Tuesday, April 30, 2024
4/30/2024
Project Summary/Abstract Prostate cancer (CaP) will cause the deaths of more than 33,000 American men in 2020 because systemic treatments for metastatic CaP fail. Actionable targets for novel treatments that work via entirely different mechanisms, bypass resistance to current therapies, and control biology that drives CaP progression are needed urgently to improve patient survival. The long-term goal is to target the mechanism(s) that control CaP cell proliferation and CaP growth for therapeutic intervention. Our objective here is to derive the insights needed to determine the feasibility and applicability of inhibiting the action of the mitotic kinase citron kinase (CIT) as novel CaP treatment. We hypothesize that the mechanism(s) by which CIT, and its kinase activity, control CaP cell proliferation can be exploited as alternative CaP treatment to overcome acquired resistance to conventional CaP therapies. This hypothesis is formulated based on preliminary work produced in our laboratory, which identified CIT and its kinase activity as a novel critical determinant of CaP growth. The rationale is that this work may lay the foundation of a much-needed novel CaP therapeutic that targets specifically CaP growth during disease progression. We will test this hypothesis by pursuing 3 Specific Aims: 1) to define the mechanism(s) that control CIT protein expression, 2) to determine the manner in which CIT conveys aggressive CaP behavior, and 3) to determine the therapeutic potential of targeting CIT during CaP progression. Aim 1 will use molecular biology and cell biology approaches to delineate the molecular mechanism by which the novel E2F2-Skp2 signaling axis induces CIT protein levels, and specifically the role of Skp2-mediated degradation of p27 herein. In Aim 2, we will define the manner in which CIT conveys aggressive CaP behavior by isolating the CIT protein interactome and CIT kinase substrates that mediate CaP cell proliferation. Integrated kinase substrate assays and proximity ligation assays coupled with mass spectrometry will be performed. Aim 3 will define the therapeutic potential of genetic or pharmacological CIT inhibition on the growth of CaP cell line xenografts, PDXs and fresh patient tissue explants before and after ADT, and compare its efficacy to that achieved by the standard of care. The proposed research is innovative because it focuses on an entirely different approach to CaP treatment: targeting the action of a novel regulator of CaP growth to inhibit progression of advanced CaP and to bypass CaP treatment resistance. This contribution is significant because it is the first step in a continuum of research that is expected to lead to the development of novel treatment modalities that target specifically the molecular mechanisms that control lethal CaP progression. With respect to expected outcomes, the proposed studies will delineate how CIT controls CaP cell proliferation and establish its value as much-needed therapeutic target during CaP progression. These results will have a significant positive impact because they will fundamentally advance knowledge of the mechanisms that control CaP growth, in general, and provide CIT as an entirely new and functionally distinct target for much-needed novel Cap treatments, specifically.
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