MedicalResearch.com Interview with:
Rajesh Kumar NV, Ph.D.
Instructor of Oncology and Pathology,
Johns Hopkins University School of Medicine, Baltimore, MD, USA
Senior Manager, Human Therapeutics Division,
MedicalResearch.com: What is the background for this study?
Response: Pancreatic ductal adenocarcinoma (a.k.a. pancreatic cancer) is one of the most deadly of all types of cancer and currently the third leading cause of cancer-related death in United States. Current therapeutic options for pancreatic cancer involve combination cytotoxic chemotherapy, which yield only minimal survival benefit. A multitude of Phase III clinical trials have failed to demonstrate efficacy, largely due to the aggressive growth of pancreatic tumors. Metabolic reprogramming is a hallmark of cancer cells, including pancreatic cancer. Altered metabolism is central to the pathogenesis of pancreatic cancer and contributes to promotion of proliferation, survival, invasiveness and chemo-resistance of cancer cells. Pharmacologic strategies targeting cancer metabolism might therefore represent a promising approach towards the development of effective drugs against pancreatic cancer.
We utilized a clinically relevant and genetically characterized platform of patient-derived pancreatic cancer xenografts, which we originally created from the freshly resected pancreatic cancer tissues of patients, to explore the in vivo anti-tumor efficacy of a panel metabolic inhibitors and investigated whether mutational status, gene expression and metabolite profile of tumors correlate with the sensitivity to metabolic inhibitors. To our knowledge, this is the largest preclinical trial which enrolled a large number of animals (over 500 mice) with established human pancreatic tumors for the comprehensive evaluation of key metabolic inhibitors in pancreatic cancer.
MedicalResearch.com: What are the main findings?
Response: In contrast to the modest and variable responses to other metabolic inhibitors (glutaminase, aspartate aminotransferase, pyruvate dehydrogenase kinase or autophagy inhibitors), the biguanide phenformin displayed the best therapeutic effects across the 12 individual pancreatic cancer xenografts. Phenformin, at a five-fold lower dose of metformin (a widely used FDA-approved oral anti-diabetic drug), significantly diminished the growth of pancreatic tumors. Of note, pancreatic tumors with shorter tumor doubling time (aggressive tumor growth) respond well to phenformin treatment, compared to the efficacy of other metabolic inhibitors including metformin.
To gain insight into the potential biomarkers of responses, we examined the whole-genome sequencing data and copy number variation of pancreatic tumors and found no correlation of response with the mutational statuses of KRAS, TP53, SMAD4 or PTEN. However, gene set enrichment analysis conducted using the baseline gene expression data of pancreatic tumors identified a gene expression signature that inversely correlated with phenformin sensitivity, which is in agreement with the phenformin gene expression signature of NIH Library of Integrated Network-based Cellular Signatures (LINCS, a large gene expression databank of human cells exposed to thousands of chemical agents at a variety of time points and doses). Baseline tumor metabolite analysis using LC-MS method revealed general metabolites difference in tumors that are more sensitive versus those that are less sensitive to phenformin. Of note, the levels of metabolites involved in glycolysis and amino acid levels were diminished in phenformin-sensitive tumors, while oxidized glutathione was elevated. These observations suggest the possibility that sensitivity to phenformin correlates with increased use of amino acids for oxidation, resulting in lower amino acids and increased oxidized glutathione.
MedicalResearch.com: What should readers take away from your report?
Response: Pancreatic cancer has the highest mortality rate of all major cancers, and death rates of pancreatic cancer are increasing globally. Despite significant advances in the understanding of pancreatic cancer biology and all available treatment options, the disease remains largely incurable and clinically challenging to treat. The outcomes of patients diagnosed with pancreatic cancer are persistently poor, demanding the exploration of new therapeutic options. Any treatment that blocks tumor progression, and extends the survival of people affected by pancreatic cancer is regarded as a major achievement.
The biguanides are a class of compounds that inhibit mitochondrial complex I activity and are of significant interest as cancer therapeutics, because cancer cells rely not only on aerobic glycolysis but also on oxidative phosphorylation and respiration to accumulate building blocks for the biosynthesis of macromolecules. Both metformin and phenformin are biguanides approved as oral anti-diabetic agents. While metformin continues to be a globally preferred oral anti-diabetic agent for improving the blood sugar control in people with type 2 diabetics, phenformin was withdrawn from US markets in the late 1978 mainly due to its predisposition to cause lactic acidosis in diabetic patients.
Our comprehensive preclinical study using patient-derived pancreatic cancer xenografts, which preserve the heterogeneity and histological characteristics of pancreatic cancer, provide evidence of significant anti-tumor efficacy of phenformin against established pancreatic tumors. Our findings suggest phenformin merits immediate attention and evaluation as an anti-cancer agent.
What recommendations do you have for future research as a result of this study?
Response: Our results demonstrated that phenformin impedes the aggressive growth of human pancreatic tumors. Studies are required to determine whether phenformin in combination with current standard of care regimen or emerging therapeutic modalities could enhance their sensitivity significantly. In addition, studies are required to test the potential of phenformin as a maintenance therapy after disease stabilization.
MedicalResearch.com: Is there anything else you would like to add?
Response: Findings of our study serve as a foundation for further investigation of phenformin in pancreatic cancer. Phenformin was removed from the market in 1978 by the FDA because of the predisposition to cause lactic acidosis in a subset of type 2 diabetics patients. However, with proper clinical vigilance, this acknowledged side effect may be manageable in the context of cancer therapy.
The authors disclose no potential conflicts of interest. This study was supported by funding from a Stand Up To Cancer Dream Team Translational Cancer Research Grant (SU2C-AACR-DT0509) and NIH Grants P30CA016520, R01CA051497, R01CA057341, R01CA163591 and R01CA113669.
Clinical Cancer Research, CCR-17-1115.
Treatment of pancreatic cancer patient-derived xenograft panel with metabolic inhibitors reveals efficacy of phenformin.
N.V. Rajeshkumar, Shinichi Yabuuchi, Shweta G. Pai, Elizabeth De Oliveira, Jurre J. Kamphorst, Joshua D. Rabinowitz, Héctor Tejero, Fátima Al-Shahrour, Manuel Hidalgo, Anirban Maitra, Chi V. Dang
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