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.
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Introduction: Variation in survival for out-of-hospital cardiac arrest (OHCA) has been described, but the intersection of urbanicity, race, and poverty and the impact on OHCA outcomes remains unclear. We sought to test whether rurality was associated with increased in-hospital mortality compared to urban and suburban communities when accounting for differences in poverty and race. Methods: We performed a retrospective analysis using 2013-2014 Medicare claims for inpatient stays originating in the emergency department. OHCA Patients (≥65 years) were identified by ICD-9-CM diagnosis code. Urbanicity was assigned based on county of residence using Rural-Urban Continuum Codes. Census data were used for county poverty and racial composition measures. Multivariate logistic regression was used to estimate the association of in-hospital mortality with urbanicity, percent of resident population in poverty, and percent black residency. Also included were individual, hospital, and community characteristics. Results: A total of 246,736 OHCA cases were identified of which 53% were male, 23% non-white, and 36% >75 years. Survival to discharge was 22%. Over 95% of OHCA patients resided in urban (85%) or suburban (11%) areas. Predicted probabilities of death (Figure) were lowest in suburban communities with moderate poverty and small black populations (0.76, CI 0.75-0.76) and highest in urban areas with moderate poverty and larger black populations (0.80, CI 0.80-0.81). All areas with high poverty and larger black populations had similar predicted probabilities (0.77-0.78), regardless of urbanicity. Conclusions: Suburban residence was associated with lower odds of mortality, even in communities with high levels of poverty. Communities with moderate poverty showed the greatest spread of outcomes in all 3 urbanicity categories. Further work should explore access to care, social determinants of health, and hospital factors that lead to the observed disparities.
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