risk for random sequence generation, detection bias, attrition bias, and reporting bias, at unclear risk for allocation concealment, and high risk for performance bias. Compared to best supportive care, chemotherapy likely results in little to no difference in overall survival (OS) (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.88 to 1.33; absolute risk of death at 12 months of 971 per 1000 versus 962 per 1000; 4 studies, 298 participants; moderate-certainty evidence). The adverse effects of chemotherapy and impacts on quality of life (QoL) were uncertain. Many of the chemotherapy regimens were outdated. Eight studies compared non-gemcitabine-based chemotherapy regimens to gemcitabine. These showed that 5-fluorouracil (5FU) likely reduces OS (HR 1.69, 95% CI 1.26 to 2.27; risk of death at 12 months of 914 per 1000 versus 767 per 1000; 1 study, 126 participants; moderate certainty), and grade 3/4 adverse events (QoL not reported). Fixed dose rate gemcitabine likely improves OS (HR 0.79, 95% CI 0.66 to 0.94; risk of death at 12 months of 683 per 1000 versus 767 per 1000; 2 studies, 644 participants; moderate certainty), and likely increase grade 3/4 adverse events (QoL not reported). FOLFIRINOX improves OS (HR 0.51, 95% CI 0.43 to 0.60; risk of death at 12 months of 524 per 1000 versus 767 per 1000; P < 0.001; 2 studies, 652 participants; high certainty), and delays deterioration in QoL, but increases grade 3/4 adverse events. Twenty-eight studies compared gemcitabine-based combinations to gemcitabine. Gemcitabine plus platinum may result in little to no difference in OS (HR 0.94, 95% CI 0.81 to 1.08; risk of death at 12 months of 745 per 1000 versus 767 per 1000; 6 studies, 1140 participants; low certainty), may increase grade 3/4 adverse events, and likely worsens QoL. Gemcitabine plus fluoropyrimidine improves OS (HR 0.88, 95% CI 0.81 to 0.95; risk of death at 12 months of 722 per 1000 versus 767 per 1000; 10 studies, 2718 participants; high certainty), likely increases grade 3/4 adverse events, and likely improves QoL. Gemcitabine plus topoisomerase inhibitors result in little to no difference in OS (HR 1.01, 95% CI 0.87 to 1.16; risk of death at 12 months of 770 per 1000 versus 767 per 1000; 3 studies, 839 participants; high certainty), likely increases grade 3/4 adverse events, and likely does not alter QoL. Gemcitabine plus taxane result in a large improvement in OS (HR 0.71, 95% CI 0.62 to 0.81; risk of death at 12 months of 644 per 1000 versus 767 per 1000; 2 studies, 986 participants; high certainty), and likely increases grade 3/4 adverse events and improves QoL. Nine studies compared chemotherapy combinations to gemcitabine plus nab-paclitaxel. Fluoropyrimidine-based combination regimens improve OS (HR 0.79, 95% CI 0.70 to 0.89; risk of death at 12 months of 542 per 1000 versus 628 per 1000; 6 studies, 1285 participants; high certainty). The treatment arms had distinct toxicity profiles, and there was little to no difference in QoL. Alternative schedules of gemcitabine plus nab-paclitaxel likely result in little to no difference in OS (HR 1.10, 95% CI 0.82 to 1.47; risk of death at 12 months of 663 per 1000 versus 628 per 1000; 2 studies, 367 participants; moderate certainty) or QoL, but may increase grade 3/4 adverse events. Four studies compared fluoropyrimidine-based combinations to fluoropyrimidines alone, with poor quality evidence. Fluoropyrimidine-based combinations are likely to result in little to no impact on OS (HR 0.84, 95% CI 0.61 to 1.15; risk of death at 12 months of 765 per 1000 versus 704 per 1000; P = 0.27; 4 studies, 491 participants; moderate certainty) versus fluoropyrimidines alone. The evidence suggests that there was little to no difference in grade 3/4 adverse events or QoL between the two groups. We included only one radiotherapy (iodine-125 brachytherapy) study with 165 participants. The evidence is very uncertain about the effect of radiotherapy on outcomes. AUTHORS' CONCLUSIONS Combination chemotherapy remains standard of care for metastatic pancreatic cancer. Both FOLFIRINOX and gemcitabine plus a taxane improve OS compared to gemcitabine alone. Furthermore, the evidence suggests that fluoropyrimidine-based combination chemotherapy regimens improve OS compared to gemcitabine plus nab-paclitaxel. The effects of radiotherapy were uncertain as only one low-quality trial was included. Selection of the most appropriate chemotherapy for individuals still remains unpersonalised, with clinicopathological stratification remaining elusive. Biomarker development is essential to assist in rationalising treatment selection for patients.
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Affiliation(s)
- Lucy Haggstrom
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- Medical Oncology, Illawarra Shoalhaven Local Health District, Wollongong, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
| | - Wei Yen Chan
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia
| | - Adnan Nagrial
- The Crown Princess Mary Cancer Centre, Westmead, Australia
- Medical School, The University of Sydney, Sydney, Australia
| | - Lorraine A Chantrill
- Medical Oncology, Illawarra Shoalhaven Local Health District, Wollongong, Australia
- University of Wollongong, Wollongong, Australia
| | - Hao-Wen Sim
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia
| | - Desmond Yip
- Department of Medical Oncology, The Canberra Hospital, Garran, Australia
- ANU Medical School, Australian National University, Acton, Australia
| | - Venessa Chin
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
- Medical Oncology, Garvan Institute of Medical Research, Sydney, Australia
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Tushoski-Alemán GW, Crespin AJ, Oguejiofor CJ, Szymkiewicz DD, Herremans KM, Han S, Hughes SJ. Variability of quality-of-life measurements and reporting in randomised controlled trials of pancreatic cancer: a systematic review. BMJ Open 2024; 14:e083696. [PMID: 39551595 PMCID: PMC11574412 DOI: 10.1136/bmjopen-2023-083696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 10/11/2024] [Indexed: 11/19/2024] Open
Abstract
OBJECTIVES This systematic review aims to evaluate the methodology used in pancreatic cancer (PC) randomised controlled trials (RCTs) measuring quality of life (QOL) and focuses on the type, frequency, survey compliance and duration of these assessments. DESIGN Systematic review of PC RCTs measuring QOL. DATA SOURCES A search of PubMed.gov and ClinicalTrials.gov was conducted for PC RCTs measuring QOL from inception to 21 March 2023. Only phase III RCTs were included. Studies were excluded if QOL was not measured, the study was phase I/II, in the second-line setting or unavailable in English. Data were independently extracted by two reviewers in a standardised fashion. PRIMARY AND SECONDARY OUTCOME MEASURES Primary outcomes included the type of QOL instrument used, the timing and frequency of assessments, methods of analysis and survey completion rates (SCRs) over time. Secondary outcomes included patient demographics, significant QOL improvements and the frequency of trials measuring QOL. RESULTS Out of 269 studies screened, 54 RCTs were identified, and 24 measured QOL (involving 11 229 patients). Instruments used included the EORTC QLQ-C30 (n=15), FACT-HEP (n=3), Spitzer-QOL-Index (n=2), EQ-5D (n=2), LASA (n=1) and FACT-PA (n=1). Most trials assessed QOL until disease progression or death (10/24), with 4-week intervals being the most common (7/24). SCRs were reported in 15/24 trials, with disease stage influencing SCRs over time. In trials with metastatic, locally advanced/metastatic, and resectable disease, the median times to reach a 50% response rate-defined as the point where the number of surveys completed was half of the enrolled participants-were 12.41 weeks (n=2), 14.14 weeks (n=10), and 54.2 weeks (n=3), respectively." Only 2/24 trials reported significant QOL improvements between treatment arms. Patient age was reported in all trials, while race/ethnicity was only reported in 4/24 trials. CONCLUSIONS Significant variability exists in the timing, methods and reporting of QOL assessments in PC trials. There is a need for further research to assess the implications of missing data and consider the temporality of QOL assessment in patients with advanced cancers and poor prognosis.
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Affiliation(s)
| | | | | | | | - Kelly M Herremans
- Department of Surgery, University of Florida, Gainesville, Florida, USA
| | - Song Han
- Department of Surgery, University of Florida, Gainesville, Florida, USA
| | - Steven J Hughes
- Department of Surgery, University of Florida, Gainesville, Florida, USA
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3
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Anderson MJM, Hayward AN, Smiley AT, Shi K, Pawlak MR, Aird EJ, Grant E, Greenberg L, Aihara H, Evans RL, Ulens C, Gordon WR. Molecular basis of proteolytic cleavage regulation by the extracellular matrix receptor dystroglycan. Structure 2024; 32:1984-1996.e5. [PMID: 39305901 PMCID: PMC11560575 DOI: 10.1016/j.str.2024.08.019] [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: 03/27/2024] [Revised: 06/13/2024] [Accepted: 08/27/2024] [Indexed: 10/05/2024]
Abstract
The dystrophin-glycoprotein-complex (DGC), anchored by the transmembrane protein dystroglycan, functions to mechanically link the extracellular matrix and actin cytoskeleton. Breaking this connection is associated with diseases such as muscular dystrophy, yet cleavage of dystroglycan by matrix-metalloproteinases (MMPs) remains an understudied mechanism to disrupt the DGC. We determined the crystal structure of the membrane-adjacent domain (amino acids 491-722) of E. coli expressed human dystroglycan to understand MMP cleavage regulation. The structural model includes tandem immunoglobulin-like (IGL) and sperm/enterokinase/agrin-like (SEAL) domains, which support proteolysis in diverse receptors to facilitate mechanotransduction, membrane protection, and viral entry. The structure reveals a C-terminal extension that buries the MMP site by packing into a hydrophobic pocket, a unique mechanism of MMP cleavage regulation. We further demonstrate structure-guided and disease-associated mutations disrupt proteolytic regulation using a cell-surface proteolysis assay. Thus disrupted proteolysis is a potentially relevant mechanism for "breaking" the DGC link to contribute to disease pathogenesis.
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Affiliation(s)
- Michael J M Anderson
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA
| | - Amanda N Hayward
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA
| | - Adam T Smiley
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA
| | - Ke Shi
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA
| | - Matthew R Pawlak
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA
| | - Eric J Aird
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA; Currently at Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Eva Grant
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA
| | - Lauren Greenberg
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA
| | - Hideki Aihara
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA
| | - Robert L Evans
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA
| | - Christopher Ulens
- Department of Cellular and Molecular Medicine, Karolinksa University Leuven, 3000 Leuven, Belgium
| | - Wendy R Gordon
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA.
