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1
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Guo H, Malone KE, Heckbert SR, Li CI. Statin use after cancer diagnosis and survival among patients with cancer. Cancer Causes Control 2025; 36:443-455. [PMID: 39719543 DOI: 10.1007/s10552-024-01939-4] [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: 07/09/2024] [Accepted: 11/07/2024] [Indexed: 12/26/2024]
Abstract
PURPOSE The association between statin use and cancer survival has been investigated in previous studies with conflicting findings. This study aimed to assess the association between statin use following cancer diagnosis and survival in six common cancers using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. METHODS Individuals aged ≥ 66 years diagnosed with prostate cancer, colorectal cancer, lung cancer, bladder cancer, pancreatic cancer, or non-Hodgkin lymphoma (NHL) from 2008 through 2017 were identified. Statin use was defined as two or more statin prescription fills after cancer diagnosis. Time-dependent Cox proportional hazard regression models were used to estimate the association between statin use and cancer-specific mortality for each cancer. RESULTS This study included 34,618 patients with prostate cancer (median follow-up 4.0 years), 20,579 with colorectal cancer (2.9 years), 20,133 with lung cancer (1.7 years), 6,163 with bladder cancer (2.1 years), 4,538 with pancreatic cancer (0.8 years), and 3,270 with NHL (2.9 years). Statin use post-diagnosis was associated with a reduced risk of cancer-specific mortality in lung cancer (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.74-0.88) and pancreatic cancer (HR, 0.72; 95% CI, 0.59-0.87). The association was not statistically significant for prostate cancer, colorectal cancer, bladder cancer, or NHL. A dose-response relationship by duration of statin use was observed in lung cancer and pancreatic cancer. CONCLUSION Statin use after cancer diagnosis appears associated with improved survival in lung cancer and pancreatic cancer. Clinical trials of statin therapy in lung and pancreatic cancer patients are warranted to confirm these findings.
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Affiliation(s)
- Hanbing Guo
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, M4-C308, Seattle, WA, 98019, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Kathleen E Malone
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, M4-C308, Seattle, WA, 98019, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Susan R Heckbert
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Christopher I Li
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, M4-C308, Seattle, WA, 98019, USA.
- Department of Epidemiology, University of Washington, Seattle, WA, USA.
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2
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Gong E, Fulop DJ, Serebrenik J, Labiner AJ, Cohen DJ, Sigel KM, Lucas AL. Antibiotic treatment and survival in patients with resected, early-stage pancreatic ductal adenocarcinoma receiving chemotherapy. JNCI Cancer Spectr 2025; 9:pkaf024. [PMID: 39982394 PMCID: PMC11917212 DOI: 10.1093/jncics/pkaf024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 01/19/2025] [Accepted: 02/10/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma is a clinically challenging malignancy largely because of its chemoresistance. Bacteria within the pancreatic ductal adenocarcinoma microbiome may mediate chemoresistance, suggesting that alteration of the microbiome with antibiotics could improve chemotherapy response. METHODS We utilized the Surveillance, Epidemiology, and End Results Program-Medicare database to select patients with resected, early-stage pancreatic ductal adenocarcinoma diagnosed between 2007 and 2017. The primary outcome of this study was overall survival. Receipt of antibiotic treatment within 1 month after adjuvant chemotherapy initiation was determined from Medicare claims data. Propensity scores were used to match patients who received antibiotics with patients who did not receive antibiotics. The Kaplan-Meier method was used to calculate 5-year overall survival rates, and Cox regression analysis was used to assess the association between receiving antibiotics and overall survival. All hypotheses were 2 sided. RESULTS Of the 712 patients with resected, early-stage pancreatic ductal adenocarcinoma, 629 (88.3%) were treated with adjuvant gemcitabine and 177 (24.9%) received antibiotics in the 1 month following chemotherapy initiation. The mean (SD) age at diagnosis was 73.7 (5.1) years, and patients were mostly women, White, and from metropolitan areas in the northeastern or western United States. A total of 143 propensity score-matched pairs were evaluated. Among patients treated with gemcitabine, antibiotic treatment was associated with a 37% improvement in overall survival and a 30% improvement in cancer-specific survival. CONCLUSIONS Antibiotic treatment in the 1 month following adjuvant gemcitabine initiation was associated with improved survival. These findings provide additional support for the hypothesis that antibiotic treatment may alter the pancreatic microbiome in a manner that reduces chemoresistance, potentially improving pancreatic ductal adenocarcinoma outcomes.
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Affiliation(s)
- Emma Gong
- Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Daniel J Fulop
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
| | - Joyce Serebrenik
- Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Arielle J Labiner
- George Washington University School of Medicine and Health Sciences, Washington, DC 20052, United States
| | - Deirdre J Cohen
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Keith M Sigel
- Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Aimee L Lucas
- Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
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3
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Lee D, Liew MS, Fourlanos S, Choi J. Metformin use and pancreatic ductal adenocarcinoma outcomes: a narrative review. ANZ J Surg 2025; 95:313-320. [PMID: 39840695 DOI: 10.1111/ans.19405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 01/04/2025] [Accepted: 01/09/2025] [Indexed: 01/23/2025]
Abstract
BACKGROUND Metformin is a diabetes medication with anti-mitotic properties. A narrative review was performed to investigate people using metformin and the risk of developing pancreatic ductal adenocarcinoma (PDAC) as well as survival outcomes in established PDAC. METHODS Relevant studies on metformin use and PDAC were retrieved from PubMed including observational studies on metformin and the risk of developing PDAC and survival outcomes in PDAC, and randomized controlled trials of metformin as a treatment in PDAC. RESULTS Of the 367 studies searched, 26 studies fulfilled the criteria for this review. Metformin was not consistently associated with a reduced risk of developing PDAC. However, metformin use, especially higher cumulative doses, in some studies was associated with longer survival in patients with established PDAC, especially in the subgroup with resectable PDAC. Metformin use was not associated with longer survival in more advanced (non-resectable metastatic) PDAC. CONCLUSION Metformin was not consistently associated with a reduced risk of developing PDAC. Metformin may be associated with overall survival benefits in patients with PDAC including the resectable PDAC subgroup but not in the metastatic PDAC subgroup. The evidence to date does not support the routine use of metformin as an adjuvant therapy for advanced PDAC.
