Biological Implications and Translational Applications of HDMX Inhibition

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The HDMX inhibition project encompasses a broad spectrum of research endeavors and has its roots on work that has published two years ago (see Bernal, et al. Cancer Cell 2010, 18, 411). There we have demonstrated that SAH-p53-8, a hydrocarbon stapled peptide based on the transactivation domain of p53, is capable of reactivating the p53 pathway in cells that overexpress either HDM2 or HDMX. While this finding is significant in the context that SAH-p53-8 is the only compound disclosed to date that is capable of disrupting p53-HDM2 and p53-HDMX protein complexes, this capability enabled us to elucidate a mechanistic framework for determining which cancer cells will be susceptible to single agent HDM2 or HDMX inhibition and overcoming p53 suppression in a resistant cell through synergistic targeting of HDM2 and HDMX. Soon after the publication of this work, we embarked on a collaboration with the group of Dr. Jean-Christophe Marine from the Laboratory for Molecular Cancer Biology at the Catholic University of Leuven in Belgium. Dr. Marine's research entails the determination of the causative agents responsible for the malignant transformation of melanocytes into melanoma. Dr. Marine's research has determined melanocyte specific overexpression of HDMX cooperates with mutations in Ras to promote the manifestation of melanoma. Moreover, their research has shown that 95% of all melanomas have wild type endogenous p53 and two-thirds overexpress HDMX. We demonstrated that the molecular blueprint we uncovered in our previous work indeed holds for melanoma. The results translate directly to the p53 transcription studies and the melanoma animal models studied in the Marine lab. The more significant discovery from this work is that HDMX is directly responsible for the resistance of metastatic melanoma towards traditional chemotherapeutic treatments such as cisplatin, melphalan and dacarbazine. In order for traditional chemotherapeutic agents to work, a fully functional p53 signaling system is necessary to induce apoptosis; however, sequestration by HDMX blocks p53 function thereby conferring upon the cancer cell resistance to cytotoxic agents. We have shown that inhibition of HDMX with SAH-p53-8 sensitizes melanoma cells to treatment with DNA damaging agents, potentially providing an additional avenue for the treatment of metastatic melanoma. This work has been recently published (see Gembarska, et al. Nature Medicine, 2012, 18, 1239). Similar studies focusing on other cancers are also being undertaken through collaborative efforts. We have been working with the group of Dr. Aart Jochemsen at the University of Leiden in the Netherlands on the applicability of HDMX inhibition towards the study and treatment of uveal melanoma. This work was recently submitted for publication. In expanding our research to more translational applications, we have expanded our research efforts to reflect the applicability of our discoveries. Given the newly found importance of HDMX inhibition in the context of drug resistance, we have begun a program in collaboration with the National Center for Advancing Translational Sciences (NCATS) to conduct a high throughput fluorescence polarization screen to find selective inhibitors of the p53-HDMX interaction. We are currently in process of validating the assay for high throughput while scaling up the production of the necessary reagents for the study with the help of the Protein Expression Laboratory at SAIC.