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Wang J, Yang J, Narang A, He J, Wolfgang C, Li K, Zheng L. Consensus, debate, and prospective on pancreatic cancer treatments. J Hematol Oncol 2024; 17:92. [PMID: 39390609 PMCID: PMC11468220 DOI: 10.1186/s13045-024-01613-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 09/25/2024] [Indexed: 10/12/2024] Open
Abstract
Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite the improvement of multi-modality treatment strategies, the prognosis of pancreatic cancer was not improved dramatically. For resectable or borderline resectable patients, the surgical strategy centered on improving R0 resection rate is consensus; however, the role of neoadjuvant therapy in resectable patients and the optimal neoadjuvant therapy of chemotherapy with or without radiotherapy in borderline resectable patients were debated. Postoperative adjuvant chemotherapy of gemcitabine/capecitabine or mFOLFIRINOX is recommended regardless of the margin status. Chemotherapy as the first-line treatment strategy for advanced or metastatic patients included FOLFIRINOX, gemcitabine/nab-paclitaxel, or NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan was the only standard of care second-line therapy. Immunotherapy is an innovative therapy although anti-PD-1 antibody is currently the only agent approved by for MSI-H, dMMR, or TMB-high solid tumors, which represent a very small subset of pancreatic cancers. Combination strategies to increase the immunogenicity and to overcome the immunosuppressive tumor microenvironment may sensitize pancreatic cancer to immunotherapy. Targeted therapies represented by PARP and KRAS inhibitors are also under investigation, showing benefits in improving progression-free survival and objective response rate. This review discusses the current treatment modalities and highlights innovative therapies for pancreatic cancer.
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Affiliation(s)
- Junke Wang
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Jie Yang
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Amol Narang
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Jin He
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Christopher Wolfgang
- Department of Surgery, New York University School of Medicine and NYU-Langone Medical Center, New York, NY, USA
| | - Keyu Li
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA.
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA.
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- The Multidisciplinary Gastrointestinal Cancer Laboratories Program, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
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Kang MJ, Li HX, Gan Y, Fang C, Yang XL, Li B, Su S. Efficacy and safety of first-line chemotherapies for patients with advanced pancreatic ductal adenocarcinoma: A systematic review and network meta-analysis. Heliyon 2024; 10:e27679. [PMID: 38681566 PMCID: PMC11046077 DOI: 10.1016/j.heliyon.2024.e27679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 02/05/2024] [Accepted: 03/05/2024] [Indexed: 05/01/2024] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, often diagnosed at an advanced stage. Systemic chemotherapy is the primary treatment, but direct comparisons of different regimens are limited. This study conducted a systematic review and network meta-analysis (NMA) to compare the efficacy and safety of various chemotherapy regimens, with the unique advantage of only including Phase III randomized controlled trials (RCTs). Methods NMA was conducted regarding the searched phase III RCTs by comparing overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of different chemotherapy protocols. Results The analysis included 24 studies with 11470 patients across 25 treatment modalities. Among the chemotherapy regimens evaluated, FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) demonstrated the highest OS and PFS, with a risk ratio (logHR) of 4.5 (95 % confidence interval 4.32-4.68) compared to gemcitabine monotherapy. The PEFG regimen (cisplatin, epirubicin, 5-fluorouracil, and gemcitabine) exhibited the highest ORR, with an odds ratio (OR) of 6.67 (2.08-20) compared to gemcitabine monotherapy. Notably, gemcitabine plus sorafenib was associated with the lowest hematological toxicity, with an odds ratio (OR) of 0.1 (0.02-0.48). Conclusion Combination therapies may offer greater benefits but also cause more toxic effects. However, combinations with targeted agents seem to have fewer adverse reactions.
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Affiliation(s)
| | | | - Yu Gan
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Sichuan, China
| | - Cheng Fang
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Sichuan, China
| | - Xiao-Li Yang
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Sichuan, China
| | - Bo Li
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Sichuan, China
| | - Song Su
- Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Sichuan, China
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Silva LGDO, Lemos FFB, Luz MS, Rocha Pinheiro SL, Calmon MDS, Correa Santos GL, Rocha GR, de Melo FF. New avenues for the treatment of immunotherapy-resistant pancreatic cancer. World J Gastrointest Oncol 2024; 16:1134-1153. [PMID: 38660642 PMCID: PMC11037047 DOI: 10.4251/wjgo.v16.i4.1134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 01/26/2024] [Accepted: 03/04/2024] [Indexed: 04/10/2024] Open
Abstract
Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53, and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.
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Affiliation(s)
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Mariana dos Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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7
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Hartupee C, Nagalo BM, Chabu CY, Tesfay MZ, Coleman-Barnett J, West JT, Moaven O. Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target. Front Immunol 2024; 15:1287459. [PMID: 38361931 PMCID: PMC10867137 DOI: 10.3389/fimmu.2024.1287459] [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: 09/01/2023] [Accepted: 01/04/2024] [Indexed: 02/17/2024] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths in the United States. Limitations in early detection and treatment barriers contribute to the lack of substantial success in the treatment of this challenging-to-treat malignancy. Desmoplasia is the hallmark of PDAC microenvironment that creates a physical and immunologic barrier. Stromal support cells and immunomodulatory cells face aberrant signaling by pancreatic cancer cells that shifts the complex balance of proper repair mechanisms into a state of dysregulation. The product of this dysregulation is the desmoplastic environment that encases the malignant cells leading to a dense, hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance, and suppresses anti-tumor immune invasion. This desmoplastic environment combined with the immunoregulatory events that allow it to persist serve as the primary focus of this review. The physical barrier and immune counterbalance in the tumor microenvironment (TME) make PDAC an immunologically cold tumor. To convert PDAC into an immunologically hot tumor, tumor microenvironment could be considered alongside the tumor cells. We discuss the complex network of microenvironment molecular and cellular composition and explore how they can be targeted to overcome immuno-therapeutic challenges.
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Affiliation(s)
- Conner Hartupee
- Division of Surgical Oncology, Department of Surgery, Louisiana State University (LSU) Health, New Orleans, LA, United States
| | - Bolni Marius Nagalo
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
- The Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Chiswili Y. Chabu
- Division of Biological Sciences, University of Missouri, Columbia, MO, United States
- Department of Surgery, School of Medicine, University of Missouri, Columbia, MO, United States
- Siteman Cancer Center, Washington University, St. Louis, MO, United States
| | - Mulu Z. Tesfay
- Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, United States
| | - Joycelynn Coleman-Barnett
- Division of Surgical Oncology, Department of Surgery, Louisiana State University (LSU) Health, New Orleans, LA, United States
- Department of Interdisciplinary Oncology, Louisiana Cancer Research Center, Louisiana State University (LSU) Health, New Orleans, LA, United States
| | - John T. West
- Department of Interdisciplinary Oncology, Louisiana Cancer Research Center, Louisiana State University (LSU) Health, New Orleans, LA, United States
| | - Omeed Moaven
- Division of Surgical Oncology, Department of Surgery, Louisiana State University (LSU) Health, New Orleans, LA, United States
- Department of Interdisciplinary Oncology, Louisiana Cancer Research Center, Louisiana State University (LSU) Health, New Orleans, LA, United States
- Louisiana State University - Louisiana Children's Medical Center (LSU - LCMC) Cancer Center, New Orleans, LA, United States
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Afshar K, Sanaei MJ, Ravari MS, Pourbagheri-Sigaroodi A, Bashash D. An overview of extracellular matrix and its remodeling in the development of cancer and metastasis with a glance at therapeutic approaches. Cell Biochem Funct 2023; 41:930-952. [PMID: 37665068 DOI: 10.1002/cbf.3846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 08/16/2023] [Accepted: 08/21/2023] [Indexed: 09/05/2023]
Abstract
The extracellular matrix (ECM) is an inevitable part of tissues able to provide structural support for cells depending on the purpose of tissues and organs. The dynamic characteristics of ECM let this system fluently interact with the extrinsic triggers and get stiffed, remodeled, and/or degraded ending in maintaining tissue homeostasis. ECM could serve as the platform for cancer progression. The dysregulation of biochemical and biomechanical ECM features might take participate in some pathological conditions such as aging, tissue destruction, fibrosis, and particularly cancer. Tumors can reprogram how ECM remodels by producing factors able to induce protein synthesis, matrix proteinase expression, degradation of the basement membrane, growth signals and proliferation, angiogenesis, and metastasis. Therefore, targeting the ECM components, their secretion, and their interactions with other cells or tumors could be a promising strategy in cancer therapies. The present study initially introduces the physiological functions of ECM and then discusses how tumor-dependent dysregulation of ECM could facilitate cancer progression and ends with reviewing the novel therapeutic strategies regarding ECM.
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Affiliation(s)
- Kimiya Afshar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrnaz Sadat Ravari
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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9
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Shoari A, Khalili-Tanha G, Coban MA, Radisky ES. Structure and computation-guided yeast surface display for the evolution of TIMP-based matrix metalloproteinase inhibitors. Front Mol Biosci 2023; 10:1321956. [PMID: 38074088 PMCID: PMC10702220 DOI: 10.3389/fmolb.2023.1321956] [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: 10/15/2023] [Accepted: 11/13/2023] [Indexed: 01/03/2024] Open
Abstract
The study of protein-protein interactions (PPIs) and the engineering of protein-based inhibitors often employ two distinct strategies. One approach leverages the power of combinatorial libraries, displaying large ensembles of mutant proteins, for example, on the yeast cell surface, to select binders. Another approach harnesses computational modeling, sifting through an astronomically large number of protein sequences and attempting to predict the impact of mutations on PPI binding energy. Individually, each approach has inherent limitations, but when combined, they generate superior outcomes across diverse protein engineering endeavors. This synergistic integration of approaches aids in identifying novel binders and inhibitors, fine-tuning specificity and affinity for known binding partners, and detailed mapping of binding epitopes. It can also provide insight into the specificity profiles of varied PPIs. Here, we outline strategies for directing the evolution of tissue inhibitors of metalloproteinases (TIMPs), which act as natural inhibitors of matrix metalloproteinases (MMPs). We highlight examples wherein design of combinatorial TIMP libraries using structural and computational insights and screening these libraries of variants using yeast surface display (YSD), has successfully optimized for MMP binding and selectivity, and conferred insight into the PPIs involved.
