Targeting the PI3K signaling cascade in PIK3CA mutated endometrial cancer in a primary human xenograft model

• Published in: Journal of clinical oncology Vol. 31; no. 15_suppl; p. e13564
• Main Authors: Bradford, Leslie Siriya, Rauh-Hain, Jose Alejandro, Clark, Rachel Marie, Groeneweg, Jolijn W, Zhang, Ling, DiGloria, Celeste M, Borger, Darrell R., Growdon, Whitfield Board, Schorge, John O., Foster, Rosemary, Rueda, Bo R
• Format: Journal Article
• Language: English
• Published: 20.05.2013
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2013.31.15_suppl.e13564

Abstract only e13564 Background: Alterations in the PI3K pathway are highly prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. Given these data, we investigated the anti-tumor activity of the PI3K inhibitor NVP-BKM120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. Methods: NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were randomly divided into two- and four-arm cohorts with equivalent tumor volumes. Three single agent experiments tested the effectiveness of NVP-BKM120 against two endometrioid (PIK3CA wild type and H1047L mutant) and one carcinosarcoma (PIK3CA R88Q mutant) endometrial cancer. Three four arm experiments tested NVP-BKM120 alone and in combination with paclitaxel and carboplatin (P/C) in two endometrioid tumors (both R88Q) and one carcinosarcoma (no PIK3CA mutation detected). Following in vivo study, tumors from the NVP-BKM120 , P/C, P/C+ NVP-BKM120 and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. Wilcoxan rank sum analysis was utilized to compare tumor growth across all treatment experiments. Results: In endometrioid single agent experiments, NVP-BKM120 resulted in tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p<0.04 in all experiments). In all experiments, tumor resurgence manifested between days 14-25 (p<0.03). When combined with P/C, the NVP-BKM120 resistance pattern failed to develop in all three xenograft lines (p<0.05) while synergistic tumor growth suppression (p< 0.05) of only one xenograft tumor harboring the R88Q mutation was observed. Acute treatment with NVP-BKM120 led to a decrease in pAKT, whereas, there was no difference in pAKT levels following chronic therapy compared to vehicle. Conclusions: These data suggest that NVP-BKM120 mediated inhibition of the PI3K pathway in endometrial tumors with and without a PIK3CA mutation precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.