My current and future interest is to develop novel therapeutics for triple negative breast cancer (TNBC). TNBC is a recalcitrant malignancy, extremely aggressive with a high rate of recurrences, and has limited therapeutic options. Identification of novel targets for TNBC treatment is urgently needed.
One of my projects involve investigating the cytotoxic effect of inhibiting the Proviral Integrations of Moloney virus 2 (PIM2), a serine/threonine kinase, in TNBC. PIM2 is overexpressed in TNBC and plays a key role in anti-apoptotic and pro-survival signaling. A novel PIM2 inhibitor, JP11646, showed significantly higher efficacy compared to the kinase inhibitors primarily due to a previously uncharacterized mechanism of PIM2 protein degradation. We hypothesize that PIM2 possesses kinase-independent functions which play a key role in pro-survival signal. We will determine the mechanism of PIM2 functions and explore how PIM2 kinase-independent functions promote TNBC survival and determine the efficacy of JP11646 in sensitizing TNBC with a goal of developing future clinical trials with JP11646 alone and in combination with other agents.
My second project focuses on using MLN4924, a neddylation inhibitor, alone and in combination with other agents for TNBC treatment. We have shown that MLN4924 showed cytotoxicity as a single agent and adding MLN4924 to cisplatin chemotherapy significantly enhanced the cytotoxicity of TNBC. Based on our results, we proposed a novel hypothesis to explain the mechanism of MLN4924 plus cisplatin sensitization. More importantly, adding CHK1 inhibitor, a cell cycle checkpoint inhibitor, to MLN4924 showed significantly higher TNBC cytotoxicity compared to the single agents due to a CHK1-dependency upon DNA damage. These drug combinations will be tested further in vivo with a goal to develop clinical trials using these single as well as combination therapies.
Ph.D. - Jadavpur University 1993
