Abstract 4804: Pre-clinical development of ISOX; A novel therapy for pancreatic cancer identified utilizing system biology approach(s)

Abstract

Abstract Background: Pancreatic Cancer (PC) remains one of the most common causes of cancer-related deaths. The low survival percentage in patients can be attributed primarily to ineffective therapeutic targeting and lack of new potent therapies. Over the years the conventional one target at a time approach for drug development has failed to achieve promising survival and better approaches are needed. Large-scale genomic database connectivity map (CMAP), a collection of perturbagen profiles from >2800 drugs is a potential tool to identify effective therapies for PC by identifying novel drugs that essentially reverse the global gene signature originating due to malignant PC. Considering this information, we hypothesize that “a big data approach using CMAP will lead to the identification of novel drugs for highly lethal PC.” Methods and Results: To generate a meta-gene signature for PC, GEO data for PC cases (N=106) and normal samples (N=68) was extracted, normalized & assessed for differential gene expression using R Bioconductor. Drugs specific to this gene signature across various datasets were identified using CMAP and the top hit ISOX chosen for further assessment. Considering the high mutational heterogeneity of PC, a five-cell line panel with diverse mutations was chosen for the validation studies. Cell line-based assessment for changes to proliferation using MTT and motility using matrigel assisted invasion showed the high potency of ISOX with an IC50 of 2.4nM-1.4µM & up to 90% reduction in invasion supporting initial hypothesis. It was further supported by the 48% induction of apoptosis. Molecular mechanism of ISOX was further assessed using an RNA-seq on ISOX treated PC cell lines followed by ingenuity pathway analyses. Gene ontology pathway analysis indicated SHH-WNT, PI3K-mTOR-AKT, and EGFR signaling as key pathways affected by ISOX. Further, 60% loss of viability was observed in pancreatic tumor organoids at 500nM of ISOX. Furthermore, about 10 fold statistically significant (p-value = 0.014) reduction in tumor weight at 50 mg/kg of ISOX both alone and in combination with 50 mg/kg 5FU (p-value=0.02) was observed in orthotopic mice models. Conclusion: Our data suggest that ISOX is a potential new therapeutic for PC. In future, we aim to evaluate the potency of newly identified drug in both transgenic mouse models of PC as well as clinical phase I studies. Citation Format: Pranita Atri, Parthasarathy Seshacharyulu, Satyanaryana Rachagani, Palanisamy Nallasamy, Sanchita Rauth, Garima Kaushik, Koelina Ganguly, Dario Ghersi, Moorthy P. Ponnusamy, Sukhwinder Kaur, Surinder K. Batra. Pre-clinical development of ISOX; A novel therapy for pancreatic cancer identified utilizing system biology approach(s) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4804.