Posted May 18, 2015
Dr. Justin Drake, Ph.D., University of California at Los Angeles
Prostate cancer cells rely on many factors to sustain their continued growth and resistance to therapeutic treatments, with some of these factors rooted in genetic and pathway changes. Work from the laboratory of Dr. Owen Witte previously discovered prominent examples of mutated tyrosine kinase genes in other cancers. This led to the development of new kinase targeting therapeutics that have had a dramatic impact on patient survival in other diseases. However, in prostate cancer there is a paucity of activating mutations suggesting other approaches must be performed to identify druggable pathways for prostate cancer therapy. Building on this knowledge with support from a 2010 PCRP Postdoctoral Prostate Cancer Training Award, Dr. Justin Drake, in the Laboratory of Dr. Witte at the University of California at Los Angeles, set out to identify and characterize the activation of tyrosine kinase pathways in lethal prostate cancer to elucidate new kinase-targeting strategies for treating advanced prostate cancer.
To accomplish this task, Dr. Drake collaborated with researchers at the University of Michigan Rapid Autopsy Program and Dr. Thomas Graeber, a phosphoproteomic expert at UCLA, to identify the activation state of kinase pathways using unbiased quantitative mass spectrometry. Surprisingly, the investigative team discovered that patients with multiple metastatic lesions at different sites in the body expressed similar kinase activation patterns. This supports the notion that a single biopsy may be sufficient to evaluate new treatment options in patients resistant to current therapies. Next, the laboratories of Dr. Drake, soon to be an Assistant Professor at the Rutgers Cancer Institute of New Jersey, and Dr. Witte plan to functionally validate their findings by evaluating these activated kinases in mouse models of human prostate cancer, which would indicate if they are good candidates for therapeutic targeting.
They envision this research will lead to the development of an early phase clinical trial to evaluate, in real time, select kinase activation states in patients with resistant tumors for the purpose of understanding which patients are most likely to respond to kinase therapies, and to develop new combination therapies. And since some kinase inhibitors are already FDA approved for treatment of other cancers, this could be quickly realized for prostate cancer patients diagnosed with castration resistant or metastatic tumors.
Drake JM, Graham NA, Stoyanova T, Sedghi A, Goldstein AS, Cai H, Smith DA, Zhang H, Komisopoulou E, Huang J, Graeber TG, Witte ON. Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression. PNAS 2011; 109(5): 1643-1648 [PMID:22307624].
Drake JM, Graham NA, Lee JK, Stoyanova T, Faltermeier CM, Sud S, Titz B, Huang J, Pienta KJ, Graeber TG, Witte ON. Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets. PNAS 2013; 110(49): E4762-9 [PMID:24248375]