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Affiliation(s)
- Dooyeon Lee
- Department of Surgery, Western Health, St. Albans, Victoria, Australia
| | - Mun Sem Liew
- Victorian Oncology Care, St John of God Specialist Centre, Berwick, Victoria, Australia
| | - Spiros Fourlanos
- Department of Diabetes & Endocrinology, Royal Melbourne Hospital, Parkville, Victoria, Australia
- Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
| | - Julian Choi
- Department of Surgery, Western Health, St. Albans, Victoria, Australia
- Department of Surgery, University of Melbourne, Parkville, Victoria, Australia
- Clinical Institute General Surgery and Gastroenterology, Epworth Healthcare, Richmond, Victoria, Australia
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4
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Anbari K, Amiri MM, Heidari-Soureshjani S, Sherwin CM, Kasiri K. A Systematic Review and Meta-analysis on the Role of Statins in the Prevention of Mortality Following Pancreatic Cancer. Anticancer Agents Med Chem 2023; 23:2073-2082. [PMID: 37622694 DOI: 10.2174/1871520623666230824095226] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 06/28/2023] [Accepted: 07/11/2023] [Indexed: 08/26/2023]
Abstract
BACKGROUND Pancreatic cancer (PC) is a type of cancer with a high incidence and case-fatality rate. OBJECTIVE This study aimed to evaluate the role of statins in preventing mortality following PC based on scientific evidence with systematic review and meta-analysis method. METHODS This meta-analysis considered studies published from 1980 till the end of 2022 in ISI Web of Science, Scopus, PubMed, Cochrane, Science Direct, Google Scholar, and Embase databases. Funnel diagrams and Begg's and Egger's tests were used to assess the publication bias. RESULTS In general, this meta-analysis has included 19 studies (13 cohort studies, 4 case-control, and 2 randomized clinical trials (RCTs)) and a total of 100,888 patients with PC. The risk of mortality of PC in statin users in total was 0.86 (95% CI: 0.80 - 0.92, P-value <0.001); in the case-control studies, it was equal to 0.53 (0.34-0.83); in the cohort studies, it was equal to 0.87 (0.82-0.92, P-value <0.001); in RCTs, it was equal to 1.19 (0.99-1.42, P-value <0.001); in studies with good quality score category, it was equal to 0.92 (0.86-0.99, P-value <0.001), and in articles of the moderate quality score category, it was equal to 0.73 (0.64-0.84, P-value <0.001). The results of statistical tests indicated the existence of publication bias (Begg's test (P-value = 0.002) and Egger's test (P-value = 0.004)). CONCLUSION Statins reduce the risk of mortality in patients with PC. However, no significant relation has been observed in RCTs. Therefore, it is necessary to be cautious in interpreting the results.
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Affiliation(s)
- Khatereh Anbari
- Department of Community Medicine, School of Medicine, Social Determinant of Health Research Center, Lorestan University of Medical Science, Khorramabad, Iran
| | - Mehdi Mohammadian Amiri
- Department of Emergency Medicine, School of Medicine, Babol University of Medical Sciences, Mazandaran, Iran
| | | | - Catherine Mt Sherwin
- Pediatric Clinical Pharmacology and Toxicology, Department of Pediatrics, Wright State University Boonshoft School of Medicine, Dayton Children's Hospital, One Children's Plaza, Dayton, Ohio, USA
| | - Karamali Kasiri
- Department of Pediatrics, Shahrekord University of Medical Sciences, Shahrekord, Iran
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5
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Scarton L, Jo A, Xie Z, O’Neal LJ, Munoz Pena JM, George TJ, Bian J. Examining the relationship between metformin dose and cancer survival: A SEER-Medicare analysis. PLoS One 2022; 17:e0275681. [PMID: 36260549 PMCID: PMC9581409 DOI: 10.1371/journal.pone.0275681] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 09/21/2022] [Indexed: 11/06/2022] Open
Abstract
Cancer is a major health problem in the U.S and type 2 diabetes mellitus (T2DM) is known to increase the risk for the development of many cancers. Metformin, a first-line therapy for treating T2DM, is increasingly being used for its anticancer effects; however, the literature is limited on the effect of metformin dose on overall survival in patients with stage IV cancer. Overall survival was defined as the time interval from the date of diagnosis to the last known follow-up or death from any cause. Subjects who were alive on December 31, 2016 were censored. In this cohort study we examined the relationship between metformin dose and overall survival in persons with both T2DM and stage IV lung, breast, colorectal, prostate, or pancreas cancers. We used a retrospective study design with Cox proportional hazards regression analysis of the 2007-2016 of the Surveillance Epidemiology and End Results-Medicare (SEER) dataset. Of the 7,725 patients, 2,981(38.5%) had been prescribed metformin. Patients who used metformin had significantly better overall survival in both unadjusted (Unadjusted HR, 0.73; 95% CI, 0.69-0.76; p < 0.001) and adjusted models (adjusted HR, 0.77; 95% CI, 0.73-0.81; p < 0.001). The overall survival between patients who took metformin with average daily dose ≥ 1000mg or < 1000mg were not statistically significant (aHR, 1.00; 95% CI, 0.93-1.08; p = 0.90). Metformin use regardless of dose is associated with increased overall survival in older adults with stage IV cancer.
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Affiliation(s)
- Lisa Scarton
- Department of Family, Community, and Health Systems Science, College of Nursing, University of Florida, Gainesville, Florida, United States of America
| | - Ara Jo
- Department of Health Services Research, Management and Policy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, United States of America
| | - Zhigang Xie
- Department of Public Health, University of North Florida, Jacksonville, Florida, United States of America
| | - LaToya J. O’Neal
- Institute of Food and Agricultural Sciences, University of Florida, Gainesville, Florida, United States of America
| | - Juan M. Munoz Pena
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Thomas J. George
- Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Jiang Bian
- Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, United States of America
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6
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Clark EH, Ahmed ST, Chang E, Chiao EY, White DL. Can statins lessen the burden of virus mediated cancers? Infect Agent Cancer 2022; 17:47. [PMID: 36058947 PMCID: PMC9441070 DOI: 10.1186/s13027-022-00460-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 08/22/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Oncogenic viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein Barr virus (EBV), and Kaposi Sarcoma Herpes virus (KSHV) contribute to a significant proportion of the world's cancers. Given the sizeable burden of virus mediated cancers, development of strategies to prevent and/or treat these cancers is critical. While large population studies suggest that treatment with hydroxymethylglutaryl-CoA reductase inhibitors, commonly known as statins, may reduce the risk of many cancer types including HBV/HCV related hepatocellular carcinoma, few studies have specifically evaluated the impact of statin use in populations at risk for other types of virus mediated cancers. MAIN BODY Studies of populations with HBV and HCV suggest a protective, dose-dependent effect of statins on hepatocellular carcinoma risk and support the theory that statins may offer clinical benefit if used as chemoprophylactic agents to reduce liver cancer incidence. However, no population level data exists describing the impact of statins on populations with other oncogenic viral infections, such as HPV, EBV, and KSHV. CONCLUSION Further study of statin use in diverse, global populations with or at high risk for oncogenic viral infections is essential to determine the impact of statin therapy on virus mediated cancer risk.
