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

Abstract

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 PIM1's 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.

The dual inhibitor of the phosphoinositol‐3 and PIM kinases, IBL‐202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment

“…Pre‐clinical studies in CLL (Chen et al , 2009c; Decker et al , ; Cervantes‐Gomez et al , ), other haematological malignancies (Garcia et al , ; Keane et al , ; Brunen et al , ; Nair et al , ; Paino et al , ) and solid tumours (Chen et al , 2009b, ; Foulks et al , ; Braso‐Maristany et al , ; O'Hayer et al , ; Warfel et al , ), suggest that, owing to their important roles in tumour cell biology, the PIM family of kinases may represent targets for novel, single agent or combination therapies. This concept is illustrated by a recent study in which the combination of a PIM and a PI3 kinase inhibitor, NMS‐P645 and GDC‐0941 respectively, had significantly more anti‐proliferative activity than either inhibitor alone against pancreatic cancer cells (Mologni et al , ).…”

“…The PIM kinases are a family of serine/threonine kinases with documented roles in drug‐resistance (Chen et al , 2009a), apoptosis (Braso‐Maristany et al , ), cell cycle (Chen et al , ) and DNA damage repair (Chen et al , ). In pancreatic ductal carcinoma (PDA) an increase in PIM1 expression induced during hypoxic stress was concomitant with resistance to oxaliplatin (O'Hayer et al , ), while induction of PIM2 expression in an in vitro stromal co‐culture model of multiple myeloma was associated with resistance to the proteasome inhibitor bortezomib (Reidy et al , ). Pre‐clinical studies suggest that further investigation of PIM kinase inhibitors may also be warranted in CLL (Chen et al , 2009c; Decker et al , ; Garcia et al , ), although no studies to date have examined the effects of inhibitors of either the PIM or PI3 kinases on CLL cells under reduced oxygen tensions.…”

“…Studies in multiple myeloma (Reidy et al , ) and PDA (O'Hayer et al , ) demonstrate the potential of IBL‐202, an inhibitor of both the PIM and PI3 kinases, for the treatment of a variety of tumour types under conditions that mimic the tumour microenvironment and confer resistance to more conventional therapies. In the current study, we explored the effects of IBL‐202 under in vitro conditions that mimic the hypoxic CLL tumour microenvironment (Herishanu et al , ).…”