Jonathan R. Brody

Abstract 394: Novel pan-PIM/pan-PI3K/mTOR inhibitors are highly active in preclinical models of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal and morbid malignancies today. Although newer chemotherapy regimens such as FOLFIRINOX and gemcitabine/nab-paclitaxel have made modest improvements in patient survival, more effective therapies are needed. With the exception of the EGFR inhibitor erlotinib, there are no approved, targeted therapies for metastatic PDA. Recent work demonstrated the importance of PIM kinases, particularly PIM1 and PIM3, in PDA. PIM kinases are involved in apoptosis, cell cycle progression, DNA damage repair mechanisms, and drug resistance mechanisms. Our work showed that hypoxic stress causes the RNA binding protein HuR to translocate to the cytoplasm where it stabilizes PIM1 mRNA leading to increased levels and activity of PIM1. Activation of PIM1 led to oxaliplatin resistance in a hypoxia specific manner and validated PIM19s upregulation upon drug exposure as a potential target for therapeutic inhibition in PDA. The KRas/PI3K/mTOR signaling pathway has been well described in PDA and PI3K as well as dual PI3K/mTOR inhibitors are currently in clinical development. Inflection Biosciences is currently developing IBL-202, a pan-PIM/pan-class I PI3K inhibitor and IBL-301, a pan-PIM/pan-class I PI3K/mTOR inhibitor. These compounds show good oral bioavailability in preclinical PK studies. Unlike prior attempts at PIM inhibition, these compounds do not interact with hERG channels or CYP enzymes, decreasing the likelihood of drug-drug interactions or prolonged QTc. Furthermore, toxicity studies in rodent models demonstrate that the compounds are well tolerated at 200mg/kg and 400mg/kg doses. Our work shows that IBL-202 and IBL-301 have significant preclinical activity in PDA cell lines with diverse genetic backgrounds, including PL5, Panc-1, and HS776t cells. Using PICOgreen assays, we show that the IC50 for IBL-202 ranges from 400nM (PL5) to 800nM (HS776t). The IC50 of IBL-301 ranges from 80nM (PL5) to 400nM (HS776t). As the PIM and PI3K pathways are important for inhibition of apoptosis, we tested the ability of these compounds to induce an apoptotic response. Cells treated for 48 hours at IC50 levels of IBL-202 showed positive cleaved caspase 3/7 staining in 31% (Panc-1) to 90% (HS776t) as examined by flow cytometry. IBL-301 elicited a positive cleaved caspase 3/7 in 28% (Panc-1) to 91% (PL5) of cells. Mechanistically, PIM and PI3K are known to lead to G1/S cell cycle progression through phosphorylation of p21 and p27. PDA cell lines dosed at IC50 levels show a potent G1 to S arrest at 48 hours in all cell lines tested. Overall, this work provides the rationale for the further preclinical development of IBL-202 and IBL-301 in PDA pre-clinical models in an effort to move these compounds towards early phase trials. Citation Format: Kevin O’Hayer, John Barbe, Avinoam Nevler, Michael O’Neill, Darren Cunningham, Jordan Winter, Jonathan Brody. Novel pan-PIM/pan-PI3K/mTOR inhibitors are highly active in preclinical models of pancreatic ductal adenocarcinoma. [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 394.

Prevalence of Homologous Recombination–Related Gene Mutations Across Multiple Cancer Types

PurposenThe prevalence of homologous recombination DNA damage repair (HR-DDR) deficiencies among all tumor lineages is not well characterized. Therapy directed toward homologous recombination DDR deficiency (HRD) is now approved in ovarian and breast cancer, and there may be additional opportunities for benefit for patients with other cancers. Comprehensive evaluations for HRD are limited in part by the lack of a uniform, cost-effective method for testing and defining HRD.nnnMethodsnMolecular profiles of 52,426 tumors were reviewed to identify pathogenic mutations in the HR-DDR genes ARID1A, ATM, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, or WRN. From solid tumors submitted to Caris Life Sciences, molecular profiles were generated using next-generation sequencing (NGS; average read depth, 500×). A total of 17,566 tumors were sequenced with NGS600 (n = 592 genes), and 34,860 tumors underwent hotspot Illumina MiSeq platform testing (n = 47 genes).nnnResultsnOf the tumors that underwent NGS600 testing, the overall frequency of HRDDR mutations detected was 17.4%, and the most commonly mutated lineages were endometrial (34.4%; n = 1,475), biliary tract (28.9%; n = 343), bladder (23.9%; n = 201), hepatocellular (20.9%; n = 115), gastroesophageal (20.8%; n = 619), and ovarian (20.0%; n = 2,489). Least commonly mutated lineages included GI stromal (3.7%; n = 108), head and neck (6.8%; n = 206), and sarcoma (9.3%; n = 592). ARID1A was the most commonly mutated gene (7.2%), followed by BRCA2 (3.0%), BRCA1 (2.8%), ATM (1.3%), ATRX (1.3%), and CHEK2 (1.3%).nnnConclusionsnHR-DDR mutations were seen in 17.4% of tumors across 21 cancer lineages, providing a path to explore the role of HRD-directed therapies, including poly-ADP ribose polymerase inhibitors, DNA-damaging chemotherapies, and newer agents such as ATR inhibitors.