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 #
2P50CA150964-06A1
Application #
9353963
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2017-09-04
Budget End
2018-07-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Berger, Nathan A; Scacheri, Peter C (2018) Targeting Epigenetics to Prevent Obesity Promoted Cancers. Cancer Prev Res (Phila) 11:125-128
Cooper, Gregory S; Markowitz, Sanford D; Chen, Zhengyi et al. (2018) Evaluation of Patients with an Apparent False Positive Stool DNA Test: The Role of Repeat Stool DNA Testing. Dig Dis Sci 63:1449-1453
Somasundaram, Saigopal; Forrest, Megan E; Moinova, Helen et al. (2018) The DNMT1-associated lincRNA DACOR1 reprograms genome-wide DNA methylation in colon cancer. Clin Epigenetics 10:127
Codipilly, Don Chamil; Chandar, Apoorva Krishna; Singh, Siddharth et al. (2018) The Effect of Endoscopic Surveillance in Patients With Barrett's Esophagus: A Systematic Review and Meta-analysis. Gastroenterology 154:2068-2086.e5
Petersen, Christine P; Meyer, Anne R; De Salvo, Carlo et al. (2018) A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach. Gut 67:805-817
Evans, Daniel R; Venkitachalam, Srividya; Revoredo, Leslie et al. (2018) Evidence for GALNT12 as a moderate penetrance gene for colorectal cancer. Hum Mutat 39:1092-1101
Otegbeye, Folashade; Ojo, Evelyn; Moreton, Stephen et al. (2018) Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models. PLoS One 13:e0191358
Desai, Amar; Zhang, Yongyou; Park, Youngsoo et al. (2018) A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independently of age, transplant dose and granulocyte colony-stimulating factor support. Haematologica 103:1054-1064
Chan, M Q; Blum, A E; Chandar, A K et al. (2018) Association of sporadic and familial Barrett's esophagus with breast cancer. Dis Esophagus 31:
Cummings III, Kenneth C; Zimmerman, Nicole M; Maheshwari, Kamal et al. (2018) Epidural compared with non-epidural analgesia and cardiopulmonary complications after colectomy: A retrospective cohort study of 20,880 patients using a national quality database. J Clin Anesth 47:12-18

Showing the most recent 10 out of 141 publications