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Affiliation(s)
| | | | | | - Evette S. Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, United States
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10
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Hau SO, Svensson M, Petersson A, Eberhard J, Jirström K. Trajectories of immune-related serum proteins and quality of life in patients with pancreatic and other periampullary cancer: the CHAMP study. BMC Cancer 2023; 23:1074. [PMID: 37936126 PMCID: PMC10629201 DOI: 10.1186/s12885-023-11562-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/24/2023] [Indexed: 11/09/2023] Open
Abstract
BACKGROUND There is still a profound lack of efficient therapeutic strategies against pancreatic and other periampullary adenocarcinoma. Surgery is seldom possible, leaving palliative chemotherapy the only option for most patients. Chemotherapy treatment is however often accompanied by serious side-effects, and the identification of biomarkers for early prediction of disease and treatment-associated symptoms could help alleviate patient suffering. This study investigated the dynamic interrelationship between immune-related serum proteins, routine biomarkers, and health-related quality of life (HRQoL) factors during chemotherapy treatment of patients enrolled in the prospective, observational study Chemotherapy, Host response And Molecular dynamics in Periampullary cancer (CHAMP). METHODS Proximity extension assay was applied to analyse 92 immune-associated proteins in longitudinal serum samples from 75 patients, 18 treated with curative and 57 with palliative intent. HRQoL data were available from all patients at baseline (BL), from 41 patients at three months, and from 23 patients at six months. Information on routine laboratory parameters albumin, CA19-9, CEA and CRP were collected from medical charts. RESULTS In total nine proteins; chemokine (C-C motif) ligand 23 (CCL23), cluster of differentiation 4 (CD4), cluster of differentiation 28 (CD28), decorin (DCN), galectin-1 (Gal-1), granzyme B (GZMB), granzyme H (GZMH), matrix metallopeptidase 7 (MMP7), and monocyte chemotactic protein-1 (MCP-1) were strongly correlated (Spearman's Rho ≤ -0.6 or ≥ 0.6) with either cognitive functioning (DCN), emotional functioning (DCN, MCP-1), dyspnoea (CD28, GZMB, GZMH) or insomnia (CCL23, CD4, Gal-1, MMP7) during treatment. Associations between routine laboratory parameters (CA 19-9, CA-125, CRP, CEA and albumin) and HRQoL factors were overall weaker. None of the investigated proteins were associated with pain. CONCLUSIONS This is, to our knowledge, the first study exploring associations between serum biomarkers and HRQoL in patients with pancreatic or other periampullary cancer, and some findings merit further validation. The associations of DCN and MCP-1with impaired cognitive and/or emotional functioning are of particular interest, given their established link to various neurodegenerative conditions. Chemotherapy is known to cause persistent cognitive dysfunction with effects on memory and executive function, referred to as "chemo brain". It would therefore be of great value to identify biomarkers for early detection and management of this debilitating condition. TRIAL REGISTRATION Clinical Trial Registration: NCT03724994.
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Affiliation(s)
- Sofie Olsson Hau
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
| | - Maja Svensson
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Alexandra Petersson
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Jakob Eberhard
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Karin Jirström
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
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11
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Fang YT, Yang WW, Niu YR, Sun YK. Recent advances in targeted therapy for pancreatic adenocarcinoma. World J Gastrointest Oncol 2023; 15:571-595. [PMID: 37123059 PMCID: PMC10134207 DOI: 10.4251/wjgo.v15.i4.571] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/11/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%–90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC – erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.
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Affiliation(s)
- Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang 065001, Hebei Province, China
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12
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Liu Y, Wu X, Chen F, Li H, Wang T, Liu N, Sun K, Zhou G, Tao K. Modulating cancer-stroma crosstalk by a nanoparticle-based photodynamic method to pave the way for subsequent therapies. Biomaterials 2022; 289:121813. [PMID: 36152513 DOI: 10.1016/j.biomaterials.2022.121813] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/02/2022]
Abstract
Cancer cells and their stromal microenvironment are mutually supportive. Either destroying cancer cells or damaging stromal components cannot guarantee a satisfactory outcome in the long-term treatment. Herein, we showed that the tumor-stroma crosstalk was disturbed by nanoparticle-based photodynamic therapy (PDT) in pancreatic tumor models, leading to the persistent inhibition of extracellular matrix (ECM) secretion and the enhanced therapeutic effect. By employing a conditioned medium method, we found that the nanoparticulate PDT at a sub-lethal dosage down-regulated TGFβ signaling pathways, leading to the decrease in drug resistance, proliferation, and migration of the cancer cells. Meanwhile, pancreatic stellate cells (PSCs) were inactivated by PDT, hindering the secretion of ECM. Combining the results that PDT indiscriminately killed PSCs and cancer cells, we showed that the mutual support between the cancer cells and the stroma was interrupted. We further presented the inhibition of the crosstalk persistently enhanced tumor penetration in stroma-rich pancreatic tumor models. The loosened stroma not only facilitated tumor eradication by subsequent therapy but also improved the efficiency of gemcitabine treatment on monthly later recurrent tumors. Therefore, our work may boost the potential of PDT to be a valuable individual or adjuvant treatment for desmoplastic cancers.
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Affiliation(s)
- Yan Liu
- Shanghai Key Laboratory of Tissue Engineering, Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China; State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, PR China
| | - Xiaodi Wu
- Research Institute of Plastic Surgery, Wei Fang Medical College, Wei Fang, Shandong, 261042, PR China
| | - Feifan Chen
- Research Institute of Plastic Surgery, Wei Fang Medical College, Wei Fang, Shandong, 261042, PR China
| | - Hao Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Tao Wang
- Research Institute of Plastic Surgery, Wei Fang Medical College, Wei Fang, Shandong, 261042, PR China
| | - Ningning Liu
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, PR China
| | - Kang Sun
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
| | - Guangdong Zhou
- Shanghai Key Laboratory of Tissue Engineering, Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China; Research Institute of Plastic Surgery, Wei Fang Medical College, Wei Fang, Shandong, 261042, PR China.
| | - Ke Tao
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
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13
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Yamaguchi K, Yoshihiro T, Ariyama H, Ito M, Nakano M, Semba Y, Nogami J, Tsuchihashi K, Yamauchi T, Ueno S, Isobe T, Shindo K, Moriyama T, Ohuchida K, Nakamura M, Nagao Y, Ikeda T, Hashizume M, Konomi H, Torisu T, Kitazono T, Kanayama T, Tomita H, Oda Y, Kusaba H, Maeda T, Akashi K, Baba E. Potential therapeutic targets discovery by transcriptome analysis of an in vitro human gastric signet ring carcinoma model. Gastric Cancer 2022; 25:862-878. [PMID: 35661943 DOI: 10.1007/s10120-022-01307-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 05/13/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. METHODS To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). RESULTS CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. CONCLUSIONS E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.
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Affiliation(s)
- Kyoko Yamaguchi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Tomoyasu Yoshihiro
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hiroshi Ariyama
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Mamoru Ito
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Michitaka Nakano
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yuichiro Semba
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Jumpei Nogami
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kenji Tsuchihashi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takuji Yamauchi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Shohei Ueno
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Taichi Isobe
- Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Shindo
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Taiki Moriyama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Nagao
- Department of Advanced Medicine and Innovative Technology, Kyushu University Hospital, Fukuoka, Japan
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tetsuo Ikeda
- Department of Advanced Medicine and Innovative Technology, Kyushu University Hospital, Fukuoka, Japan
| | - Makoto Hashizume
- Department of Advanced Medicine and Innovative Technology, Kyushu University Hospital, Fukuoka, Japan
| | | | - Takehiro Torisu
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomohiro Kanayama
- Department of Tumor Pathology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hitoshi Kusaba
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takahiro Maeda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Eishi Baba
- Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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14
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Gumberger P, Bjornsson B, Sandström P, Bojmar L, Zambirinis CP. The Liver Pre-Metastatic Niche in Pancreatic Cancer: A Potential Opportunity for Intervention. Cancers (Basel) 2022; 14:3028. [PMID: 35740692 PMCID: PMC9221452 DOI: 10.3390/cancers14123028] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/30/2022] [Accepted: 06/11/2022] [Indexed: 12/16/2022] Open
Abstract
Cancer-related mortality is primarily a consequence of metastatic dissemination and associated complications. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and tends to metastasize early, especially in the liver. Emerging evidence suggests that organs that develop metastases exhibit microscopic changes that favor metastatic growth, collectively known as "pre-metastatic niches". By definition, a pre-metastatic niche is chronologically established before overt metastatic outgrowth, and its generation involves the release of tumor-derived secreted factors that modulate cells intrinsic to the recipient organ, as well as recruitment of additional cells from tertiary sites, such as bone marrow-all orchestrated by the primary tumor. The pre-metastatic niche is characterized by tumor-promoting inflammation with tumor-supportive and immune-suppressive features, remodeling of the extracellular matrix, angiogenic modulation and metabolic alterations that support growth of disseminated tumor cells. In this paper, we review the current state of knowledge of the hepatic pre-metastatic niche in PDAC and attempt to create a framework to guide future diagnostic and therapeutic studies.
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Affiliation(s)
- Peter Gumberger
- Department of Surgery, Linköping University, 58183 Linköping, Sweden; (P.G.); (B.B.); (P.S.)
- Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden;
| | - Bergthor Bjornsson
- Department of Surgery, Linköping University, 58183 Linköping, Sweden; (P.G.); (B.B.); (P.S.)
- Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden;
| | - Per Sandström
- Department of Surgery, Linköping University, 58183 Linköping, Sweden; (P.G.); (B.B.); (P.S.)
- Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden;
| | - Linda Bojmar
- Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden;
- Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021, USA
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15
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an intractable cancer and a leading cause of cancer deaths worldwide. Over 90% of patients die within 1 year of diagnosis. Deaths from PDAC are increasing and it remains a cancer of substantial unmet need. A number of factors contribute to its poor prognosis: namely, late presentation, early metastases and limited systemic therapy options because of chemoresistance. A variety of research approaches underway are aimed at improving patient survival. Here, we review high-risk groups and efforts for early detection. We examine recent developments in the understanding of complex molecular and metabolic alterations which accompany PDAC. We explore artificial intelligence and biological targets for therapy and examine the role of tumour stroma and the immune microenvironment. We also review recent developments with respect to the PDAC microbiome. It is hoped that current research efforts will translate into earlier diagnosis, improvements in treatment and better outcomes for patients.
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Affiliation(s)
- Martyn C Stott
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Lucy Oldfield
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Jessica Hale
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Eithne Costello
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Christopher M Halloran
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
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16
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Opitz FV, Haeberle L, Daum A, Esposito I. Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia. Cancers (Basel) 2021; 13:cancers13246188. [PMID: 34944807 PMCID: PMC8699458 DOI: 10.3390/cancers13246188] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive neoplasm with a poor survival rate. This is mainly due to late detection, which substantially limits therapy options. A better understanding of the early phases of pancreatic carcinogenesis is fundamental for improving patient prognosis in the future. In this article, we focused on the tumor microenvironment (TME), which provides the biological niche for the development of PDAC from its most common precursor lesions, PanIN (pancreatic intraepithelial neoplasias). Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression.
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17
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Structure-based molecular insights into matrix metalloproteinase inhibitors in cancer treatments. Future Med Chem 2021; 14:35-51. [PMID: 34779649 DOI: 10.4155/fmc-2021-0246] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Protease inhibitors are of considerable interest as anticancer agents. Matrix metalloproteinases (MMPs) were the earliest type of proteases considered as anticancer targets. The developments of MMP inhibitors (MMPIs) by pharmaceutical companies can be dated from the early 1980s. Thus far, none of the over 50 MMPIs entering clinical trials have been approved. This work summarizes the reported studies on the structure of MMPs and complexes with ligands and inhibitors, based on which, the authors analyzed the clinical failures of MMPIs in a structural biological manner. Furthermore, MMPs were systematically compared with urokinase, a protease-generating plasmin, which plays similar pathological roles in cancer development; the reasons for the clinical successes of urokinase inhibitors and the clinical failures of MMPIs are discussed.
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18
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Truong LH, Pauklin S. Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches. Cancers (Basel) 2021; 13:5028. [PMID: 34638513 PMCID: PMC8507722 DOI: 10.3390/cancers13195028] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/01/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research.
