Research Interest
We are interested in understanding the mode of deregulation of tyrosine kinase oncogenes in human epithelial cancers and the cellular addiction to them.
In particular, we are interested in identifying the signaling and structural mechanisms that account for their tumorigenic functions, and the mechanisms that render them resistant to treatment with targeted therapies. Selective and potent inhibitors of many tyrosine kinases have now been developed and tested in preclinical and clinical studies. The experience with this first generation of anti-tumor agents has revealed complexities in their targets not previously appreciated in the pre-TKI era. We seek deeper mechanistic insights into the physiologic and pathologic functions of tyrosine kinase oncogenes in order to lay the foundation for potentially eradicative therapies for epithelial cancers. Two major areas of focus in the lab are the ErbB/HER and the Src family of tyrosine kinases. Our studies encompass a wide range of techniques in protein biochemistry, cell biology, mouse models, human tissues, and early phase clinical trials, and involve extensive multidisciplinary collaborations with numerous other labs.
The overexpression of HER2 is etiologically linked with many epithelial cancers, and numerous pharmaceutical drugs have been developed to target its functions. But these targetted therapies have made only incremental impact, and their efficacies fall far below scientific expectations. We believe that the true potential in the targeted therapy of HER2-driven cancers has yet to be realized. As such, we seek to better understand the mode of function of HER2 in the pathological state of overexpression, in order to define a mechanistic basis for treatments that may one day eradicate cancers driven by HER2 overexpression. Click here for more.
Oncogenes signal excessively causing cell transformation. This is a reversible mechanistic paradigm such that inactivation of the oncogene should restore the cell to a state somewhat reminiscent of the untransformed state. However the widely observed effects of oncogene inactivation in the treatment of human cancers is the non-restorative apoptotic cell death. This phenomenon of oncogene addiction remains mechanistically unexplained. We have been interested in understanding the molecular basis for the phenotype of oncogene addiction and have developed tools and reagents to explore this in unprecedented depth. Click here for more.
The discovery of the v-src oncogene of the Rous Sarcoma Virus and its cellular homolog, the c-Src proto-oncogene, initiated the era of molecular oncology, leading to the identification of the oncogenic basis for many human cancers. But after three decades of study the role of Src family kinases in human cancers remains undefined and a driving role for them remains presumptive, and further challenged by the limited efficacy of Src-selective tyrosine kinase inhibitors in clinical trials. We seek to understand how the functions of Src kinases are perturbed in human cancers in order to understand if and how such cancers can be effectively treated through interference with some or all of the functions of Src kinases. Click here for more.