Abstract B07: Screening of patient-derived carcinoma cells and animal models identifies transcription as target in pancreatic cancer.

Abstracts: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; February 11-14, 2016; New Orleans, LAPancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy that affects 44,000 individuals yearly in the US. With almost 90% lethality even when diagnosed prior to metastasis, there is an urgent unmet medical need for new therapies or better matching of existing therapies to patients. To address this emergency, we first had developed a panel of new physiological models for study of PDAC, rapidly expanding surgical PDAC tumor samples in culture with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). Using this panel, we evaluated sensitivity to a large panel of existing drugs. Only a small minority of agents were cytotoxic in vitro in a significant number of independent PDAC models. Among these, transcriptional repressors were predominated. From a short list of drugs not previously used in PDAC, triptolide, a covalent inhibitor of the ERCC3, a bifunctional regulator of transcription and DNA repair, was most consistently effective in vitro and highly effective in vivo, causing prolonged complete regression in multiple PDX models. Triptolide is a natural product compound from Chinese medicinal plant Tripterygium wilfordii, and it was found to be the most active agent in the screen. Importantly, triptolide showed superior activity in MYC-amplified PDX models, suggesting a critical role for ERCC3 in this subset. Triptolide elicited rapid and profound depletion of MYC oncoprotein, a transcriptional co-factor for ERCC3. Expression of ERCC3 was MYC-dependent, while resistance to triptolide was associated with elevated ERCC3 and MYC expression. These findings provide preclinical evidences for transcriptional vulnerability in PDAC via ERCC3 targeting and a new mechanistic approach for disruption of MYC-dependent pancreatic cancers.Citation Format: Vladimir Khazak, Natalia Skobeleva, Natalia Beglyarova, Egor Bobrov, Yan Zhou, Sandra A. Jablonski, Louis M. Weiner, Keren Paz, Igor Astsaturov. Screening of patient-derived carcinoma cells and animal models identifies transcription as target in pancreatic cancer.. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B07.