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Affiliation(s)
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK;
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Ferrara B, Pignatelli C, Cossutta M, Citro A, Courty J, Piemonti L. The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options. Cancers (Basel) 2021; 13:cancers13174442. [PMID: 34503252 PMCID: PMC8430646 DOI: 10.3390/cancers13174442] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 01/18/2023] Open
Abstract
The stroma is a relevant player in driving and supporting the progression of pancreatic ductal adenocarcinoma (PDAC), and a large body of evidence highlights its role in hindering the efficacy of current therapies. In fact, the dense extracellular matrix (ECM) characterizing this tumor acts as a natural physical barrier, impairing drug penetration. Consequently, all of the approaches combining stroma-targeting and anticancer therapy constitute an appealing option for improving drug penetration. Several strategies have been adopted in order to target the PDAC stroma, such as the depletion of ECM components and the targeting of cancer-associated fibroblasts (CAFs), which are responsible for the increased matrix deposition in cancer. Additionally, the leaky and collapsing blood vessels characterizing the tumor might be normalized, thus restoring blood perfusion and allowing drug penetration. Even though many stroma-targeting strategies have reported disappointing results in clinical trials, the ECM offers a wide range of potential therapeutic targets that are now being investigated. The dense ECM might be bypassed by implementing nanoparticle-based systems or by using mesenchymal stem cells as drug carriers. The present review aims to provide an overview of the principal mechanisms involved in the ECM remodeling and of new promising therapeutic strategies for PDAC.
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Affiliation(s)
- Benedetta Ferrara
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
| | - Cataldo Pignatelli
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
| | - Mélissande Cossutta
- INSERM U955, Immunorégulation et Biothérapie, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris-Est Créteil, 94010 Créteil, France; (M.C.); (J.C.)
- AP-HP, Centre d’Investigation Clinique Biothérapie, Groupe Hospitalo-Universitaire Chenevier Mondor, 94010 Créteil, France
| | - Antonio Citro
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
| | - José Courty
- INSERM U955, Immunorégulation et Biothérapie, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris-Est Créteil, 94010 Créteil, France; (M.C.); (J.C.)
- AP-HP, Centre d’Investigation Clinique Biothérapie, Groupe Hospitalo-Universitaire Chenevier Mondor, 94010 Créteil, France
| | - Lorenzo Piemonti
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
- Correspondence:
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Heumann T, Azad N. Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance. Cancer Metastasis Rev 2021; 40:837-862. [PMID: 34591243 PMCID: PMC9804001 DOI: 10.1007/s10555-021-09981-3] [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: 06/02/2021] [Accepted: 07/26/2021] [Indexed: 01/03/2023]
Abstract
To date, the use of immune checkpoint inhibitors has proven largely ineffective in patients with advanced pancreatic ductal adenocarcinoma. A combination of low tumor antigenicity, deficits in immune activation along with an exclusive and suppressive tumor microenvironment result in resistance to host defensives. However, a deepening understanding of these immune escape and suppressive mechanisms has led to the discovery of novel molecular targets and treatment strategies that may hold the key to a long-awaited therapeutic breakthrough. In this review, we describe the tumor-intrinsic and microenvironmental barriers to modern immunotherapy, examine novel immune-based and targeted modalities, summarize relevant pre-clinical findings and human experience, and, finally, discuss novel synergistic approaches to overcome immune-resistance in pancreatic cancer. Beyond checkpoint inhibition, immune agonists and anti-tumor vaccines represent promising strategies to stimulate host response via activation and expansion of anti-tumor immune effectors. Off-the-shelf natural killer cell therapies may offer an effective method for bypassing downregulated tumor antigen presentation. In parallel with this, sophisticated targeting of crosstalk between tumor and tumor-associated immune cells may lead to enhanced immune infiltration and survival of anti-tumor lymphocytes. A future multimodal treatment strategy involving immune priming/activation, tumor microenvironment reprogramming, and immune checkpoint blockade may help transform pancreatic cancer into an immunogenic tumor.
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Affiliation(s)
- Thatcher Heumann
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nilofer Azad
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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21
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Das S, Amin SA, Jha T. Inhibitors of gelatinases (MMP-2 and MMP-9) for the management of hematological malignancies. Eur J Med Chem 2021; 223:113623. [PMID: 34157437 DOI: 10.1016/j.ejmech.2021.113623] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/18/2021] [Accepted: 06/03/2021] [Indexed: 12/30/2022]
Abstract
Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are collectively known as gelatinases whereas MMP-2 is gelatinase-A and MMP-9 is termed as gelatinase-B. Gelatinases and other matrix metalloproteinases (MMPs) have long been associated with solid tumor invasion, metastasis and angiogenesis. However, there is paucity of data available regarding the role of gelatinases in hematological malignancies. Recent studies have shown that gelatinases activities or functions are correlated with hematological malignancies. Strategies for designing more specific gelatinase inhibitors like catalytic (CAT) domain inhibitors and hemopexin (PEX) domain inhibitors as well as signaling pathway based or gelatinase expression inhibitors had been reported against hematologic malignant cells. Several substrate based non-selective to non-substrate based relatively selective synthetic matrix metalloproteinase inhibitors (MMPIs) had been developed. Few MMPIs had reached in clinical trials during the period of 1990s-2000s. Unfortunately the anti-tumor and anti-metastatic efficacies of these MMPIs were not justified with patients having several advanced stage solid tumor cancers in any substantial number of clinical trials. Till date not a single MMPI passed phase III clinical trials designed for advanced metastatic cancers due to adverse events as well as lack of ability to show uniformity in disease prolongation. With the best of our knowledge no clinical trial study has been reported with small molecule synthetic inhibitors against hematological malignancies. This review looks at the outcome of clinical trials of MMPIs for advanced stage solid tumors. This can therefore, act as a learning experience for future development of successful gelatinase inhibitors for the management of hematological malignancies.
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Affiliation(s)
- Sanjib Das
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India.
| | - Sk Abdul Amin
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India.
| | - Tarun Jha
- Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India.
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22
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Polani F, Grierson PM, Lim KH. Stroma-targeting strategies in pancreatic cancer: Past lessons, challenges and prospects. World J Gastroenterol 2021; 27:2105-2121. [PMID: 34025067 PMCID: PMC8117738 DOI: 10.3748/wjg.v27.i18.2105] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/09/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is projected to emerge as the second leading cause of cancer-related death after 2030. Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC. To date, combination chemotherapy remains the mainstay of treatment for most PDAC patients. Compared to other cancer types, treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorter-lived. Aside from typically harboring genetic alterations that to date remain un-druggable and are drivers of treatment resistance, PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance. However, emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes. These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression. The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells, stromal fibroblasts, and immune cells. This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease. Here, we provide a concise review on lessons learned from past stroma-targeting strategies, new challenges revealed from recent preclinical and clinical studies, as well as new prospects in the treatment of PDAC.
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Affiliation(s)
- Faran Polani
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, United States
| | - Patrick M Grierson
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, United States
| | - Kian-Huat Lim
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, United States
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Abstract
The extracellular matrix is a fundamental, core component of all tissues and organs, and is essential for the existence of multicellular organisms. From the earliest stages of organism development until death, it regulates and fine-tunes every cellular process in the body. In cancer, the extracellular matrix is altered at the biochemical, biomechanical, architectural and topographical levels, and recent years have seen an exponential increase in the study and recognition of the importance of the matrix in solid tumours. Coupled with the advancement of new technologies to study various elements of the matrix and cell-matrix interactions, we are also beginning to see the deployment of matrix-centric, stromal targeting cancer therapies. This Review touches on many of the facets of matrix biology in solid cancers, including breast, pancreatic and lung cancer, with the aim of highlighting some of the emerging interactions of the matrix and influences that the matrix has on tumour onset, progression and metastatic dissemination, before summarizing the ongoing work in the field aimed at developing therapies to co-target the matrix in cancer and cancer metastasis.
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Affiliation(s)
- Thomas R Cox
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia.
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24
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Liu X, Li Z, Wang Y. Advances in Targeted Therapy and Immunotherapy for Pancreatic Cancer. Adv Biol (Weinh) 2021; 5:e1900236. [PMID: 33729700 DOI: 10.1002/adbi.201900236] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 08/19/2020] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is a highly aggressive malignancy with an overall 5-year survival rate of <6% due to therapeutic resistance and late-stage diagnosis. These statistics have not changed despite 50 years of research and therapeutic development. Pancreatic cancer is predicted to become the second leading cause of cancer mortality by the year 2030. Currently, the treatment options for pancreatic cancer are limited. This disease is usually diagnosed at a late stage, which prevents curative surgical resection. Chemotherapy is the most frequently used approach for pancreatic cancer treatment and has limited effects. In many other cancer types, targeted therapy and immunotherapy have made great progress and have been shown to be very promising prospects; these treatments also provide hope for pancreatic cancer. The need for research on targeted therapy and immunotherapy is pressing due to the poor prognosis of pancreatic cancer, and in recent years, there have been some breakthroughs for targeted therapy and immunotherapy in pancreatic cancer. This review summarizes the current preclinical and clinical studies of targeted therapy and immunotherapy for pancreatic cancer and ends by describing the challenges and outlook.
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Affiliation(s)
- Xiaoxiao Liu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhang Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuexiang Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
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25
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Ouellette JN, Drifka CR, Pointer KB, Liu Y, Lieberthal TJ, Kao WJ, Kuo JS, Loeffler AG, Eliceiri KW. Navigating the Collagen Jungle: The Biomedical Potential of Fiber Organization in Cancer. Bioengineering (Basel) 2021; 8:17. [PMID: 33494220 PMCID: PMC7909776 DOI: 10.3390/bioengineering8020017] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 01/10/2021] [Accepted: 01/13/2021] [Indexed: 02/07/2023] Open
Abstract
Recent research has highlighted the importance of key tumor microenvironment features, notably the collagen-rich extracellular matrix (ECM) in characterizing tumor invasion and progression. This led to great interest from both basic researchers and clinicians, including pathologists, to include collagen fiber evaluation as part of the investigation of cancer development and progression. Fibrillar collagen is the most abundant in the normal extracellular matrix, and was revealed to be upregulated in many cancers. Recent studies suggested an emerging theme across multiple cancer types in which specific collagen fiber organization patterns differ between benign and malignant tissue and also appear to be associated with disease stage, prognosis, treatment response, and other clinical features. There is great potential for developing image-based collagen fiber biomarkers for clinical applications, but its adoption in standard clinical practice is dependent on further translational and clinical evaluations. Here, we offer a comprehensive review of the current literature of fibrillar collagen structure and organization as a candidate cancer biomarker, and new perspectives on the challenges and next steps for researchers and clinicians seeking to exploit this information in biomedical research and clinical workflows.
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Affiliation(s)
- Jonathan N. Ouellette
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA; (J.N.O.); (C.R.D.); (T.J.L.); (W.J.K.)
- Laboratory for Optical and Computational Instrumentation, Center for Quantitative Cell Imaging, University of Wisconsin-Madison, Madison, WI 53706, USA; (K.B.P.); (Y.L.)
| | - Cole R. Drifka
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA; (J.N.O.); (C.R.D.); (T.J.L.); (W.J.K.)