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Affiliation(s)
- Eva H Clark
- Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA.
- Section of Pediatric Tropical Medicine, Baylor College of Medicin, Feigin Building Suite 550, Houston, TX, 77030, USA.
| | - Sarah T Ahmed
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Elaine Chang
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Elizabeth Y Chiao
- Departments of Epidemiology and General Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Donna L White
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
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7
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Greco SH, Chao JC, Heath NG, Lin Y, Gall VA, Grandhi MS, Kennedy TJ, Carpizo DR, Alexander HR, Langan RC, August DA. Surgery is Associated With Improved Overall Survival in Patients With Metastatic Gastric Cancer: A National Cancer Database Analysis. Am Surg 2022; 88:2637-2643. [PMID: 35649712 DOI: 10.1177/00031348221086800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND The 5-year overall survival (OS) rate for patients with metastatic gastric cancer (mGC) is 5.3%. Surgery for mGC is controversial. METHODS We identified all mGC patients who received chemotherapy using the National Cancer Database (2004-2015). Patients were grouped according to surgery of: (1) the primary site (PS) only, (2) primary and distant sites (PDS), (3) distant site only (DS), or (4) no surgery (NS). A propensity score adjustment and multivariate regression was used to compare OS. RESULTS Overall, 18,772 patients met the inclusion criteria: (1) PS (n = 962, 5.1%), (2) PDS (n = 380, 2.1%), (3) DS (n = 984, 5.2%), and 16,446 NS (87.6%). Surgery was associated with improved OS in the PS and PDS groups (hazard ratios: .489 (95% CI: .376-.636); .583 (95% CI: .420-.811), P < .001) (median OS 15.8 and 15.9 months vs 8.6 for NS patients, respectively). CONCLUSIONS Gastrectomy with or without metastasectomy is associated with improved survival in stage IV gastric cancer patients receiving chemotherapy. This warrants further prospective studies.
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Affiliation(s)
- Stephanie H Greco
- Department of Surgical Oncology, 6565Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Joshua C Chao
- Department of Surgery, 43982Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Nicole G Heath
- Department of Neurology, 2006Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yong Lin
- Section of Gastrointestinal Surgical Oncology, 145249Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.,Department of Biostatistics, Rutgers School of Public Health, Piscataway, NJ, USA
| | - Victor A Gall
- Department of Surgery, Community Medical Center, 4598RWJBarnabas Health, Toms River, NJ, USA
| | - Miral S Grandhi
- Section of Gastrointestinal Surgical Oncology, 145249Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Timothy J Kennedy
- Section of Gastrointestinal Surgical Oncology, 145249Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Darren R Carpizo
- Division of Surgical Oncology, 200792University of Rochester Medical Center, Rochester, NY, USA
| | - H Richard Alexander
- Section of Gastrointestinal Surgical Oncology, 145249Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Russell C Langan
- Section of Gastrointestinal Surgical Oncology, 145249Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.,Saint Barnabas Medical Center, 4598RWJBarnabas Health, Livingston, NJ, USA
| | - David A August
- Department of Surgery, 43982Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.,Section of Gastrointestinal Surgical Oncology, 145249Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
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8
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Gyawali M, Venkatesan N, Ogeyingbo OD, Bhandari R, Botleroo RA, Kareem R, Ahmed R, Elshaikh AO. Magic of a Common Sugar Pill in Cancer: Can Metformin Raise Survival in Pancreatic Cancer Patients? Cureus 2021; 13:e16916. [PMID: 34367843 PMCID: PMC8343553 DOI: 10.7759/cureus.16916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/04/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is one of the common cancers globally, with a poor survival outcome. Metformin, a popular anti-diabetic drug, has gained popularity for its use in the chemoprevention of cancer. However, results regarding the survival benefit of metformin in pancreatic cancer have been unpredictable. In this review, we aim to analyze the use of metformin in pancreatic cancer patients with pre-existing diabetes mellitus for survival benefit. We systematically conducted a literature search in PubMed, Science Direct, and Scopus databases to collect the relevant articles and reviewed them. Eventually, 11 quality appraised articles were included accessing overall survival as the primary outcome. Our results concluded that metformin can efficaciously improve survival in pancreatic cancer patients with coexisting diabetes mellitus, but the results are still incongruent. Hence, further prospective studies and clinical trials are essential to provide a strong evidence-based recommendation that will help prolong the lifespan of patients.
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Affiliation(s)
- Mallika Gyawali
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nanditha Venkatesan
- Internal Medicine, All India Institute of Medical Sciences, Raipur, IND.,Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Opemipo D Ogeyingbo
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Saint James School of Medicine, Park Ridge, USA.,Public Health, Walden University, Minneapolis, USA
| | - Renu Bhandari
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Manipal College of Medical Sciences, Pokhara, NPL
| | - Rinky A Botleroo
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Roaa Kareem
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Rowan Ahmed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Abeer O Elshaikh
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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9
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Afshari AR, Mollazadeh H, Henney NC, Jamialahmad T, Sahebkar A. Effects of statins on brain tumors: a review. Semin Cancer Biol 2021; 73:116-133. [DOI: 10.1016/j.semcancer.2020.08.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/04/2020] [Accepted: 08/09/2020] [Indexed: 02/06/2023]
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10
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Hayashi H, Uemura N, Zhao L, Matsumura K, Sato H, Shiraishi Y, Baba H. Biological Significance of YAP/TAZ in Pancreatic Ductal Adenocarcinoma. Front Oncol 2021; 11:700315. [PMID: 34395269 PMCID: PMC8358930 DOI: 10.3389/fonc.2021.700315] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/12/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer. Despite major advances in defining the molecular mutations driving PDAC, this disease remains universally lethal with an overall 5-year survival rate of only about 7–8%. Genetic alterations in PDAC are exemplified by four critical genes (KRAS, TP53, CDKN2A, and SMAD4) that are frequently mutated. Among these, KRAS mutation ranges from 88% to 100% in several studies. Hippo signaling is an evolutionarily conserved network that plays a key role in normal organ development and tissue regeneration. Its core consists of the serine/threonine kinases mammalian sterile 20-like kinase 1 and 2 (MST1/2) and large tumor suppressor 1 and 2. Interestingly, pancreas-specific MST1/2 double knockout mice have been reported to display a decreased pancreas mass. Many of the genes involved in the Hippo signaling pathway are recognized as tumor suppressors, while the Hippo transducers Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are identified as oncogenes. By dephosphorylation, YAP and TAZ accumulate in the nucleus and interact with transcription factors such as TEA domain transcription factor-1, 2, 3, and 4. Dysregulation of Hippo signaling and activation of YAP/TAZ have been recognized in a variety of human solid cancers, including PDAC. Recent studies have elucidated that YAP/TAZ play a crucial role in the induction of acinar-to-ductal metaplasia, an initial step in the progression to PDAC, in genetically engineered mouse models. YAP and TAZ also play a key role in the development of PDAC by both KRAS-dependent and KRAS-independent bypass mechanisms. YAP/TAZ have become extensively studied in PDAC and their biological importance during the development and progression of PDAC has been uncovered. In this review, we summarize the biological significance of a dysregulated Hippo signaling pathway or activated YAP/TAZ in PDAC and propose a role for YAP/TAZ as a therapeutic target.
