The overarching goal of this project is to develop precision therapies that target glutamine metabolism of colorectal cancers (CRCs) that harbor PIK3CA mutations. As a metabolite, glutamine is first converted to glutamate by glutaminase and then to ?-ketoglutarate (?-KG) by transaminases to replenish the tricarboxylic acid (TCA) cycle. This proposal is based on our preliminary studies showing that: (i) CRCs with PIK3CA mutations are addicted to glutamine through upregulation of glutamate pyruvate transaminase 2 (GPT2); (ii) a glutaminase inhibitor, CB-839, suppresses the growth of PIK3CA mutant CRC xenografts; (iii) aminooxyacetate (AOA), an inhibitor of GPT2 and other aminotransferases, inhibits the growth of PIK3CA mutant CRC xenografts; (iv) neither CB-839 nor AOA inhibit growth of CRC xenograft with WT PIK3CA; and (v) combination of CB-839 with 5-FU overcomes resistance to 5-FU alone in xenografts.
In Aim 1, we will elucidate the mechanisms by which CB-839 augments the activity of 5-FU in PIK3CA mutant CRCs.
In Aim 2, we will perform clinical trials to assess the pharmacodynamic effects and clinical activity of CB-839 in CRC patients with PIK3CA mutant tumors.
In Aim 3, we will develop more potent and specific GPT2 inhibitors as tool compounds to validate GPT2 as a viable cancer target. One of the PIs (ZW) co-discovered that PIK3CA is highly mutated in many human cancers, including ~20% of CRCs. These studies will lead to an innovative selective approach to treating CRC patients whose tumors harbor PIK3CA mutations, and development of novel GPT2 inhibitors that could be further developed as potential anti-cancer drugs.

Public Health Relevance

Colorectal cancer is the second most common cause of cancer deaths in the United States, with 133,000 new cases and 50,000 deaths per year. Thus, novel therapies are urgently needed to treat this deadly disease. The goal of this project is to develop a new personalized approach to treat colorectal cancers. We discovered that colorectal cancers that have an abnormality (called a mutation) in a gene called PIK3CA require a particular nutrient, glutamine, to grow. We were able to cure mice with abnormal PIK3CA colorectal cancers, by giving a drug that interferes with glutamine. In this project we will perform a clinical trial that will be the first test of treating human colon cancer patients, whose tumors have PIK3CA mutations, with a new drug that blocks tumor's ability to use glutamine. In parallel we will do lab studies to better understand how this treatment works, and how to improve it further.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA150964-07
Application #
9557000
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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