- Laboratory for Optical and Computational Instrumentation, Center for Quantitative Cell Imaging, University of Wisconsin-Madison, Madison, WI 53706, USA; (K.B.P.); (Y.L.)
| | - Kelli B. Pointer
- Laboratory for Optical and Computational Instrumentation, Center for Quantitative Cell Imaging, University of Wisconsin-Madison, Madison, WI 53706, USA; (K.B.P.); (Y.L.)
| | - Yuming Liu
- Laboratory for Optical and Computational Instrumentation, Center for Quantitative Cell Imaging, University of Wisconsin-Madison, Madison, WI 53706, USA; (K.B.P.); (Y.L.)
| | - Tyler J Lieberthal
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA; (J.N.O.); (C.R.D.); (T.J.L.); (W.J.K.)
| | - W John Kao
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA; (J.N.O.); (C.R.D.); (T.J.L.); (W.J.K.)
- Department of Industrial and Manufacturing Systems Engineering, Faculty of Engineering, University of Hong Kong, Pokfulam, Hong Kong
| | - John S. Kuo
- Department of Neurosurgery, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA;
| | - Agnes G. Loeffler
- Department of Pathology, MetroHealth Medical Center, Cleveland, OH 44109, USA;
| | - Kevin W. Eliceiri
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA; (J.N.O.); (C.R.D.); (T.J.L.); (W.J.K.)
- Laboratory for Optical and Computational Instrumentation, Center for Quantitative Cell Imaging, University of Wisconsin-Madison, Madison, WI 53706, USA; (K.B.P.); (Y.L.)
- Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705, USA
- Morgridge Institute for Research, Madison, WI 53715, USA
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Das N, Benko C, Gill SE, Dufour A. The Pharmacological TAILS of Matrix Metalloproteinases and Their Inhibitors. Pharmaceuticals (Basel) 2020; 14:ph14010031. [PMID: 33396445 PMCID: PMC7823758 DOI: 10.3390/ph14010031] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 12/27/2020] [Accepted: 12/28/2020] [Indexed: 01/07/2023] Open
Abstract
Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches, such as proteomics and N-terminomics, to identify new MMP substrates. We present some examples of new MMP substrates and their implications in regulating biological functions. By characterizing the roles and substrates of individual MMP, MMP inhibitors could be utilized more effectively in the optimal disease context or in diseases never tested before where MMP activity is elevated and contributing to disease progression.
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Affiliation(s)
- Nabangshu Das
- Faculty of Kinesiology, University of Calgary, Calgary, AB T2N 4N1, Canada;
- McCaig Institute for Bone and Join Healthy, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada;
| | - Colette Benko
- McCaig Institute for Bone and Join Healthy, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada;
- Department of Physiology and Pharmacology, Cumming School of Medicine, Foothills Hospital, 3330 Hospital Dr, Calgary, AB T2N 4N1, Canada
| | - Sean E. Gill
- Centre for Critical Illness Research, Victoria Research Labs, Lawson Health Research Institute, A6-134, London, ON N6A 5W9, Canada;
- Division of Respirology, Department of Medicine, Western University, London, ON N6A 5W9, Canada
| | - Antoine Dufour
- Faculty of Kinesiology, University of Calgary, Calgary, AB T2N 4N1, Canada;
- McCaig Institute for Bone and Join Healthy, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada;
- Department of Physiology and Pharmacology, Cumming School of Medicine, Foothills Hospital, 3330 Hospital Dr, Calgary, AB T2N 4N1, Canada
- Correspondence:
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27
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Aloizou AM, Pateraki G, Siokas V, Mentis AFA, Liampas I, Lazopoulos G, Kovatsi L, Mitsias PD, Bogdanos DP, Paterakis K, Dardiotis E. The role of MiRNA-21 in gliomas: Hope for a novel therapeutic intervention? Toxicol Rep 2020; 7:1514-1530. [PMID: 33251119 PMCID: PMC7677650 DOI: 10.1016/j.toxrep.2020.11.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/30/2020] [Accepted: 11/02/2020] [Indexed: 12/20/2022] Open
Abstract
Gliomas are the most common primary brain tumors in adults. They are generally very resistant to treatment and are therefore associated with negative outcomes. MicroRNAs (miRNAs) are small, non-coding RNA molecules that affect many cellular processes by regulating gene expression and, post-transcriptionally, the translation of mRNAs. MiRNA-21 has been consistently shown to be upregulated in glioma and research has shown that it is involved in a wide variety of biological pathways, promoting tumor cell survival and invasiveness. Furthermore, it has been implicated in resistance to treatment, both against chemotherapy and radiotherapy. In this review, we gathered the existent data on miRNA-21 and gliomas, in terms of its expression levels, association with grade and prognosis, the pathways it involves and its targets in glioma, and finally how it leads to treatment resistance. Furthermore, we discuss how this knowledge could be applied in clinical practice in the years to come. To our knowledge, this is the first review to assess in extent and depth the role of miRNA-21 in gliomas.
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Affiliation(s)
- Athina-Maria Aloizou
- Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece
| | - Georgia Pateraki
- Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece
| | - Vasileios Siokas
- Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece
| | - Alexios-Fotios A Mentis
- Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.,Public Health Laboratories, Hellenic Pasteur Institute, Athens, Greece
| | - Ioannis Liampas
- Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece
| | - George Lazopoulos
- Department of Cardiothoracic Surgery, University General Hospital of Heraklion, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Leda Kovatsi
- Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Panayiotis D Mitsias
- Department of Neurology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, University General Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Viopolis 40500, Larissa, Greece
| | - Konstantinos Paterakis
- Department of Neurosurgery, University of Thessaly, University Hospital of Larissa, Larissa, Greece
| | - Efthimios Dardiotis
- Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece
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28
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Jiang B, Zhou L, Lu J, Wang Y, Liu C, You L, Guo J. Stroma-Targeting Therapy in Pancreatic Cancer: One Coin With Two Sides? Front Oncol 2020; 10:576399. [PMID: 33178608 PMCID: PMC7593693 DOI: 10.3389/fonc.2020.576399] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 09/25/2020] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with one of the worst prognoses worldwide and has an overall 5-year survival rate of only 9%. Although chemotherapy is the recommended treatment for patients with advanced PDAC, its efficacy is not satisfactory. The dense dysplastic stroma of PDAC is a major obstacle to the delivery of chemotherapy drugs and plays an important role in the progression of PDAC. Therefore, stroma-targeting therapy is considered a potential treatment strategy to improve the efficacy of chemotherapy and patient survival. While several preclinical studies have shown encouraging results, the anti-tumor potential of the PDAC stroma has also been revealed, and the extreme depletion might promote tumor progression and undermine patient survival. Therefore, achieving a balance between stromal abundance and depletion might be the further of stroma-targeting therapy. This review summarized the current progress of stroma-targeting therapy in PDAC and discussed the double-edged sword of its therapeutic effects.
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Affiliation(s)
- Bolun Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Lu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yizhi Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengxi Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Junchao Guo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Hessmann E, Buchholz SM, Demir IE, Singh SK, Gress TM, Ellenrieder V, Neesse A. Microenvironmental Determinants of Pancreatic Cancer. Physiol Rev 2020; 100:1707-1751. [DOI: 10.1152/physrev.00042.2019] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) belongs to the most lethal solid tumors in humans. A histological hallmark feature of PDAC is the pronounced tumor microenvironment (TME) that dynamically evolves during tumor progression. The TME consists of different non-neoplastic cells such as cancer-associated fibroblasts, immune cells, endothelial cells, and neurons. Furthermore, abundant extracellular matrix components such as collagen and hyaluronic acid as well as matricellular proteins create a highly dynamic and hypovascular TME with multiple biochemical and physical interactions among the various cellular and acellular components that promote tumor progression and therapeutic resistance. In recent years, intensive research efforts have resulted in a significantly improved understanding of the biology and pathophysiology of the TME in PDAC, and novel stroma-targeted approaches are emerging that may help to improve the devastating prognosis of PDAC patients. However, none of anti-stromal therapies has been approved in patients so far, and there is still a large discrepancy between multiple successful preclinical results and subsequent failure in clinical trials. Furthermore, recent findings suggest that parts of the TME may also possess tumor-restraining properties rendering tailored therapies even more challenging.
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Affiliation(s)
- Elisabeth Hessmann
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Soeren M. Buchholz
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Ihsan Ekin Demir
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Shiv K. Singh
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Thomas M. Gress
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Volker Ellenrieder
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Albrecht Neesse
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
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Ho WJ, Jaffee EM, Zheng L. The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nat Rev Clin Oncol 2020; 17:527-540. [PMID: 32398706 PMCID: PMC7442729 DOI: 10.1038/s41571-020-0363-5] [Citation(s) in RCA: 742] [Impact Index Per Article: 148.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2020] [Indexed: 12/17/2022]
Abstract
Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumours despite the use of multi-agent conventional chemotherapy regimens. Such poor outcomes have fuelled ongoing efforts to exploit the tumour microenvironment (TME) for therapy, but strategies aimed at deconstructing the surrounding desmoplastic stroma and targeting the immunosuppressive pathways have largely failed. In fact, evidence has now shown that the stroma is multi-faceted, which illustrates the complexity of exploring features of the TME as isolated targets. In this Review, we describe ways in which the PDAC microenvironment has been targeted and note the current understanding of the clinical outcomes that have unexpectedly contradicted preclinical observations. We also consider the more sophisticated therapeutic strategies under active investigation - multi-modal treatment approaches and exploitation of biologically integrated targets - which aim to remodel the TME against PDAC.
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Affiliation(s)
- Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center, The Skip Viragh Pancreatic Cancer Center for Clinical Research and Care, and The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elizabeth M Jaffee
- Sidney Kimmel Comprehensive Cancer Center, The Skip Viragh Pancreatic Cancer Center for Clinical Research and Care, and The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lei Zheng
- Sidney Kimmel Comprehensive Cancer Center, The Skip Viragh Pancreatic Cancer Center for Clinical Research and Care, and The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Quality of life of patients with metastatic pancreatic adenocarcinoma initiating first-line chemotherapy in routine practice. BMC Palliat Care 2020; 19:103. [PMID: 32650765 PMCID: PMC7350578 DOI: 10.1186/s12904-020-00610-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 06/30/2020] [Indexed: 02/04/2023] Open
Abstract
Background Despite advances in surgery, radiotherapy, and chemotherapy, pancreatic adenocarcinoma often progresses rapidly and causes death. The physical decline of these patients is expected to impact their quality of life (QoL). Therefore, in addition to objective measures of effectiveness, the evaluation of health-related QoL should be considered a matter of major concern when assessing therapy outcomes. Methods Observational, prospective, multicenter study including patients with metastatic pancreatic adenocarcinoma who started first-line chemotherapy in 12 Spanish centers. Treatment and clinical characteristics were recorded at baseline. Patients’ health-related quality of life, ECOG, and Karnofsky index were measured at baseline, at Days 15 and 30, and every four weeks up to 6 months of chemotherapy. Health-related quality of life was measured using the EORTC-QLQ-C30 and EQ-5D questionnaires. Other endpoints included overall survival and progression-free survival. Results The study sample included 116 patients (median age of 65 years). Mean (SD) scores for the QLQ-C30 global health status scale showed a significant increasing trend throughout the treatment (p = 0.005). Patients with either a Karnofsky index of 70–80 or ECOG 2 showed greater improvement in the QLQ-C30 global health status score than the corresponding groups with better performance status (p ≤ 0.010). Pain, appetite, sleep disturbance, nausea, and constipation significantly improved throughout the treatment (p < 0.005). Patients with QLQ-C30 global health status scores ≥50 at baseline had significantly greater overall survival and progression-free survival (p = 0.005 and p = 0.021, respectively). No significant associations were observed regarding the EQ-5D score. Conclusions Most metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy showed an increase in health-related quality of life scores throughout the treatment. Patients with lower performance status and health-related quality of life at baseline tended to greater improvement. The EORTC QLQ-C30 scale allowed us to measure the health-related quality of life of metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy.
