James Korkola, PhD, Research Assistant Professor, Department of Biomedical Engineering
Schnitzer Investment Corporation Pilot Project Award
Title: "Designing rational drug combinations against oncogenic tyrosine kinases using high sensitivity phosphoproteomics"
Abstract: With our knowledge of the molecular events that occur within tumors greatly increasing with large sequencing studies, we can begin to envision a time when treatment will be done based on molecular signatures within a patient’s tumor. Indeed, biopharmaceutical companies have spent the past decade developing so-called “targeted” therapeutics, which are designed to attack aberrant proteins found in tumors that lead to uncontrolled growth of cancers. Unfortunately, many of these targeted agents have had disappointing results in clinical applications. Laboratory research has demonstrated that in many cases, tumors can activate secondary survival pathways to circumvent the action of targeted therapeutics. Thus, it has been proposed that combinatorial treatments will instead be needed to achieve significant efficacy, with one drug hitting the target, and the second drug hitting the compensatory pathway. The major difficulty with this approach is identifying which other pathways become activated as a result of treatment with the initial inhibitor. Our funded proposal aims to identify what secondary pathways are activated in breast cancer cells following treatment with targeted inhibitors. This will be an unbiased approach that will entail treating different breast cancer cell lines with an inhibitor, then isolating proteins from the treated cells. We will specifically isolate proteins that have become activated as a result of the initial treatment and then identify what these proteins are using a technique known as mass spectrometry. The identification of which proteins are activated to compensate for blockage of the primary target will enable us to test the effects of blockage of the secondary targets using drug combinations. This represents an essential first step in devising combinations that can be employed in the clinic to improve the efficacy of targeted therapeutic agents.