Harnessing the Pro-apoptotic Activity of Myc for Therapeutic Purposes
While Myc is a gene known to drive tumor cell proliferation, it also accounts for high levels of cell death, and in certain types of B-lymphomas the so-called MYC signature correlates with improved survival. The unmet challenge is to boost the pro-apoptotic effects of Myc without promoting growth of neoplastic cells.
We had begun to address this challenge by refining our murine B-cell neoplasm models to include conditional activation of MYC or transient reactivation of the p53 tumor suppressor. Subsequently, we demonstrated that the increase in therapeutic apoptosis could be achieved by inhibiting microRNAs that target endogenous MYC such as miR-34a. We are currently pursuing the idea that chemosensitization could be achieved pharmacologically by transiently elevating MYC levels with small-molecules inhibitors of GSK3.