Abstract 4826: ONC212 exhibits increased cytotoxicity relative to ONC201 in a subset of human pancreatic cancer cell lines

Abstract

Abstract Pancreatic cancer is one of the most deadly types of cancer with five-year survival rate of ∼6%. This poor prognosis is attributed to aggressive growth of the tumor cells, metastasis at an early stage and resistance to standard chemotherapy. Therefore, finding new treatments and improving outcomes of pancreatic cancer patients have been high priorities. ONC201 is a small molecule that selectively targets a broad range of tumor types tested. It is currently in phase I/II clinical trials for advanced solid, hematopoietic, and lymphoid tumors. The ONC201 analogue, ONC212, is in preclinical development for certain cancers that are not lead indications for the parent compound ONC201. We examined the efficacy of ONC201 and ONC212 in a panel of human pancreatic cancer cell lines. Among seven cell lines tested, three cell lines were relatively insensitive to ONC201, with IC50 values of 100 ìM or greater. However, these cell lines showed greater sensitivity to ONC212 with IC50 values of 31-56 ìM. We compared ONC201-resistant PANC-1 cells and ONC201-sensitive HPAF-II cells. Both ONC201 and ONC212 induced apoptosis in HPAF-II cells, as assessed by PARP cleavage, while PARP cleavage was detected only when PANC-1 cells were treated with ONC212 but not ONC201. We are currently evaluating the efficacy of ONC201 and ONC212 in a panel of patient-derived low passage pancreatic cancer cell lines. We found a correlation between high expression levels of RTKs (c-MET, ALK, EGFR, IGFR, HER2) and decreased sensitivity to ONC201 in pancreatic cancer cell lines. We investigated the effect of ONC201 on EGFR and IGFR, which are highly expressed in PANC-1 and found that ONC201 does not inhibit receptor activation by the specific growth factors. We are studying the effects of ONC201 and ONC212 on RTKs and their signal transduction pathways. Lastly, since aggressive drug-resistant pancreatic cancer cells express high levels of RTKs, we are developing a rationale combining ONC201/ONC212 with specific small molecule RTK inhibitors such as crizotinib or lapatinib. We are exploring these combination treatments using cell lines, organoids and PDX models to unravel specific therapy options for therapy-refractory pancreatic cancer cells. Our goal is to provide the preclinical rationale for clinical trials of ONC201 or ONC212 as mono-agents or in combination with other therapies for pancreatic cancer patients. Citation Format: Avital Lev, Jessica Wagner, David T. Dicker, Martin Stogniew, Joshua E. Allen, Lee Schalop, Wolfgang Oster, Gary L. Olson, Wafik S. El-Deiry. ONC212 exhibits increased cytotoxicity relative to ONC201 in a subset of human pancreatic cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4826.