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Affiliation(s)
- Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Liu Zhao
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kazuki Matsumura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroki Sato
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuta Shiraishi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
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11
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Tamburrino D, Guarneri G, Pagnanelli M, Crippa S, Partelli S, Belfiori G, Capurso G, Falconi M. Chemopreventive Agents After Pancreatic Resection for Ductal Adenocarcinoma: Legend or Scientific Evidence? Ann Surg Oncol 2021; 28:2312-2322. [PMID: 32920722 DOI: 10.1245/s10434-020-09097-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 08/16/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related death in the USA. A wealth of evidence has demonstrated the chemopreventive activity of aspirin, statins, and metformin against PDAC. The aim of this study is to investigate the effect of aspirin, statins, and metformin on disease-free survival (DFS) and disease-specific survival (DSS) in a large population of PDAC patients undergoing pancreatic resection. PATIENTS AND METHODS All patients who underwent pancreatic resections between January 2015 and September 2018 were retrospectively reviewed. The potentially "chemopreventive agents" considered for the analysis were aspirin, statins, and metformin. Drug use was defined in case of regular assumption at least 6 months before diagnosis and regularly after surgery along the follow-up period. RESULTS A total of 430 patients were enrolled in this study, with median DFS and DSS of 21 months (IQR 13-30) months and 34 (IQR 26-52) months, respectively. On multivariable analysis, use of aspirin was associated with better DFS (HR: 0.62; p = 0.038). Metformin was associated with better DFS, without reaching statistical significance (p = 0.083). Use of statins did not influence DFS in the studied population. Aspirin, metformin, and statins were not associated with better DSS on multivariable analysis. Factors influencing DSS were pT3/pT4, N1, N2, no adjuvant treatment, G3, and ASA score > 3. CONCLUSIONS The results suggest that chronic use of aspirin is associated with increased DFS but not with better DSS after surgical resection in patients with PDAC.
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Affiliation(s)
- Domenico Tamburrino
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy
| | - Giovanni Guarneri
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy
| | - Michele Pagnanelli
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy
| | - Stefano Crippa
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Stefano Partelli
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Giulio Belfiori
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy
| | - Gabriele Capurso
- Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy
| | - Massimo Falconi
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy.
- Vita-Salute San Raffaele University, Milan, Italy.
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Lavu S, Therneau TM, Harmsen WS, Mara KC, Wongjarupong N, Hassan M, Ali HA, Antwi S, Giama NH, Miyabe K, Roberts LR. Effect of Statins on the Risk of Extrahepatic Cholangiocarcinoma. Hepatology 2020; 72:1298-1309. [PMID: 32119126 PMCID: PMC8155698 DOI: 10.1002/hep.31146] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 12/23/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND AIMS Statins have been proven to be cytotoxic to human cholangiocarcinoma cells by inhibiting cell division and inducing apoptosis. We aimed to determine the effect of statin use on the risk of cancer development and survival in patients with extrahepatic cholangiocarcinoma (ECC), including perihilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). APPROACH AND RESULTS A total of 394 patients with ECC and hyperlipidemia who received care at Mayo Clinic Rochester between 2005 and 2015 were matched by age, sex, race, ethnicity, and residency to 788 controls with hyperlipidemia. Clinical and outcome data were abstracted. The odds ratios (ORs) for risk and hazard ratios for outcomes were calculated. The mean age and standard deviation (SD) for cases and controls was 65.6 years (13.8). The number of statin users in cases and controls was 73 (19%) and 403 (51%), respectively. Hepatitis C virus infection (OR, 15.84; 95% confidence interval [CI], 4.06-61.87; P < 0.001) was the most significant risk factor for pCCA followed by inflammatory bowel disease and cirrhosis, whereas other liver disease, including biliary stone disease (OR, 4.06; CI, 2.24-7.36; P < 0.001), was the only significant risk factor for dCCA. Statin use was associated with significantly reduced risk for all ECC (OR, 0.22; CI, 0.16-0.29) as well as for the subtypes pCCA (OR, 0.3; CI, 0.21-0.41) and dCCA (OR, 0.06; CI, 0.03-0.14), all P < 0.0001. Moderate-intensity dosage was found to decrease the risk of ECC (OR, 0.48; CI, 0.34-0.67; P < 0.001). Comparing statin ever users to nonusers, patients with dCCA who used statins had significantly overall better survival (hazard ratio = 0.53; CI, 0.29-0.97; P = 0.04). CONCLUSIONS This case-control study suggests that statins decrease the risk of ECC and may improve survival in patients with dCCA. Additional validation studies are warranted.
