Abstract LB-294: Targeting glutamine addiction of PIK3CA mutant colorectal cancers: From preclinical models to clinical trials

Abstract

Abstract Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. As a metabolite, glutamine is first converted to glutamate by glutaminase (GLS) and then to α-ketoglutarate (α-KG) by either a transaminase or a glutamate dehydrogenase. PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is frequently mutated in human cancers including 20 to 30% of colorectal cancer (CRC). We found that oncogenic PIK3CA mutations render CRCs addicted to glutamine through an upregulation of glutamate pyruvate transaminase 2 (GPT2), thereby facilitating conversion of glutamate to α-KG. Here, we report that CB-839, a potent GLS inhibitor developed by Calithera Biosciences, inhibits xenograft tumor growth of PIK3CA mutant, but not WT, colorectal cancers. Remarkably, combination of CB-839 with 5-fluorouracil (5-FU) induces regression of xenograft tumors in four different PIK3CA mutant CRC models. These exciting preclinical data prompted us to perform a Phase I and Phase II clinical trial to assess combination of CB-839 with capecitabine, an oral prodrug of 5-FU. For the Phase I trial, patients with advanced solid tumors and disease progression on standard treatment, or for whom capecitabine is an acceptable treatment option, were enrolled. A standard 3+3 design was used to assess escalating doses of CB-839 (400-800 mg) and capecitabine (500-1000 mg/m2) in four dose levels. CB-839 was given orally twice daily continuously and capecitabine was given orally twice daily on days 14/21 of a 21 day treatment cycle. Dose-limiting toxicity period was 21 days. Restaging CT scans were obtained every 9 weeks with response assessment per RECIST. Adverse events were assessed per CTCAEv4. Sixteen patients were enrolled with 7 patients being treated at the final dose level (CB-839 800 mg and Capecitabine 1000 mg/m2). No dose-limiting toxicity were observed. Ten patients achieved stable disease as their best response with 9 being fluoropyrimidine resistant. Among the 16 patients, 12 were CRC patients who were 5-FU resistant. Consistent with our preclinical data, the median progress-free survival (PFS) of seven PIK3CA mutant CRC patients was 25 weeks, whereas the median PFS of five PIK3CA WT CRC patients was 16 weeks. Notably, the PFS of three PIK3CA mutant CRC patients was over six months (8, 9 and 13 months respectively). A Phase II trial of the drug combination in metastatic PIK3CA mutant CRC patients is ongoing. In summary, our preclinical and clinical studies suggest that targeting glutamine metabolism may be a promising approach to treat CRCs with PIK3CA mutations. Citation Format: Yiqing Zhao, Jennifer Eads, David Bajor, zhenghe wang. Targeting glutamine addiction of PIK3CA mutant colorectal cancers: From preclinical models to clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-294.