James S. Duncan, PhD
Office Phone: 215-728-2565
Lab Phone: 215-728-2565
Protein kinases represent one the most tractable drug targets in the pursuit of new and effective cancer treatments. Although kinase inhibitors have shown great promise for the treatment of cancer, most single agent kinase inhibitor therapies have had limited clinical success due to rapid development of drug resistance. Tumors can evade drug therapy by activating compensatory protein kinase networks that promote cell growth and survival overcoming initial treatment. Therefore, combination therapies blocking these changes in kinase activity will likely be required to prevent tumor resistance in cancer.
To meet this challenge, our laboratory employs a mass spectrometry based technology that identifies protein kinases responsible for drug resistance, providing an innovative approach to rationally design new combination treatments for cancer. Using this technology, we can capture the majority of the human kinome and detect altered kinome patterns in response to kinase inhibitors currently used to treat cancer. Kinases from all major kinome subfamilies are captured including the majority of kinases implicated in cancer development and progression, as well as a significant proportion of the understudied or (un)targeted kinome. Overall, the goals of our research are to utilize this innovative approach to assess global kinome behavior and its response to small molecule inhibitors to identify previously undiscovered kinase targets leading to new and effective combination therapies to treat cancer.
Project 1. Designing combination therapies for MEK and/or AKT inhibitors in PI3K/RAS altered breast and ovarian cancers
Altered PI3K/RAS signaling has been observed in many cancers including breast and ovarian cancer. Interestingly, recent large-scale genomic studies carried out by the TCGA demonstrated that basal-like TNBC shares strong molecular similarities to High-Grade Serous Ovarian Carcinoma (HGS-OvCa) suggesting the potential for overlapping targeted therapies. HGS-OvCa is the most common and deadly subtype of epithelial ovarian cancer but currently has no effective molecular targeted therapies. Similar to TNBC, elevated MEK-ERK and/or PI3K/AKT activity has been reported in HGS-OvCa cell lines as well as patient tumors leading to the proposed use of MEK and/or AKT inhibitors as a promising therapeutic approach and are currently in the early stages of clinical trials for ovarian cancer. Using a novel mass spectrometry approach that globally measures kinase activity, we are interested in defining kinase targets driving tumor survival and MEK and/or AKT inhibitor resistance in HGS-OvCa. These discoveries will facilitate the design of new clinical trials involving MEK and/or AKT inhibitor combination therapies for HGS-OvCa.
Project 2. Define Discoidin Domain Receptors (DDR1/2) kinase signaling networks involved in tumor growth and resistance to targeted therapies in breast and ovarian cancers
Our current work has revealed a role for a number of previously understudied kinases promoting drug resistance, including DDR1 and DDR2, which represent novel drug targets in breast and ovarian cancers. DDR1/2 have been implicated in a number of biological processes including epithelial-mesenchymal transition (EMT), metastasis and tumor growth; however, the molecular mechanisms and kinase signaling pathways regulated by DDR1/2 remain elusive. Recently, oncogenic mutations in DDR2 have been documented in patients with non-small cell lung carcinomas, establishing DDR2 as a potential driver tyrosine kinase in the progression of cancers. However, the signaling networks regulated by DDR1/2 in cancer have yet to be defined. We believe that DDR1 and DDR2 contribute to the tumorigenic features of breast and ovarian cancer and their activation plays a significant role in resistance to targeted therapy. Our studies are focused on defining DDR1/2 as kinases that when targeted in combination therapies will provide more effective treatment of breast and ovarian cancers.