Abstract 4910: Unveiling the role of network and systems biology in pancreatic cancer drug discovery
Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL

Over the last half decade our laboratory has extensively worked on the preclinical development of small molecule inhibitor of HDM2 (MI-219-Ascenta Therapeutics) in multiple tumor models with especial emphasis on the intractable pancreatic cancer (PC). During this discourse we have observed significant anti-tumor activity when MI-219 was given with oxaliplatin that lead to tumor free survival in 50% of the animals. However, not much is known about the exact mechanism behind this synergy. Here we applied a network-centric approach to identify the global expression changes and the networks involved in this two drug combination without losing the key molecular details. Gene analysis of wt-p53 capan-2 cells shows that MI-219 alone induces a minimal alteration (only 48 genes). Oxaliplatin (a cytotoxic drug) treatment, on the other hand showed alterations of 700 genes. However, the combination of MI-219-oxaliplatin resulted in emergence of 286 synergy unique genes. Principal component analysis revealed that each drug treatment had unique global gene signatures. Further analysis of the synergy unique genes revealed the presence of 14 statistically enriched functional pathways. Overall, the central p53 activity hub was found to be supported by 5 crucial players; CREBBP which is ubiquitously expressed in PC and is involved in the transcriptional co-activation of p53. CARF that is responsible for p53 stability along with NF-κB and EGR1 tumor suppressor modules, all positively affecting p53 re-activation that drives cells towards apoptosis. Additionally, our analysis revealed a novel role of hepatocyte nuclear factor alpha (HNF4α) in aiding this synergy. In addition to PC, the gene signatures could be verified and validated at the RNA and protein level in multiple wt-p53 solid tumor cell lines like MCF-7 for breast and HCT-116 for Colon. siRNA knockdown of key network genes abrogated apoptotic potential of MI-219-oxaliplatin in all three cell lines and confirmed their key role in the observed anticancer effects of this combination. Our findings show that Network and Systems biology can be utilized in identification of crucial driver genes and help in the design of drug combinations in a genetically pre-defined subset of patients that would positively impact treatment outcome.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4910. doi:10.1158/1538-7445.AM2011-4910