Abstract CT338: Combination of a PI3K- and a PARP-inhibitor to treat high-grade serous ovarian or triple-negative breast cancer
Authors: Wulf Gerburg M. , Juvekar Ashish , Lyssiotis Costas A. , Hu Hai , Yadegarynia Sina , Liu Hui , Kim Baek , Winter Eric , Scully Ralph , Asara John , Cantley Lewis C. , Matulonis Ursula 
Published: May 2015

Abstract
Clinical trials have shown promising responses of BRCA-linked breast and ovarian cancers to PARP inhibitor therapy, but remissions are often short-lived and incomplete. The PI3K pathway is frequently activated in these malignancies. Recently, we reported in vivo synergy of a PI3K- and a PARP-inhibitor in a mouse model of BRCA1-related breast cancer. While the PARP-inhibitor olaparib alone attenuated tumor growth modestly, a dramatic reduction in tumor growth was observed when olaparib was combined with the PI3K-inhibitor BKM120. In BRCA1-mutant HCC1937 BC cells, PI3K- (but not akt-) inhibition increased indicators of DNA damage, such as poly-ADP-ribosylation and γH2AX, suggesting a critical role of PI3K activity for the maintenance of genomic stability. Here, we report on the molecular mechanism underlying this synergy, on treatment outcomes in an improved mouse model system and the development of an early-phase clinical study. Pre-clinical modeling was done in BRCA1-mutant HCC1937 cells and in a mouse model based on the syngenic transplantation of tumors derived on the K14-Cre BRCA1f/fp53f/f background. Metabolic profiling in vitro and in vivo showed that PI3K-inhibition decreased flux through glycolysis and specifically through the non-oxidative pentose-phosphate pathway, the main source of ribose-5-phosphate required for the de novo synthesis of nucleotides in HCC1937 cells. Within 3 hours and preceding cell cycle changes, BKM120 caused a decrease in nucleotide pools that was further exacerbated by the addition of olaparib. Nucleotide shortage led to to replication stress with the appearance of γH2AX and increased poly-ADP-ribosylation. Tumors with complete loss of BRCA1 and p53 proved particularly vulnerable to this treatment strategy. We were able to induce complete and durable remissions of murine tumors arising on the K14-Cre BRCA1f/fp53f/f background with a 28-day course of BKM120 and Olaparib. These preclinical data have served as the rationale for a phase I, multi-center study (NCT01623349) combining the oral PARP inhibitor olaparib with the oral PI3-kinase inhibitor BKM120 in patients with recurrent HGSC or recurrent TNBC. The study is being conducted through the Stand Up to Cancer (SU2C)'s Targeting PI3-kinase in Women's Cancers Dream Team. It has a 3 + 3 design, escalating if 0/3 or 1/6 participants have a DLT during the first cycle of therapy. The study objectives are to determine the recommended phase II dose (RP2D) of daily continuous oral olaparib (using the tablet formulation) and BKM120, assess toxicities, safety, and preliminary activity of this combination, and determine pharmacokinetic profiles of both agents as well as translational endpoints. The study serves as an example for the development of a clinical trials concept for TNBC and HGSC based on a close collaboration of basic and clinical scientists through the SU2C mechanism.
Citation Format: Gerburg M. Wulf, Ashish Juvekar, Costas A. Lyssiotis, Hai Hu, Sina Yadegarynia, Hui Liu, Baek Kim, Eric Winter, Ralph Scully, John Asara, Lewis C. Cantley, Ursula Matulonis. Combination of a PI3K- and a PARP-inhibitor to treat high-grade serous ovarian or triple-negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT338. doi:10.1158/1538-7445.AM2014-CT338