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Lum LG, Thakur A, Choi M, Deol A, Kondadasula V, Schalk D, Fields K, Dufrense M, Philip P, Dyson G, Aon HD, Shields AF. Clinical and immune responses to anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (EGFR BATs) in pancreatic cancer patients. Oncoimmunology 2020; 9:1773201. [PMID: 32939319 PMCID: PMC7480816 DOI: 10.1080/2162402x.2020.1773201] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 05/14/2020] [Accepted: 05/15/2020] [Indexed: 01/05/2023] Open
Abstract
Purpose This was a phase I/II adoptive T cell trial in 7 locally advanced and metastatic pancreatic cancer patients using 3-8 infusions of anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (BATs) to determine safety, the maximum tolerated dose (MTD), immune responses, time to progression (TTP), and overall survival (OS). Study Design: T cells obtained by apheresis were expanded and armed with EGFRBi, cryopreserved for infusions. In a phase I dose escalation, five patients received three weekly infusions of 10-40 × 109 BATs/infusion followed by a booster infusion 3 months later, and 2 patients received 8 infusions twice weekly for 4 weeks in a phase II. The trials were registered at http://www.clinicaltrials.gov, NCT01420874 and NCT02620865. Results: There were no dose-limiting toxicities (DLTs), and the targeted dose of 80 × 109 BATs was met. The median TTP is 7 months, and the median OS is 31 months. Two patients had stable disease for 6.5 and 25+ months, and two patients developed complete responses (CRs) after restarting chemotherapy. Infusions of BATs induced anti-pancreatic cancer cytotoxicity, innate immune responses, cytokine responses (IL-12, IP-10), and shifts in CD4 and CD8 Vβ repertoire with enhanced cytoplasmic IFN-γ staining in the Vβ repertoire of the CD8 subset that suggest specific clonal TCR responses. Conclusions: Infusions of BATs are safe, induce endogenous adaptive anti-tumor responses, and may have a potential to improve overall survival.
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Affiliation(s)
- Lawrence G. Lum
- Stem Cell Transplantation Program, Division of Oncology/Hematology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, USA
| | - Archana Thakur
- Stem Cell Transplantation Program, Division of Oncology/Hematology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, USA
| | - Minsig Choi
- Department of Oncology, Stony Brook University, Stony Brook, NY, USA
| | - Abhinav Deol
- Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA
| | - Vidya Kondadasula
- Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA
| | - Dana Schalk
- Stem Cell Transplantation Program, Division of Oncology/Hematology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, USA
| | - Kristie Fields
- Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA
| | - Melissa Dufrense
- Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA
| | - Philip Philip
- Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA
| | - Gregory Dyson
- Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA
| | - Hussein D. Aon
- Department of Radiology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA
| | - Anthony F. Shields
- Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA
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R S P, Mal A, Valvi SK, Srivastava R, De A, Bandyopadhyaya R. Noninvasive Preclinical Evaluation of Targeted Nanoparticles for the Delivery of Curcumin in Treating Pancreatic Cancer. ACS APPLIED BIO MATERIALS 2020; 3:4643-4654. [DOI: 10.1021/acsabm.0c00515] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Prabhuraj R S
- Centre for Research in Nanotechnology and Science, Indian Institute of Technology Bombay, Powai, Mumbai, India
| | - Arijit Mal
- Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Navi Mumbai, and Life Science Department, Homi Bhaba National Institute, Mumbai, India
| | - Snehal K. Valvi
- Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Navi Mumbai, and Life Science Department, Homi Bhaba National Institute, Mumbai, India
| | - Rohit Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India
| | - Abhijit De
- Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Navi Mumbai, and Life Science Department, Homi Bhaba National Institute, Mumbai, India
| | - Rajdip Bandyopadhyaya
- Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai, India
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Napoli S, Scuderi C, Gattuso G, Di Bella V, Candido S, Basile MS, Libra M, Falzone L. Functional Roles of Matrix Metalloproteinases and Their Inhibitors in Melanoma. Cells 2020; 9:cells9051151. [PMID: 32392801 PMCID: PMC7291303 DOI: 10.3390/cells9051151] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/01/2020] [Accepted: 05/06/2020] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix (ECM) plays an important role in the regulation of the tissue microenvironment and in the maintenance of cellular homeostasis. Several proteins with a proteolytic activity toward several ECM components are involved in the regulation and remodeling of the ECM. Among these, Matrix Metalloproteinases (MMPs) are a class of peptidase able to remodel the ECM by favoring the tumor invasive processes. Of these peptidases, MMP-9 is the most involved in the development of cancer, including that of melanoma. Dysregulations of the MAPKs and PI3K/Akt signaling pathways can lead to an aberrant overexpression of MMP-9. Even ncRNAs are implicated in the aberrant production of MMP-9 protein, as well as other proteins responsible for the activation or inhibition of MMP-9, such as Osteopontin and Tissue Inhibitors of Metalloproteinases. Currently, there are different therapeutic approaches for melanoma, including targeted therapies and immunotherapies. However, no biomarkers are available for the prediction of the therapeutic response. In this context, several studies have tried to understand the diagnostic, prognostic and therapeutic potential of MMP-9 in melanoma patients by performing clinical trials with synthetic MMPs inhibitors. Therefore, MMP-9 may be considered a promising molecule for the management of melanoma patients due to its role as a biomarker and therapeutic target.
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Affiliation(s)
- Salvatore Napoli
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Chiara Scuderi
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Giuseppe Gattuso
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Virginia Di Bella
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
| | - Maria Sofia Basile
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
- Correspondence: (M.L.); or (L.F.); Tel.: +39-095-478-1271 (M.L.); +39-094-478-1278 (L.F.)
| | - Luca Falzone
- Epidemiology Unit, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, 80131 Naples, Italy
- Correspondence: (M.L.); or (L.F.); Tel.: +39-095-478-1271 (M.L.); +39-094-478-1278 (L.F.)
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Slapak EJ, Duitman J, Tekin C, Bijlsma MF, Spek CA. Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression? BIOLOGY 2020; 9:biology9040080. [PMID: 32325664 PMCID: PMC7235986 DOI: 10.3390/biology9040080] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/15/2020] [Accepted: 04/15/2020] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer is a dismal disorder that is histologically characterized by a dense fibrotic stroma around the tumor cells. As the extracellular matrix comprises the bulk of the stroma, matrix degrading proteases may play an important role in pancreatic cancer. It has been suggested that matrix metalloproteases are key drivers of both tumor growth and metastasis during pancreatic cancer progression. Based upon this notion, changes in matrix metalloprotease expression levels are often considered surrogate markers for pancreatic cancer progression and/or treatment response. Indeed, reduced matrix metalloprotease levels upon treatment (either pharmacological or due to genetic ablation) are considered as proof of the anti-tumorigenic potential of the mediator under study. In the current review, we aim to establish whether matrix metalloproteases indeed drive pancreatic cancer progression and whether decreased matrix metalloprotease levels in experimental settings are therefore indicative of treatment response. After a systematic review of the studies focusing on matrix metalloproteases in pancreatic cancer, we conclude that the available literature is not as convincing as expected and that, although individual matrix metalloproteases may contribute to pancreatic cancer growth and metastasis, this does not support the generalized notion that matrix metalloproteases drive pancreatic ductal adenocarcinoma progression.
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Affiliation(s)
- Etienne J. Slapak
- Center of Experimental and Molecular Medicine, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; (E.J.S.); (J.D.); (C.T.)
- Laboratory for Experimental Oncology and Radiobiology, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
- Oncode Institute, 1105 AZ Amsterdam, The Netherlands
| | - JanWillem Duitman
- Center of Experimental and Molecular Medicine, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; (E.J.S.); (J.D.); (C.T.)
- Laboratory for Experimental Oncology and Radiobiology, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
| | - Cansu Tekin
- Center of Experimental and Molecular Medicine, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; (E.J.S.); (J.D.); (C.T.)
- Laboratory for Experimental Oncology and Radiobiology, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
- Oncode Institute, 1105 AZ Amsterdam, The Netherlands
| | - Maarten F. Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
- Oncode Institute, 1105 AZ Amsterdam, The Netherlands
| | - C. Arnold Spek
- Center of Experimental and Molecular Medicine, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; (E.J.S.); (J.D.); (C.T.)
- Laboratory for Experimental Oncology and Radiobiology, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
- Correspondence:
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Yalcin S, Dane F, Oksuzoglu B, Ozdemir NY, Isikdogan A, Ozkan M, Demirag GG, Coskun HS, Karabulut B, Evrensel T, Ustaoglu MA, Ozdemir F, Turna H, Yavuzsen T, Aykan F, Sevinc A, Akbulut H, Yuce D, Hayran M, Kilickap S. Quality of life study of patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma treated with gemcitabine+nab-paclitaxel versus gemcitabine alone: AX-PANC-SY001, a randomized phase-2 study. BMC Cancer 2020; 20:259. [PMID: 32228512 PMCID: PMC7106641 DOI: 10.1186/s12885-020-06758-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 03/17/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Combination of gemcitabine and nab-paclitaxel has superior clinical efficacy than gemcitabine alone. Nevertheless, health-related quality of life. (QoL) associated with this combination therapy when administered at first-line in advanced pancreatic adenocarcinoma is unknown. METHODS A total of 125 patients were randomized to combination therapy (1000 mg/m2 gemcitabine + 125 mg/m2 nab-paclitaxel) and single-agent gemcitabine (1000 mg/m2) arms to take treatment weekly for 7 of 8 weeks, and following 3 of 4 weeks, until progression or severe toxicity. Primary endpoints were three-months of definitive deterioration free percent of patients, and QoL. RESULTS Overall QoL analyses showed that 34 and 58.3% of cases in gemcitabine and gemcitabine+nab-P arms had no deterioration in 3rd month QoL scores (p = 0.018). These proportions were 27.3 and 36.6% in 6th month assessments, respectively (p = 0.357). Median overall survivals in combination and single-agent arms were 9.92 months and 5.95 months, respectively (HR: 0.64, 95% CI: 0.42-0.86, p = 0.038). Median progression free survivals in these treatment arms were 6.28 and 3.22 months, respectively (HR: 0.58, 95% CI: 0.39-0.87, p = 0.008). Median time-to-deterioration were 5.36 vs 3.68 months, and objective response rates were 37.1% vs 23.7% (p = 0.009), respectively in combination and single-agent arms. CONCLUSIONS Combination therapy with gemcitabine + nab-paclitaxel had better overall and progression-free survival than gemcitabine alone. Also, combination therapy showed increased response rate without toxicity or deteriorated QoL. Combination treatment with gemcitabine and nab-paclitaxel may provide significant benefit for advanced pancreatic cancer. TRIAL REGISTRATION This study has been registered in ClinicalTrials.gov as NCT03807999 on January 8, 2019 (retrospectively registered).
