Ayush Trivedi
UROP Fellowship: Biomedical and Life Sciences
Research Mentor(s): Peter Kim, PhD Candidate, Costas Lyssiotis, PhD
Department of Molecular and Integrative Physiology
Presentation Date: Monday, July 27, 2020 | Session 1 | Presenter: 5
Authors: Ayush Trivedi, Peter K. Kim, Costas A. Lyssiotis
Abstract
Pancreatic cancer is one of the deadliest cancers with no effective therapies, and an overall five-year survival rate of 10%. One major obstacle against effective therapies is the tumor microenvironment, which can make up to 90% of the tumor cellularity. The tumor microenvironment is responsible for the high intratumoral pressure, which collapses the vasculature. This inhibits effective drug delivery and also leads to a nutrient-poor environment. To survive and proliferate in the austere tumor microenvironment, pancreatic cancer cell reprogram their metabolism. Thus, elucidating this metabolic rewiring could reveal metabolic vulnerabilities that may be targeted for therapy.
We have previously demonstrated that pancreatic cancer cells rely on a non-canonical glutamine metabolic pathway. The first step of this pathway is mediated by glutaminase (GLS), which converts glutamine into glutamate. Studies have shown that CB-839, an orally bioavailable GLS inhibitor, is effective in inhibiting pancreatic cancer proliferation in vitro but not in vivo. Thus, a combination therapy that increases the efficacy of CB-839 is needed.
Further literature search identified that the hexosamine biosynthetic pathway (HBP) is up-regulated in pancreatic cancer. HBP is an evolutionarily conserved metabolic pathway whose end product is a crucial precursor for glycosylation and O-GlcNAcylation, which are essential post-translational modifications. Like GLS1, the first and rate-limiting enzyme of the HBP, glutamine fructose-6-phosphate amidotransferase 1 (GFAT1), also generates glutamate from glutamine. We propose that inhibition of GFAT1 could lead to a higher GLS activity as a compensatory mechanism to restore the intracellular glutamate levels. In conclusion, we hypothesize that inhibition of the hexosamine biosynthetic pathway can sensitize pancreatic cancer to CB-839.
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Research Disciplines
Health Sciences, Life Sciences