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Affiliation(s)
- Sravanthi Lavu
- Department of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Terry M. Therneau
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States
| | - William S. Harmsen
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States
| | - Kristin C. Mara
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States
| | - Nicha Wongjarupong
- Department of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Mohamed Hassan
- Department of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Hamdi A. Ali
- Department of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, United States
| | | | - Nasra H. Giama
- Department of Nursing, University of Minnesota, Rochester, MN, United States
| | - Katsuyuki Miyabe
- Department of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Lewis R. Roberts
- Department of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, United States
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Shi YQ, Zhou XC, Du P, Yin MY, Xu L, Chen WJ, Xu CF. Relationships are between metformin use and survival in pancreatic cancer patients concurrent with diabetes: A systematic review and meta-analysis. Medicine (Baltimore) 2020; 99:e21687. [PMID: 32925714 PMCID: PMC7489714 DOI: 10.1097/md.0000000000021687] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/14/2020] [Accepted: 07/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Increased risk and cancer-related mortality is observed in pancreatic cancer (PC) patients with diabetes mellitus (DM). Whether using metformin as glucose-lowering therapy can result in survival benefit in this group of patients is still unclear. METHODS A meta-analysis of 21 studies that including 38,772 patients was performed to investigate the association between metformin and overall survival in patients with PC and concurrent DM. RESULTS A significant survival benefit was observed in metformin treatment group compared with non-metformin group (hazard ratio [HR] = 0.83, 95% confidence interval [CI]: 0.74-0.91). These associations were observed in both subgroups of Asian countries (HR = 0.69, 95% CI: 0.60-0.79) and Western countries (HR = 0.86, 95% CI: 0.76-0.95), the former was more obvious. Survival benefit was gained for patients at early stage (HR = 0.75, 95% CI: 0.64-0.85) and mixed stage (HR = 0.81, 95% CI: 0.70-0.91), but not for patients at advanced stage (HR = 0.99, 95% CI: 0.74-1.24). Similarly, survival benefit was also observed in patients receiving surgery (HR = 0.82, 95% CI: 0.69-0.94) and comprehensive treatment (HR = 0.85, 95% CI: 0.77-0.93), but not in chemotherapy group (HR = 0.99, 95% CI: 0.67-1.30). No obvious benefit was suggested when pooled by time-varying COX model (HR = 0.94, 95% CI: 0.86-1.03). CONCLUSIONS These results suggest that metformin is associated with survival benefit in patients with PC and concurrent DM. Further randomized controlled trials and prospective studies with larger sample sizes are required to confirm our findings.
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Affiliation(s)
- Yu-Qi Shi
- Department of Gastroenterology, the First Affiliated Hospital of Soochow University
| | | | - Peng Du
- Department of Invasive Technology, The First Affiliated Hospital of Soochow University
| | | | | | | | - Chun-Fang Xu
- The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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Zhang J, Ma J, Guo L, Yuan B, Jiao Z, Li Y. Survival Benefit of Metformin Use for Pancreatic Cancer Patients Who Underwent Pancreatectomy: Results From a Meta-Analysis. Front Med (Lausanne) 2020; 7:282. [PMID: 32850872 PMCID: PMC7406684 DOI: 10.3389/fmed.2020.00282] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 05/21/2020] [Indexed: 01/11/2023] Open
Abstract
Objective: To evaluate the survival benefit of metformin use for pancreatic cancer (PC) patients underwent pancreatectomy. Methods: Databases including EMBASE, PubMed, the Cochrane Library were searched to identify studies relevant to the outcomes on the survival benefit of metformin use for the PC patients who underwent pancreatectomy until June 30, 2019. STATA 12.0 software was used to performed the meta-analysis. Results: 12 studies involving 35,346 PC patients were included in this meta-analysis. With a random-model, there are significant differences in overall survival (HR = 0.85, 95% CI: 0.77–0.94, P = 0.002) between PC patients who were treated with metformin underwent pancreatectomy and those who underwent pancreatectomy without metformin use. Subgroup analyses showed Caucasians (HR = 0.903, 95% CI = 0.825–0.940, P = 0.008) and Asian (HR = 0.691, 95% CI = 0.588–0.813, P = 0.001) PC patients have a significantly reduced risk of death for metformin users. Subgroup analyses also showed a survival benefit for PC patients at stage I-II (HR = 0.762, 95% CI = 0.677–0.858, P = 0.0001). Conclusions: Metformin use is related to a better survival benefit for PC patients who underwent pancreatectomy, which would be a potential drug for the treatment of PC.
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Affiliation(s)
- Junqiang Zhang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Jichun Ma
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Lingyun Guo
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Bo Yuan
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Zuoyi Jiao
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
| | - Yumin Li
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
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Tamburrino D, Crippa S, Partelli S, Archibugi L, Arcidiacono PG, Falconi M, Capurso G. Statin use improves survival in patients with pancreatic ductal adenocarcinoma: A meta-analysis. Dig Liver Dis 2020; 52:392-399. [PMID: 32113888 DOI: 10.1016/j.dld.2020.01.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/21/2020] [Accepted: 01/23/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Previous studies on statins' effect on survival of patients with pancreatic ductal adenocarcinoma (PDAC) report conflicting results. AIMS To evaluate the association between statin use and PDAC patients' survival. METHODS A systematic review and meta-analysis was performed including case-control, cohort studies and randomized controlled trials assessing the association between statin use and survival in PDAC patients. Pooled HRs with 95%CIs were calculated using random effects model; publication bias was assessed through Begg and Mazumdar test and heterogeneity by I2 value. RESULTS 14 studies with 33,137 PDAC patients, 40% under statins, were included. Statins use was associated to a reduced death risk (HR 0.871; 95%CI: 0.819; 0.927; p = 0.0001) suggesting a protective effect, homogeneous for different geographic areas. This effect was significant in surgically resected patients (HR 0.50; 95%CI: 0.32; 0.76; p = 0.001) but not in those with advanced disease (HR 0.78; 95%CI: 0.59; 1.02; p = 0.07). In studies providing information on statin type, only rosuvastatin resulted associated to a reduced risk of death (HR 0.88; 95%CI: 0.81; 0.96; p = 0.004). CONCLUSIONS Statins use is significantly associated with a reduced risk of death in resected PDAC patients. This finding has to be considered with caution due to publication bias and the availability of only few studies for sensitivity analyses.
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Affiliation(s)
- Domenico Tamburrino
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; PhD Candidate in Digestive Oncology, "La Sapienza University" Rome, Italy
| | - Stefano Crippa
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; Vita Salute University, Milan, Italy
| | - Stefano Partelli
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; Vita Salute University, Milan, Italy
| | - Livia Archibugi
- Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan, Italy
| | - Paolo Giorgio Arcidiacono
- Vita Salute University, Milan, Italy; Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan, Italy
| | - Massimo Falconi
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; Vita Salute University, Milan, Italy
| | - Gabriele Capurso
- Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan, Italy.
