Alterations in nutritional requirements, such as increased glucose consumption, are known to be a defining feature of cancerous cells. However, many of the metabolic processes governing these alterations are difficult to target pharmacologically due to significant toxicity to healthy cells. This creates a need for alternative therapeutic approaches, as well as the identification of genetic aberrations that may confer metabolic vulnerabilities inherently exclusive to tumor cells. Interestingly, it has been shown that many cancers (~15%) exhibit homozygous deletions of chromosome 9p21, which encodes for both the tumor suppressor protein p16 and the methionine salvage enzyme MTAP. I propose that deletion of MTAP induces an altered metabolic profile in cancer cells that can confer a differential responsiveness to amino acid deprivation, and that this alteration can ultimately enhance tumor sensitivity to dietary nutrient availability. Furthermore, I believe that this altered sensitivity will not be dependent on the tissue of origin.
In aim 1, I will utilize state of the art metabolomics technology to generate metabolic profiles of human cancer cell lines both with and without endogenous MTAP deletion, originating from multiple tissues. I will then characterize the shifts in metabolite expression in these cell lines in response to nutrient deprivation, and determine what role MTAP status has in mediating these differences in adaptation.
In aim 2, I will observe whether tumors exhibiting deletion of MTAP display an enhanced sensitivity to dietary methionine restriction. The outcome of this study will contribute to our understanding of gene-environment interactions in the context of tumor metabolism and cancer outcome, as well as potentially uncover dietary intervention as a novel therapeutic approach in the treatment of this large subset of cancers.

Public Health Relevance

There exists a scarcity of research investigating how lifestyle factors such as diet can impact tumor metabolism and contribute to cancer treatment. Utilizing state of the art metabolomics technology, the proposed study investigates which genetic factors may enhance tumor sensitivity to dietary nutrient availability. This study has the potential to uncover dietary intervention as a novel therapeutic for a large subset of cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA224973-02
Application #
9638426
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schmidt, Michael K
Project Start
2018-02-01
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705