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Affiliation(s)
- Suayib Yalcin
- Hacettepe University Faculty of Medicine, Ankara, Turkey
- Hacettepe University Cancer Institute, Ankara, Turkey
| | - Faysal Dane
- Marmara University Faculty of Medicine, İstanbul, Turkey
| | - Berna Oksuzoglu
- Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey
| | | | | | - Metin Ozkan
- Erciyes University Faculty of Medicine, Kayseri, Turkey
| | | | | | | | | | | | - Feyyaz Ozdemir
- Karadeniz Teknik University Faculty of Medicine, Trabzon, Turkey
| | - Hande Turna
- İstanbul University Cerrahpasa Faculty of Medicine, Bursa, Turkey
| | - Tugba Yavuzsen
- Dokuz Eylül University Faculty of Medicine, İzmir, Turkey
| | - Faruk Aykan
- İstanbul University Cancer Institute, İstanbul, Turkey
| | - Alper Sevinc
- Gaziantep University Faculty of Medicine, Gaziantep, Turkey
| | - Hakan Akbulut
- Ankara University Faculty of Medicine, Ankara, Turkey
| | - Deniz Yuce
- Hacettepe University Cancer Institute, Ankara, Turkey
| | - Mutlu Hayran
- Hacettepe University Cancer Institute, Ankara, Turkey
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Colloca GA, Venturino A, Guarneri D. Neutrophil count kinetics during the first cycle of chemotherapy predicts the outcome of patients with locally advanced or metastatic pancreatic cancer. Asia Pac J Clin Oncol 2020; 16:247-253. [PMID: 32129930 DOI: 10.1111/ajco.13325] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 01/28/2020] [Indexed: 01/04/2023]
Abstract
BACKGROUND Neutrophil count reduction after chemotherapy has been related with longer survival of patients with metastatic pancreatic adenocarcinoma, but there is not a standardized measurement for this phenomenon. METHODS Some parameters related to the change in neutrophil count between the first and the second cycle of chemotherapy or between the baseline count and the nadir have been evaluated among patients with advanced pancreatic cancer at a single institution. A Cox regression model was built which included, in addition to the common prognostic variables, some variables related to the change of the neutrophil count after chemotherapy. RESULTS One hundred patients were selected. Two neutrophil kinetics related variables predicted overall survival independently, such as the neutrophil count growth rate (hazard ratio [HR] = 1.245; confidence intervals [CIs], 1.077-1.440) and the chemotherapy-induced neutropenia after one cycle (HR = 0.499; CIs, 0.269-0.927). CONCLUSION The kinetics of neutrophil count after chemotherapy is an early and independent prognostic factor, which appears to be simple to measure at the start of the second cycle of chemotherapy by means of the neutrophil count growth rate.
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The past, present and future perspectives of matrix metalloproteinase inhibitors. Pharmacol Ther 2020; 207:107465. [DOI: 10.1016/j.pharmthera.2019.107465] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 12/13/2019] [Indexed: 12/12/2022]
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Ordonez AA, Pokkali S, Sanchez-Bautista J, Klunk MH, Urbanowski ME, Kübler A, Bishai WR, Elkington PT, Jain SK. Matrix Metalloproteinase Inhibition in a Murine Model of Cavitary Tuberculosis Paradoxically Worsens Pathology. J Infect Dis 2019; 219:633-636. [PMID: 29920600 DOI: 10.1093/infdis/jiy373] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 06/15/2018] [Indexed: 12/12/2022] Open
Abstract
Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in tuberculosis pathogenesis and cavitation. In particular, MMP-7 is induced by hypoxia and highly expressed around pulmonary cavities of Mycobacterium tuberculosis-infected C3HeB/FeJ mice. In this study, we evaluated whether administration of cipemastat, an orally available potent inhibitor of MMP-7, could reduce pulmonary cavitation in M. tuberculosis-infected C3HeB/FeJ mice. We demonstrate that, compared with untreated controls, cipemastat treatment paradoxically increases the frequency of cavitation (32% vs 7%; P = .029), immunopathology, and mortality. Further studies are needed to understand the role of MMP inhibitors as adjunctive treatments for pulmonary tuberculosis.
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Affiliation(s)
- Alvaro A Ordonez
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Supriya Pokkali
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Julian Sanchez-Bautista
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mariah H Klunk
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michael E Urbanowski
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - André Kübler
- Queen's Hospital, Barking, Havering, and Redbridge University Hospital National Health Service Trust, Romford
| | - William R Bishai
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Paul T Elkington
- Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, NIHR Biomedical Research Centre.,Institute of Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Sanjay K Jain
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
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40
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Lakkakula BVKS, Farran B, Lakkakula S, Peela S, Yarla NS, Bramhachari PV, Kamal MA, Saddala MS, Nagaraju GP. Small molecule tyrosine kinase inhibitors and pancreatic cancer-Trials and troubles. Semin Cancer Biol 2019; 56:149-167. [PMID: 30314681 DOI: 10.1016/j.semcancer.2018.09.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 09/18/2018] [Accepted: 09/29/2018] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer (PC) is an aggressive carcinoma and the fourth cause of cancer deaths in Western countries. Although surgery is the most effective therapeutic option for PC, the management of unresectable, locally advanced disease is highly challenging. Our improved understanding of pancreatic tumor biology and associated pathways has led to the development of various treatment modalities that can control the metastatic spread of PC. This review intends to present trials of small molecule tyrosine kinase inhibitors (TKIs) in PC management and the troubles encountered due to inevitable acquired resistance to TKIs.
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Affiliation(s)
| | - Batoul Farran
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA
| | - Saikrishna Lakkakula
- Department of Zoology, Visvodaya Government Degree College, Venkatagiri, AP-524132, India
| | - Sujatha Peela
- Department of Biotechnology, Dr.B.R.Ambedkar University, Srikakulam, Andhra Pradesh, India
| | - Nagendra Sastry Yarla
- Dr. LV Prasad Diagnostics and Research Laboratory, Khairtabad, Hyderabad, AP- 500004, India
| | | | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia; Novel Global Community Educational Foundation, Australia
| | | | - Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA.
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41
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Pandey V, Storz P. Targeting the tumor microenvironment in pancreatic ductal adenocarcinoma. Expert Rev Anticancer Ther 2019; 19:473-482. [PMID: 31148495 PMCID: PMC6548630 DOI: 10.1080/14737140.2019.1622417] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/20/2019] [Indexed: 12/18/2022]
Abstract
Introduction: The dismally slow improvement in patient survival over the years for pancreatic cancer patients is mainly due to two factors: the late diagnosis, at which point the disease is spread to distant organs; and the fact that tumor cells are surrounded by a dense, highly immunosuppressive microenvironment. The tumor microenvironment not only shields pancreatic cancer cells from chemotherapy but also leaves it unsusceptible to various immunotherapeutic strategies that have been proven successful in other types of cancer. Areas covered: This review highlights the main components of the pancreatic tumor microenvironment, how they cross-talk with each other to generate stroma and promote tumor growth. Additionally, we discuss the most promising treatment targets in the microenvironment whose modulation can be robustly tested in combination with standard of care chemotherapy. Currently, active clinical trials for pancreatic cancer involving components of the microenvironment are also listed. Expert opinion: Although immunotherapeutic approaches involving checkpoint inhibition are being pursued enthusiastically, there is still more work to be done with several other emerging immune targets that could provide therapeutic benefit.
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Affiliation(s)
- Veethika Pandey
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
| | - Peter Storz
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, USA
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42
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van Mackelenbergh MG, Stroes CI, Spijker R, van Eijck CHJ, Wilmink JW, Bijlsma MF, van Laarhoven HWM. Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 11:E588. [PMID: 31035512 PMCID: PMC6562438 DOI: 10.3390/cancers11050588] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/19/2019] [Accepted: 04/22/2019] [Indexed: 12/14/2022] Open
Abstract
The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90-1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA)high tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26-1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients.
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Affiliation(s)
- Madelaine G van Mackelenbergh
- Laboratory of Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Charlotte I Stroes
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - René Spijker
- Medical Library, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
- Cochrane Netherlands, Julius Center, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
| | - Casper H J van Eijck
- Department of Surgery, Erasmus MC, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands.
| | - Johanna W Wilmink
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Maarten F Bijlsma
- Laboratory of Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
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43
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Awasthi N, Mikels-Vigdal AJ, Stefanutti E, Schwarz MA, Monahan S, Smith V, Schwarz RE. Therapeutic efficacy of anti-MMP9 antibody in combination with nab-paclitaxel-based chemotherapy in pre-clinical models of pancreatic cancer. J Cell Mol Med 2019; 23:3878-3887. [PMID: 30941918 PMCID: PMC6533474 DOI: 10.1111/jcmm.14242] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 02/01/2019] [Indexed: 12/22/2022] Open
Abstract
Matrix metalloproteinase 9 (MMP9) is involved in the proteolysis of extracellular proteins and plays a critical role in pancreatic ductal adenocarcinoma (PDAC) progression, invasion and metastasis. The therapeutic potential of an anti‐MMP9 antibody (αMMP9) was evaluated in combination with nab‐paclitaxel (NPT)‐based standard cytotoxic therapy in pre‐clinical models of PDAC. Tumour progression and survival studies were performed in NOD/SCID mice. The mechanistic evaluation involved RNA‐Seq, Luminex, IHC and Immunoblot analyses of tumour samples. Median animal survival compared to controls was significantly increased after 2‐week therapy with NPT (59%), Gem (29%) and NPT+Gem (76%). Addition of αMMP9 antibody exhibited further extension in survival: NPT+αMMP9 (76%), Gem+αMMP9 (47%) and NPT+Gem+αMMP9 (94%). Six‐week maintenance therapy revealed that median animal survival was significantly increased after NPT+Gem (186%) and further improved by the addition of αMMP9 antibody (218%). Qualitative assessment of mice exhibited that αMMP9 therapy led to a reduction in jaundice, bloody ascites and metastatic burden. Anti‐MMP9 antibody increased the levels of tumour‐associated IL‐28 (1.5‐fold) and decreased stromal markers (collagen I, αSMA) and the EMT marker vimentin. Subcutaneous tumours revealed low but detectable levels of MMP9 in all therapy groups but no difference in MMP9 expression. Anti‐MMP9 antibody monotherapy resulted in more gene expression changes in the mouse stroma compared to the human tumour compartment. These findings suggest that anti‐MMP9 antibody can exert specific stroma‐directed effects that could be exploited in combination with currently used cytotoxics to improve clinical PDAC therapy.
