During my PhD training as a biochemist and cancer biologist at the University of Pittsburgh I studied the role of signaling transduction pathways in immunity and tumorigenesis, with focus on the NF-κB pathway. After joining the Chiosis lab at Memorial Sloan Kettering Cancer Center, I expanded my interests to chemical biology and translational research. Here I am integrating my knowledge in cancer signaling biology into using chemical biology approaches to determine the oncogenic mechanisms and understand the modulation of chaperones in cancer.
Using HSP90 paralog-specific chemical tools discovered by my colleagues, I investigated the roles of individual HSP90 paralogs in malignant transformation. I observed that inhibition of the ER HSP90 paralog Grp94 but not of the cytosolic Hsp90α and Hsp90β was toxic to HER2 breast cancer cells. I pursued the mechanisms behind these findings and identified an unappreciated role for Grp94 in cancer. Inhibition of Grp94 in Her2-overexpressing cells was sufficient to destabilize membrane HER2, process it towards a degradation pathway, inhibit its signaling properties and consequently kill the cancer cell. Importantly, it resulted in no feed-back induction of Hsp70, a phenomenon appreciated to limit the anti-tumor activity of pan-HSP90 inhibitors. These findings thus are first to implicate Grp94 in regulating oncogenic signal transduction at the plasma membrane and to indicate Grp94 as a target in HER2-overexpressing breast cancer. Currently, together with my colleagues in the Chiosis lab and those at the Breast Cancer Service (Drs. Modi and Corben) I continue to investigate the translation of this approach to breast cancer.
In addition, in collaboration with the laboratory of Dr. Ari Melnick (WCMC) and our clinical colleagues Drs. Leonard and Gerecitano, I am currently investigating the MYC/Hsp90 axis and its relevance to malignant transformation in a subset of DLBCLs. The findings will be incorporated into the planned clinical studies of PU-H71, the Hsp90 inhibitor developed by my lab, in lymphoma.
In the Chiosis laboratory I find myself in a multidisciplinary research environment where the opportunity to learn never ceases to amaze me. I am part of a research team which incorporates chemists, biologists and medical doctors, all driven by a goal in mind – to contribute to the development and rational clinical translation of anti-cancer therapies. This is a great lab and institution to gain experience, skills and credentials all which help me propel my desired independent career path in cancer research.