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Tan X, E J, Lin Y, Rebbeck TR, Lu S, Shang M, Kelly WK, D'Amico A, Stein MN, Zhang L, Jang TL, Kim IY, Demissie K, Ferrari A, Lu‐Yao G. Individual and joint effects of metformin and statins on mortality among patients with high-risk prostate cancer. Cancer Med 2020; 9:2379-2389. [PMID: 32035002 PMCID: PMC7131852 DOI: 10.1002/cam4.2862] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/26/2019] [Accepted: 12/27/2019] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Pre-clinical studies suggest that metformin and statins may delay prostate cancer (PCa) metastases; however, data in humans are limited. To the best of our knowledge, this is the first human study aimed to quantify the individual and joint effects of statin and metformin use among patients with high-risk PCa. METHODS This population-based retrospective cohort study identified patients from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Exposure to metformin and statins was ascertained from Medicare Prescription Drug Event files. The association with all-cause and PCa mortality were evaluated using Cox proportional hazard model with competing causes of death, where propensity scores were used to adjusted imbalances in covariates across groups. RESULTS Based on 12 700 patients with high-risk PCa, statin alone or in combination with metformin was significantly associated with reduced all-cause mortality (Hazard Ratio [HR]: 0.89; 95% Confidence Interval [CI]: 0.83, 0.96; and HR: 0.75; 95% CI, 0.67-0.83, respectively) and PCa mortality (HR, 0.80; 95% CI: 0.69, 0.92) and 0.64; 95% CI, d 0.51-0.81, respectively. The effects were more pronounced in post-diagnostic users: combination use of metformin/statins was associated with a 32% reduction in all-cause mortality (95% CI, 0.57-0.80), and 54% reduction in PCa mortality (95% CI, 0.30-0.69). No significant association of metformin alone was observed with either all-cause mortality or PCa mortality. CONCLUSIONS Statin use alone or in combination with metformin was associated with lower all-cause and PCa mortality among high-risk patients, particularly in post-diagnostic settings; further studies are warranted.
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Affiliation(s)
- Xiang‐Lin Tan
- Rutgers Cancer Institute of New JerseyRutgers, The State University of New JerseyNew BrunswickNJUSA
- Department of EpidemiologySchool of Public HealthRutgers, The State University of New JerseyPiscatawayNJUSA
- Department of MedicineRobert Wood Johnson Medical SchoolRutgers, The State University of New JerseyNew BrunswickNJUSA
| | - Jian‐Yu E
- Rutgers Cancer Institute of New JerseyRutgers, The State University of New JerseyNew BrunswickNJUSA
- Department of EpidemiologySchool of Public HealthRutgers, The State University of New JerseyPiscatawayNJUSA
- Department of EpidemiologyBloomberg School of Public HealthThe Johns Hopkins UniversityBaltimoreMDUSA
| | - Yong Lin
- Rutgers Cancer Institute of New JerseyRutgers, The State University of New JerseyNew BrunswickNJUSA
- Department of BiostatisticsSchool of Public HealthRutgers, The State University of New JerseyPiscatawayNJUSA
| | - Timothy R. Rebbeck
- Dana Farber Cancer InstituteHarvard TH Chan School of Public HealthBostonMAUSA
| | - Shou‐En Lu
- Rutgers Cancer Institute of New JerseyRutgers, The State University of New JerseyNew BrunswickNJUSA
- Department of BiostatisticsSchool of Public HealthRutgers, The State University of New JerseyPiscatawayNJUSA
| | - Mingyi Shang
- Department of Interventional RadiologySchool of MedicineTongren HospitalShanghai Jiao Tong UniversityShanghaiChina
| | - William K. Kelly
- Department of Medical OncologySidney Kimmel Cancer Center at JeffersonSidney Kimmel Medical CollegePhiladelphiaPAUSA
- Sidney Kimmel Cancer Center at JeffersonPhiladelphiaPAUSA
| | - Anthony D'Amico
- Brigham and Women's Hospital and Dana Farber Cancer InstituteBostonMAUSA
| | - Mark N. Stein
- Rutgers Cancer Institute of New JerseyRutgers, The State University of New JerseyNew BrunswickNJUSA
- Department of MedicineRobert Wood Johnson Medical SchoolRutgers, The State University of New JerseyNew BrunswickNJUSA
| | - Lanjing Zhang
- Rutgers Cancer Institute of New JerseyRutgers, The State University of New JerseyNew BrunswickNJUSA
- Department of PathologyUniversity Medical Center of PrincetonPlainsboroNJUSA
- Department of Biological SciencesRutgers, The State University of New JerseyNewarkNJUSA
| | - Thomas L. Jang
- Rutgers Cancer Institute of New JerseyRutgers, The State University of New JerseyNew BrunswickNJUSA
- Department of MedicineRobert Wood Johnson Medical SchoolRutgers, The State University of New JerseyNew BrunswickNJUSA
| | - Isaac Yi Kim
- Rutgers Cancer Institute of New JerseyRutgers, The State University of New JerseyNew BrunswickNJUSA
- Department of MedicineRobert Wood Johnson Medical SchoolRutgers, The State University of New JerseyNew BrunswickNJUSA
| | - Kitaw Demissie
- Rutgers Cancer Institute of New JerseyRutgers, The State University of New JerseyNew BrunswickNJUSA
- Department of EpidemiologySchool of Public HealthRutgers, The State University of New JerseyPiscatawayNJUSA
| | - Anna Ferrari
- Rutgers Cancer Institute of New JerseyRutgers, The State University of New JerseyNew BrunswickNJUSA
- Department of MedicineRobert Wood Johnson Medical SchoolRutgers, The State University of New JerseyNew BrunswickNJUSA
| | - Grace Lu‐Yao
- Department of Medical OncologySidney Kimmel Cancer Center at JeffersonSidney Kimmel Medical CollegePhiladelphiaPAUSA
- Sidney Kimmel Cancer Center at JeffersonPhiladelphiaPAUSA
- Jefferson College of Population HealthPhiladelphiaPAUSA
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Antwi SOP, Li Z, Mody K, Roberts LR, Patel T. Independent and Joint Use of Statins and Metformin by Elderly Patients With Diabetes and Overall Survival Following HCC Diagnosis. J Clin Gastroenterol 2020; 54:468-476. [PMID: 32271517 PMCID: PMC7150664 DOI: 10.1097/mcg.0000000000001182] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
GOAL To investigate associations of prediagnosis and postdiagnosis use of statins and metformin on overall survival of patients with diabetes who later developed HCC. BACKGROUND Statins and metformin have received considerable interest as potential chemopreventive agents against hepatocellular carcinoma (HCC) development in individuals with type 2 diabetes mellitus (T2DM); however, their impact on overall survival of patients with T2DM who later develop HCC (diabetic HCC patients) is unclear. STUDY Data on 2499 elderly diabetic HCC patients obtained from the SEER-Medicare program (2009 to 2013) were analyzed. Patients were categorized based on use of statins only, metformin only, both, or neither (reference for all comparisons). The patients were further categorized based on: (1) metformin dose: ≤1500 or >1500 mg/d; (2) statins functional form: hydrophilic (pravastatin and rosuvastatin) or lipophilic (atorvastatin, fluvastatin, lovastatin, and simvastatin); (3) statins potency: high (atorvastatin, rosuvastatin, and simvastatin) or low (fluvastatin, lovastatin, and pravastatin); and (4) individual statins type. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models. RESULTS Prediagnosis use of metformin dose ≤1500 mg/d was associated with lower risk of death after HCC diagnosis in patients with T2DM (HR, 0.72; 95% CI, 0.58-0.91), adjusting for postdiagnosis metformin dose, diabetes severity, Charlson comorbidity index, tumor characteristics, and other relevant factors. No association was found for prediagnosis metformin dose >1500 mg/d or postdiagnosis metformin use. Further, no association was found for either prediagnosis or postdiagnosis statins use. CONCLUSIONS Prediagnosis use of metformin dose ≤1500 mg/d is associated with longer overall survival of elderly diabetic HCC patients.