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Affiliation(s)
- Niranjan Awasthi
- Department of Surgery, Indiana University School of Medicine, South Bend, Indiana.,Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
| | | | | | - Margaret A Schwarz
- Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.,Department of Pediatrics, Indiana University School of Medicine, South Bend, Indiana
| | - Sheena Monahan
- Department of Surgery, Indiana University School of Medicine, South Bend, Indiana
| | | | - Roderich E Schwarz
- Department of Surgery, Indiana University School of Medicine, South Bend, Indiana.,Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana
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44
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Consensus statement on mandatory measurements in pancreatic cancer trials (COMM-PACT) for systemic treatment of unresectable disease. Lancet Oncol 2019; 19:e151-e160. [PMID: 29508762 DOI: 10.1016/s1470-2045(18)30098-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 09/19/2017] [Accepted: 10/04/2017] [Indexed: 12/17/2022]
Abstract
Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.
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45
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Schnittert J, Bansal R, Prakash J. Targeting Pancreatic Stellate Cells in Cancer. Trends Cancer 2019; 5:128-142. [PMID: 30755305 DOI: 10.1016/j.trecan.2019.01.001] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/20/2018] [Accepted: 01/03/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic stellate cells (PSCs) are the major contributor to the aggressive, metastatic, and resilient nature of pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis with a 5-year survival rate of 8%. PSCs constitute more than 50% of the tumor stroma in PDAC, where they induce extensive desmoplasia by secreting abundant extracellular matrix (ECM) proteins. In addition, they establish dynamic crosstalk with cancer cells and other stromal cells, which collectively supports tumor progression via various inter- and intracellular pathways. These cellular interactions and associated pathways may reveal novel therapeutic opportunities against this unmet clinical problem. In this review article, we discuss the role of PSCs in inducing tumor progression, their crosstalk with other cells, and therapeutic strategies to target PSCs.
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Affiliation(s)
- Jonas Schnittert
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Ruchi Bansal
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Jai Prakash
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands; ScarTec Therapeutics BV, Enschede, The Netherlands.
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46
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Elshimi E, Sakr MASM, Morad WS, Mohammad L. Optimizing the Diagnostic Role of Alpha-Fetoprotein and Abdominal Ultrasound by Adding Overexpressed Blood mRNA Matrix Metalloproteinase-12 for Diagnosis of HCV-Related Hepatocellular Carcinoma. Gastrointest Tumors 2019; 5:100-108. [PMID: 30976581 DOI: 10.1159/000495838] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 11/22/2018] [Indexed: 12/19/2022] Open
Abstract
Background and Aims Matrix metalloproteinase-12 (MMP-12) is involved in tumor invasiveness and metastasis and significantly overexpressed in hepatocellular carcinoma (HCC) tissues. We aimed to investigate the diagnostic and prognostic value of blood mRNA MMP-12 overexpression in patients with HCC. Patients and Methods From January 2017 to June 2017, 100 patients with HCC (HCV-related cirrhosis) and 100 patients with HCV-related cirrhosis (without HCC) were included in this study. All patients were subjected to triphasic CT abdomen when indicated, liver profile, alpha-fetoprotein (AFP), and molecular characterization of metalloproteinase-12 expression. Results There were no statistically significant differences between both groups regarding CBC parameters and liver profile (p value > 0.05). There was a statistically significant difference between patients with and without HCC regarding blood mRNA MMP-12 overexpression (p value < 0.01), blood mRNA MMP-12, and/or AFP (sensitivity 84.0%, specificity 60.0%, PPV 51.2%, and NPP 88.2%). The accuracy of mRNA MMP-12 and/or AFP in detection of HCC was 68.0%. Conclusion Blood mRNA MMP-12 has a good sensitivity and a bad specificity but is accurate in HCC diagnosis. Adding blood mRNA MMP-12 to AFP optimizes the current screening program to improve early diagnosis of HCC and hence better prognosis.
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Affiliation(s)
- Esam Elshimi
- Hepatology Department, National Liver Institute, Menoufia University, Shebin Al-Kom, Egypt
| | | | - Wesam Saber Morad
- Community Department, National Liver Institute, Menoufia University, Shebin Al-Kom, Egypt
| | - Lobna Mohammad
- Genetic Engineering Institute, Sadat University, Sadat, Egypt
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47
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Chandana S, Babiker HM, Mahadevan D. Therapeutic trends in pancreatic ductal adenocarcinoma (PDAC). Expert Opin Investig Drugs 2018; 28:161-177. [DOI: 10.1080/13543784.2019.1557145] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Sreenivasa Chandana
- Phase I program, START Midwest, Grand Rapids, MI, USA
- Department of Gastrointestinal Medical Oncology, Cancer and Hematology Centers of Western Michigan, Grand Rapids, MI, USA
- Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Hani M. Babiker
- Early Phase Therapeutics Program, University of Arizona Cancer Center, Tucson, AZ, USA
| | - Daruka Mahadevan
- Early Phase Therapeutics Program, University of Arizona Cancer Center, Tucson, AZ, USA
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48
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Zhang S, Xie W, Zou Y, Xie S, Zhang J, Yuan W, Ma J, Zhao J, Zheng C, Chen Y, Wang C. First-line chemotherapy regimens for locally advanced and metastatic pancreatic adenocarcinoma: a Bayesian analysis. Cancer Manag Res 2018; 10:5965-5978. [PMID: 30538546 PMCID: PMC6254987 DOI: 10.2147/cmar.s162980] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Background Systemic chemotherapy is the standard treatment for locally advanced and metastatic pancreatic cancer, but there is no consensus on the optimum regimen. We aimed to compare and rank the locally advanced and metastatic pancreatic adenocarcinoma chemotherapy regimens evaluated in randomized controlled trials (RCTs) in the past 15 years. Materials and methods PubMed, Embase, Cochrane Collaboration database, and ClinicalTrials.gov were searched for RCTs comparing chemotherapy regimens as first-line treatment for locally advanced and metastatic pancreatic adenocarcinomas. By using Bayesian network meta-analysis, we compared and ranked all included chemotherapy regimens in terms of overall survival, progression-free survival, response rate, and hematological toxicity. Results The analysis included 68 RCTs, with 14,908 patients and 63 treatment strategies. For overall survival, NSC-631570 (hazard ratio [HR] vs gemcitabine monotherapy 0.44, 95% credible interval: 0.24–0.76) and gemcitabine+NSC-631570 (HR 0.45, 0.24–0.86) were the two top-ranked chemotherapy regimens. For progression-free survival, PEFG (cisplatin + epirubicin + fluorouracil + gemcitabine) ranked first (HR 0.51, 0.34–0.77). PG (gemcitabine + pemetrexed) (odds ratio [OR] 4.68, 2.24–9.64) and FLEC (fluorouracil + leucovorin + epirubicin + carboplatin) (OR 4.52, 1.14–24.00) were ranked the most hematologically toxic, with gastrazole having the least toxicity (OR 0.03, 0.00–0.46). Conclusion The chemotherapy regimens NSC-631570 and gemcitabine+NSC-631570 were ranked the most efficacious for locally advanced and metastatic pancreatic adenocarcinomas in terms of overall survival, which warrants further confirmation in large-scale RCTs.
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Affiliation(s)
- Shuisheng Zhang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ; .,Department of General Surgery, Peking University Third Hospital
| | - Weimin Xie
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital
| | - Yinghua Zou
- Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital
| | - Shuanghua Xie
- Department of Cancer Epidemiology and Health Statistics
| | - Jianwei Zhang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ;
| | - Wei Yuan
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Clinical Immunology Center, Chinese Academy of Medical Science
| | - Jie Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Clinical Immunology Center, Chinese Academy of Medical Science.,Department of Biotherapy, Beijing Hospital, National Center of Gerontology, Beijing
| | - Jiuda Zhao
- Department of Medical Oncology, Affiliated Hospital of Qinghai University, Xining
| | - Cuiling Zheng
- Department of Clinical Laboratory, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yingtai Chen
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ;
| | - Chengfeng Wang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ;
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49
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Chromatin dynamics at the core of kidney fibrosis. Matrix Biol 2018; 68-69:194-229. [DOI: 10.1016/j.matbio.2018.02.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 02/16/2018] [Accepted: 02/17/2018] [Indexed: 02/06/2023]
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50
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Erstad DJ, Sojoodi M, Taylor MS, Ghoshal S, Razavi AA, Graham-O'Regan KA, Bardeesy N, Ferrone CR, Lanuti M, Caravan P, Tanabe KK, Fuchs BC. Orthotopic and heterotopic murine models of pancreatic cancer and their different responses to FOLFIRINOX chemotherapy. Dis Model Mech 2018; 11:dmm.034793. [PMID: 29903803 PMCID: PMC6078400 DOI: 10.1242/dmm.034793] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 06/11/2018] [Indexed: 12/16/2022] Open
Abstract
Syngeneic, immunocompetent allograft tumor models recapitulate important aspects of the tumor microenvironment and have short tumor latency with predictable growth kinetics, making them useful for trialing novel therapeutics. Here, we describe surgical techniques for orthotopic and heterotopic pancreatic ductal adenocarcinoma (PDAC) tumor implantation and characterize phenotypes based on implantation site.Mice (n=8 per group) were implanted with 104 cells in the pancreas or flank. Hy15549 and Han4.13 cell lines were derived from primary murine PDAC (Ptf1-Cre; LSL-KRAS-G12D; Trp53 Lox/+) on C57BL/6 and FVB strains, respectively. Single-cell suspension and solid tumor implants were compared. Tumors were treated with two intravenous doses of FOLFIRINOX and responses evaluated.All mice developed pancreatic tumors within 7 days. Orthotopic tumors grew faster and larger than heterotopic tumors. By 3 weeks, orthotopic mice began losing weight, and showed declines in body condition requiring euthanasia starting at 4 weeks. Single-cell injection into the pancreas had near 100% engraftment, but solid tumor implant engraftment was ∼50% and was associated with growth restriction. Orthotopic tumors were significantly more responsive to intravenous FOLFIRINOX compared with heterotopic tumors, with greater reductions in size and increased apoptosis. Heterotopic tumors were more desmoplastic and hypovascular. However, drug uptake into tumor tissue was equivalent regardless of tumor location or degree of fibrosis, indicating that microenvironment differences between heterotopic and orthotopic tumors influenced response to therapy.Our results show that orthotopic and heterotopic allograft locations confer unique microenvironments that influence growth kinetics, desmoplastic response and angiogenesis. Tumor location influences chemosensitivity to FOLFIRINOX and should inform future preclinical trials.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Derek J Erstad
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Mozhdeh Sojoodi
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Martin S Taylor
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Sarani Ghoshal
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Allen A Razavi
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Katherine A Graham-O'Regan
- Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States
| | - Nabeel Bardeesy
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Michael Lanuti
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Peter Caravan
- Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States.,Institute for Innovation in Imaging, Massachusetts General Hospital, Boston, MA 02114, United States
| | - Kenneth K Tanabe
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
| | - Bryan C Fuchs
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
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