Abstract 1465: Development of patient-derived platform to assess activity of anticancer agents in pancreatic cancer

Abstract

Abstract Pancreatic cancer (PDAC) affects 44,000 individuals yearly in the US. This cancer is almost universally lethal, with a very limited efficacy of approved chemotherapy (gemcitabine, nab-paclitaxel, platinum, 5FU). Clinical trials seeking to expand the portfolio of anti-cancer agents active in PDAC have been largely unsuccessful. PDAC is almost always characterized by activating mutations in the KRAS oncogene, which is difficult to directly inhibit, focusing therapeutic strategies on inhibiting downstream KRAS effectors in the RAF-MEK-ERK signaling cascade. However, disruption of these effectors has been complicated by the existence of extensive redundancies in signaling leading to rapid reversal of inhibition. Thus, there is a clear and urgent need for the development of new anti-PDAC agents as well as reliable models of PDAC that better recapitulate biological properties of pancreatic cancer. Here, we report on the development of a new drug screening platform to evaluate the activity of existing and emerging chemotherapeutics against pancreatic cancer. Surgically resected pancreatic tumors were implanted in immunocompromised mice to develop direct patient-derived xenografts (PDX). Cell lines derived from the PDX models were subsequently screened for proliferation and viability following exposure to 867 clinical grade or FDA approved drugs. Top hits were then validated in mice bearing the PDX tumors as well as in a genetically modified KRAS/p53 mutant mouse model of pancreatic cancer (KPC). Triptolide, a natural product compound from Chinese medicinal plant Tripterygium wilfordii, was found to be the most active agent in the screen. In vivo, triptolide produced complete tumor regressions for up to 6 weeks in c-Myc amplified PDX models. Molecular analysis revealed the specific ability of triptolide to quickly deplete c-Myc protein in Myc-amplified cancers by binding and inactivating ERCC3 protein. Finally, we used our PDX platform to evaluate the activity of a novel anticancer agent STA-12-8666 (Synta Pharmaceuticals), a small molecule drug conjugate consisting of a tumor selective delivery moiety (HSP90 inhibitor) attached via a cleavable linker to SN38, the active metabolite of the topoisomerase I inhibitor irinotecan. HSP90 inhibitors and irinotecan, members of the screening library, showed only modest activity when tested individually in the primary pancreatic cell lines and PDAC PDX models suggesting that the potent antitumor activity of STA-12-8666 is due in part to its tumor targeted delivery and prolonged SN38 exposure. Thus, STA-12-8666, that provides targeted delivery to the tumor with activated HSP90, was significantly more effective than irinotecan in all pancreatic PDX models tested, and providing complete, durable responses in a subset. In conclusion, our patient-derived platform provides a valuable tool for preclinical analysis of promising therapeutic agents for treatment of pancreatic cancer. Citation Format: Vladimir Khazak, Natalia Skobeleva, Natalia Beglyarova, Eugenia Banina, Elena Lysenko, Igor Astsaturov, Sandra A. Jablonski, Louis M. Weiner, Ilya Serebriiskii, David A. Proia. Development of patient-derived platform to assess activity of anticancer agents in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1465. doi:10.1158/1538-7445.AM2015-1465