Abstract 1251: Fisetin for the management of PIK3CA-mutant colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths in the United States and is one of the most frequent and deadliest cancers worldwide. The relative survival rate is very poor for patients with metastatic CRC, regardless of the progress in chemotherapy. 5-Fluorouracil (5-FU) is widely used chemotherapeutic drug for the treatment of colon cancer, and the efficacious tumor therapy is generally obstructed by the progression of tumor resistance mechanisms. PIK3CA is one of the most frequently mutated genes in CRC, as about 15-20% of advanced CRC harbor activating mutations in PIK3CA exon 9 and/or exon 20. Therefore, modeling the effects of this type of mutation in the mammalian colon is significant. Fisetin (3,3',4',7-tetrahydroxyflavone), a naturally occurring flavonoid, is present in several fruits and vegetables. We have earlier shown that treatment of PIK3CA-mutant colon cancer cells with fisetin and 5-FU caused induction of apoptosis, decrease in the expression of PI3K, phosphorylation of Akt, phosphorylation of mTOR and its target proteins with an increase in the phosphorylation of AMPKα. Based on these exciting results, we determined the effect of the treatment of combination of fisetin and 5-FU on the multiplicity of colonic tumors and on the regression of invasive adenocarcinomas in FC13K1ApcMin/+ mice. In this in-vivo model of colon cancer, synergy exists between the loss of the tumor suppressor APC and the presence of a dominant active PI3K. The tumors form as adenomas, progress to invasive adenocarcinomas and eventually metastasize to regional lymph nodes, as observed in human patients. The anti-tumorigenic properties of fisetin were tested by treating these mice either early when mice had no or few visible colon polyps and late when mice had developed cancers. The treatment regime was the same for both groups. The only difference was age when treatment initiated; the early group started treatment between 25 and 30 days, whereas late group started treatment between 45 and 50 days. In the early treatment groups, fewer fisetin-treated mice developed tumors than controls and fisetin-treated animals bearing tumors developed fewer colon tumors than controls. We also found that 5-FU suppressed growth of tumors and the effects of fisetin and 5-FU are additive. At the end of the experiment, as compared to control group, there was 27% decrease in tumor counts on treatment of animals with 5-FU, 36% decrease with fisetin and 49% decrease on treatment with combination of fisetin and 5-FU. There was also decrease in tumor incidence on treatment of animals with fisetin and combination of fisetin and 5-FU. Treatment with fisetin, 5-FU, or the combination did not appear to affect tumorigenesis when given late. Interestingly, the activation of PI3K appears to make 5-FU less effective at this stage. Our data suggest that fisetin could be used as a preventive agent as well as an adjuvant with 5-FU for the prevention of PIK3CA-mutant CRC. Citation Format: Naghma Khan, Farah Jajeh, Devon Miller, Rachel Van Doorn, Emily Lauren Eberhardt, Richard B. Halberg, Hasan Mukhtar. Fisetin for the management of PIK3CA-mutant colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1251.