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Affiliation(s)
| | - Zhuo Li
- Health Sciences Research, Mayo Clinic, Jacksonville, FL
| | - Kabir Mody
- Medical Oncology, Mayo Clinic, Jacksonville, FL
| | | | - Tushar Patel
- Transplant Hepatology, Mayo Clinic, Jacksonville, FL
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Fatehi Hassanabad A. Current perspectives on statins as potential anti-cancer therapeutics: clinical outcomes and underlying molecular mechanisms. Transl Lung Cancer Res 2019; 8:692-699. [PMID: 31737505 DOI: 10.21037/tlcr.2019.09.08] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Statins have been shown to inhibit cell proliferation in vitro and tumor growth in animal models. Various studies have also shown a decreased cancer-specific mortality rate in patients who were prescribed these medications. Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway. Statins induce tumour-specific apoptosis through mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate (GGPP) biosynthesis. However, there is no consensus on the molecular targets of statins for their anti-cancer effects. Several studies have been conducted to further assess the association between statin use and mortality in different types of cancer. In this review, current perspectives on clinical significance of statins in prevention and treatment of various types of cancers and proposed mechanisms are discussed.
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Song M, Sun M, Xia L, Chen W, Yang C. miR-19b-3p promotes human pancreatic cancer Capan-2 cells proliferation by targeting phosphatase and tension homolog. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:236. [PMID: 31317006 DOI: 10.21037/atm.2019.04.61] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Background Pancreatic cancer is a common cancer with a poor prognosis and an increasing morbidity. miR-19b-3p has been implicated in some cancers, however, its role in pancreatic cancer is unclear. Methods Human pancreatic cancer cell line Capan-2 cells were transfected with miR-19b-3p mimic and inhibitor. Cell proliferation was measured by 5-Ethynyl-2'-deoxyuridine (EdU) staining assays. Cell cycle of Capan-2 cells was examined by flow cytometry. The expression of phosphatase and tension homolog (PTEN) was determined by real-time quantitative polymerase chain reaction (PCR) and western blotting analysis. Functional rescue experiments were performed through PTEN overexpression and miR-19b-3p mimic by using EdU staining assays. Results miR-19b-3p mimic significantly increased miR-19b-3p while miR-19b-3p inhibitor decreased that. EdU staining showed that miR-19b-3p overexpression promoted Capan-2 cells proliferation while miR-19b-3p inhibition decreased that. Flow cytometry analysis of cell cycle indicated that miR-19b-3p overexpression increased the percentage of Capan-2 cells in S phase while miR-19b-3p inhibition decreased that. PTEN was confirmed to be a target gene of miR-19b-3p and PTEN overexpression eliminated the pro-proliferation effects of miR-19b-3p in Capan-2 cells. Conclusions Our study demonstrates that miR-19b-3p promotes Capan-2 cells proliferation by targeting PTEN.
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Affiliation(s)
- Meiyi Song
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Mengxue Sun
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Lu Xia
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Wei Chen
- Emergency Department, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Changqing Yang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
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Rozengurt E, Eibl G. Central role of Yes-associated protein and WW-domain-containing transcriptional co-activator with PDZ-binding motif in pancreatic cancer development. World J Gastroenterol 2019; 25:1797-1816. [PMID: 31057295 PMCID: PMC6478619 DOI: 10.3748/wjg.v25.i15.1797] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/20/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC. Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network. Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.
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Affiliation(s)
- Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
- CURE: Digestive Diseases Research Center, Los Angeles, CA 90095, United States
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
- CURE: Digestive Diseases Research Center, Los Angeles, CA 90095, United States
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Wei M, Liu Y, Bi Y, Zhang ZJ. Metformin and pancreatic cancer survival: Real effect or immortal time bias? Int J Cancer 2019; 145:1822-1828. [PMID: 30848544 DOI: 10.1002/ijc.32254] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 02/25/2019] [Accepted: 03/05/2019] [Indexed: 12/20/2022]
Abstract
High heterogeneity has been reported among cohort studies investigating the association between metformin and pancreatic cancer survival. Immortal time bias may be one importance source of heterogeneity, as it is widely present in previous cohort studies and may severely impair the validity. Our study aimed to examine whether metformin therapy improves pancreatic cancer survival, and to assess the impact of immortal time bias on the effect estimation of metformin in cohort studies. PubMed, EMbase and SciVerse Scopus were searched. Pooled relative risks (RRs) were derived using a random-effects model. Pooled RR from the six studies without immortal time bias showed no association between metformin and mortality in pancreatic cancer patients (RR 0.93, 95% CI 0.82, 1.05; p = 0.22 and I2 = 75%). In contrast, pooled RR from the nine studies with immortal time bias showed a reduction of 24% in mortality associated with metformin (RR 0.76, 95% CI 0.69, 0.84; p < 0.001 and I2 = 1%). From a meta-regression model, existence of immortal time bias was associated with a reduction of 18% in the effect estimate of metformin on pancreatic cancer survival (ratio of RR 0.82, 95% CI 0.70, 0.96; p = 0.02). In conclusions, cumulative evidence from cohort studies does not support a beneficial effect of metformin on pancreatic cancer survival. The association between metformin and pancreatic cancer survival has been greatly exaggerated in previous cohort studies due to the wide existence of immortal time bias. More rigorous designs and statistical methods are needed to account for immortal time bias.
