Dr. Ajay Rana
I have a broad background in Cancer Biology, with specific training and expertise in signal transduction and antineoplastic drugs resistance. Since my post-doctoral training at Harvard Medical School in Dr. Joseph Avruch’ s laboratory, I have continued working on a novel family of kinases, called Mixed Lineage Kinases (MLKs). The MLK family members are unique in the sense that the kinase domain contains the signature sequences for both, Ser/Thr and Tyr kinases. We were first to demonstrate that one of its family member, MLK3 was a functional Ser/Thr-kinase, however, its Tyr-kinase activity is still unknown (JBC. I received my first NIH grant in 1999, which was primarily focused to define the detail signaling mechanisms via MLK3. For the first time, we identified two specific agonists of MLK3 (Mol. Cell, 2002). We showed that MLK3 was specifically activated by bio-active lipid, ceramides and also by TNFα. We also defined the pro-apoptotic functions of MLK3, which was downregulated by survival kinase, AKT (JBC, 2003). My laboratory was also first to demonstrate the functional role of MLK3 in breast cancer. Quite unexpectedly, we observed that MLK3 kinase activities were significantly lower in human ER+ breast tumors. Subsequently, we published that in response to cytotoxic drug (Taxol) in breast cancer, MLK3’s pro-apoptotic function was downregulated by estrogen via PI3K/AKT activation, suggesting that MLK3 activity is necessary for cytotoxic drug (Taxol)-induced ER+ breast cancer cell death (Cancer Res., 2010 ). This particular report was highlighted by NIH, as well as by several international and national print media. Similar to the effect of estrogen on MLK3’s kinase activity in ER+ breast cancer, recently we reported that the HER2 amplification (i.e. HER2+ breast cancer) also inhibited MLK3 kinase activity in HER2+ breast cancer cells and tumors, and this inhibition was necessary for HER2+ breast cancer cell survival (JBC, 2015). Collectively, these are clinically significant results, because ER, PR and HER2 expression serve as prognostic markers in breast cancer. It is possible that MLK3, and perhaps other MLK family members, serve significant role in conferring resistance to therapeutics that target these receptors? The main goal of this proposal is to target MLK3/MLKs in anti-HER2 therapy resistant tumors by using nanoparticles, conjugated to MLK3 agonist, ceramide. I started my career at the time, when MLK3 or any MLK members’ antibodies were not available. Since then, we have amassed enormous amounts of reagents, including several MLK antibodies, ShRNAs and MLK3 knockout mice, which will help us to achieve the goals of the current proposal.