Role of LMPTP in Prostate Cancer

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ABSTRACT The objective of this proposal is to perform exploratory examination of the low molecular weight protein tyrosine phosphatase (LMPTP) as a new target for prostate cancer therapy. Prostate cancer is among the leading causes of cancer death in American men, and novel therapies to inhibit prostate tumor growth and metastasis are a major unmet medical need in cancer. LMPTP is a tyrosine phosphatase encoded by the ACP1 gene. Several recent reports have demonstrated that LMPTP is overexpressed in human prostate tumors, and that LMPTP expression associates with post-surgical biochemical recurrence and shorter patient survival time. Since little was known about the role of LMPTP in tumor growth, we decided to investigate the role of LMPTP in prostate cancer cells. We generated prostate cancer cell lines carrying LMPTP knockout (KO), and found that loss of LMPTP significantly impaired their proliferation, colony formation, and invasiveness in vitro. We also found that LMPTP is a key promoter of prostate tumor growth in vivo. We have additional preliminary data demonstrating that LMPTP promotes activation of the androgen receptor in prostate cancer cells. Here, our goal is to gain exploratory evidence of the potential for LMPTP as a novel target for prostate cancer therapy. We seek to determine the molecular mechanism by which LMPTP promotes prostate cancer cell growth (Aim 1) and to demonstrate that pharmacological LMPTP inhibition reverses castration- resistant prostate tumor growth and impairs prostate tumor bone metastasis (Aim 2). Our project is exploratory, high-risk, and has a clear translational perspective for prostate cancer. We will pursue this project using unique resources that we have developed, including a novel patient-derived bone metastasis model for prostate cancer and a newly developed LMPTP inhibitor with excellent pharmacological properties. We are uniquely positioned to succeed in this study and are excited to uncover the potential of LMPTP as a novel target for prostate cancer therapy.