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Affiliation(s)
- Min Wei
- Department of Obstetrics and Gynecology, Renmin Hospital, Wuhan University, Wuhan, China.,Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, China
| | - Yu Liu
- Department of Statistics and Management, School of Management, Wuhan Institute of Technology, Wuhan, China
| | - Yongyi Bi
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, China
| | - Zhi-Jiang Zhang
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, China
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Macchini M, Chiaravalli M, Zanon S, Peretti U, Mazza E, Gianni L, Reni M. Chemotherapy in elderly patients with pancreatic cancer: Efficacy, feasibility and future perspectives. Cancer Treat Rev 2018; 72:1-6. [PMID: 30414985 DOI: 10.1016/j.ctrv.2018.10.013] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 10/27/2018] [Indexed: 12/27/2022]
Abstract
By 2030 70% of newly diagnosed pancreatic ductal adenocarcinoma (PDAC) will occur in older adults. Elderly patients, defined by the World Health Organization (WHO) as people older than 65 years, represent a heterogeneous group with different biological and functional characteristics that need personalized anticancer treatments. Since older patients are under-represented in randomized phase III trials, their management is mostly extrapolated from studies performed in younger patients, without robust evidence-based recommendations. However, data from retrospective studies and case-control series show that elderly may benefit from chemotherapy in both the adjuvant and advanced disease settings. Although with discordant results, gemcitabine-based treatment and dose-adapted fluorouracil combination regimens seem to be effective and well tolerated in this subset of patients. A proper balance of potential treatment benefits and side effects represent the crucial point for managing elderly patients with PDAC. Therefore an appropriate patient selection is essential to maximize the therapeutic benefit in the older population: randomized studies aiming to better standardizing fitness parameters and implementing the routine use of comprehensive geriatric assessments are strongly warranted. In this light, the detection of molecular prognostic markers able to detect patients who may benefit more from oncological treatments should be a primary endpoint of age-focused clinical trials. Altogether, the field of geriatric oncology will expand in the next years, and the clinical management of elderly patients affected by PDAC will become a major public health issue.
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Affiliation(s)
- Marina Macchini
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Marta Chiaravalli
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Silvia Zanon
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Umberto Peretti
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Elena Mazza
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Luca Gianni
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Michele Reni
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
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Hamada T, Khalaf N, Yuan C, Morales-Oyarvide V, Babic A, Nowak JA, Qian ZR, Ng K, Rubinson DA, Kraft P, Giovannucci EL, Stampfer MJ, Fuchs CS, Ogino S, Wolpin BM. Prediagnosis Use of Statins Associates With Increased Survival Times of Patients With Pancreatic Cancer. Clin Gastroenterol Hepatol 2018; 16:1300-1306.e3. [PMID: 29474971 PMCID: PMC6056316 DOI: 10.1016/j.cgh.2018.02.022] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 01/29/2018] [Accepted: 02/11/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Statin medications, most commonly prescribed to reduce lipid levels and prevent cardiovascular disease, may be associated with longer survival times of patients with cancer. However, the association of statins with outcomes of patients with pancreatic adenocarcinoma is not clear. METHODS We analyzed the association of statin use before a diagnosis of pancreatic cancer with survival times of 648 participants in the Nurses' Health Study and Health Professionals Follow-up Study who were diagnosed with pancreatic adenocarcinoma from 2000 through 2013. We estimated hazard ratios (HRs) for overall mortality using Cox proportional hazards models with adjustment for potential confounders. We assessed the temporal association between prediagnosis statin use and cancer survival by 2-year lag periods to account for a possible latency period between statin use and cancer survival. RESULTS Regular statin use before diagnosis of pancreatic cancer was associated with modestly prolonged survival compared with nonregular use (adjusted HR, 0.82; 95% CI, 0.69-0.97; P = .02). A 1-month longer median survival was observed in regular statin users compared with nonregular users. Regular statin use within the 2 years prior to cancer diagnosis was most strongly associated with longer survival. We observed no statistically significant effect modification by smoking status, body mass index, diabetes, or cancer stage (all Pinteraction > .53). Regular statin use before diagnosis was similarly associated with survival in the Nurses' Health Study (HR, 0.79; 95% CI, 0.64-0.97) and Health Professionals Follow-up Study (HR, 0.86; 95% CI, 0.63-1.15). CONCLUSIONS Regular statin use before diagnosis of pancreatic cancer was associated with modest increases in survival times in 2 large prospective cohort studies.
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Affiliation(s)
- Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Natalia Khalaf
- Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Chen Yuan
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Vicente Morales-Oyarvide
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Ana Babic
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Jonathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Zhi Rong Qian
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Kimmie Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Douglas A Rubinson
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Peter Kraft
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Edward L Giovannucci
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Meir J Stampfer
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Charles S Fuchs
- Yale Cancer Center, New Haven, Connecticut; Department of Medicine, Yale School of Medicine, New Haven, Connecticut; Smilow Cancer Hospital, New Haven, Connecticut
| | - Shuji Ogino
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
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Eibl G, Rozengurt E. KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops. Semin Cancer Biol 2017; 54:50-62. [PMID: 29079305 DOI: 10.1016/j.semcancer.2017.10.007] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 10/22/2017] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) continues to be a lethal disease with no efficacious treatment modalities. The incidence of PDAC is expected to increase, at least partially because of the obesity epidemic. Increased efforts to prevent or intercept this disease are clearly needed. Mutations in KRAS are initiating events in pancreatic carcinogenesis supported by genetically engineered mouse models of the disease. However, oncogenic KRAS is not entirely sufficient for the development of fully invasive PDAC. Additional genetic mutations and/or environmental, nutritional, and metabolic stressors, e.g. inflammation and obesity, are required for efficient PDAC formation with activation of KRAS downstream effectors. Multiple factors "upstream" of KRAS associated with obesity, including insulin resistance, inflammation, changes in gut microbiota and GI peptides, can enhance/modulate downstream signals. Multiple signaling networks and feedback loops "downstream" of KRAS have been described that respond to obesogenic diets. We propose that KRAS mutations potentiate a signaling network that is promoted by environmental factors. Specifically, we envisage that KRAS mutations increase the intensity and duration of the growth-promoting signaling network. As the transcriptional activator YAP plays a critical role in the network, we conclude that the rationale for targeting the network (at different points), e.g. with FDA approved drugs such as statins and metformin, is therefore compelling.
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Affiliation(s)
- Guido Eibl
- Departments of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; CURE: Digestive Diseases Research Center, University of California at Los Angeles, Los Angeles, CA, United States.
| | - Enrique Rozengurt
- Departments of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; CURE: Digestive Diseases Research Center, University of California at Los Angeles, Los Angeles, CA, United States
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