Network Perspectives on HDM2 Inhibitor Chemotherapy Combinations

Asfar      S. Azmi; Frances      W.J. Beck; Fazlul      H. Sarkar; Ramzi      M. Mohammad

Abstract

The discovery of small molecule inhibitors of HDM2-p53 interaction is considered one of the most significant therapeutic developments in the area p53 research. Intensive work on different classes of HDM2 inhibitors has proven their therapeutic utility as activators of p53 in multiple tumor models. Many laboratories have shown that HDM2 inhibitors can synergize with chemotherapeutic agents resulting in enhanced efficacy through both p53-dependent and independent mechanisms. In our hands HDM2 inhibitor and platinum drug combination showed remarkable antitumor activity that led tumor free survival in one of the most resistant and complex pancreatic xenograft models. Although antitumor efficacy of such combinations has been studied in detail, not much is known on the molecular mechanisms governing this synergy. This is partly due to complexity of multiple pathways modulated by p53 and HDM2. We are of the view that in order to decode this complexity, an integrated approach is needed that considers both HDM2 and p53 as components of a network and not in isolation. This review highlights recent advancements in our understanding of HDM2 inhibitor combination therapy based on network modeling and systems biology driven science. Our recent findings support such a network view as integrated gene expression profiling and pathway network modeling on MI-219-oxaliplatin treated cells revealed activation of multiple and closely knit biological networks. We anticipate that in the near future such network-centric approaches will benefit clinical development of HDM2 inhibitors for genetically predefined subsets of cancer patients and this will be a step towards personalized medicine.

Keywords: p53, HDM2, HDM2 inhibitors, chemotherapy, combination therapy, network modeling, systems biology, tailored therapy, genome, pro-apoptotic, WAF1/CIP1, CDK1, CDK2 and CDK3, protein, N-terminal, Phosphorylation, cancers, Trp23, inhibitor-oxaliplatin, cDNA, HNF4A, amino acids