Role of LMPTP in Prostate Cancer

LMPTP 在前列腺癌中的作用

• 批准号: 10198250
• 负责人: Stephanie Stanford
• 金额: $ 42.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198250
• 关键词: Address; American; Androgen Receptor; Attention; Bioavailable; Biochemical; Biology; CRISPR/Cas technology; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Castration; Cessation of life; Chemicals; Data; Disseminated Malignant Neoplasm; Extracellular Matrix; Generations; Genes; Glycogen Synthase Kinase 3; Goals; Growth; Health; Human; Impairment; In Vitro; Insulin Antagonists; Insulin Receptor; Insulin Resistance; Knock-out; Liver; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Medical; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Weight; Mus; Neoplasm Metastasis; Nuclear Translocation; Obesity; Operative Surgical Procedures; Oral; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacological Treatment; Pharmacology; Phosphorylation; Positioning Attribute; Prognostic Factor; Property; Prostate; Prostate Adenocarcinoma; Prostate Cancer therapy; Prostatic Neoplasms; Protein Dephosphorylation; Protein Tyrosine Phosphatase; Proto-Oncogene Proteins c-akt; Receptor Activation; Receptor Signaling; Recurrence; Reporting; Research Personnel; Resistance; Resources; Role; Signal Pathway; Signal Transduction; Surveys; Systemic Therapy; The Cancer Genome Atlas; Time; Transactivation; Tumor Tissue; Tyrosine; Validation; Vertebral column; Xenograft Model; Xenograft procedure; advanced prostate cancer; androgen deprivation therapy; bone; castration resistant prostate cancer; cell growth; growth promoting activity; high reward; high risk; improved outcome; in vivo; inhibitor/antagonist; men; new therapeutic target; novel; novel therapeutics; overexpression; phosphatase inhibitor; promoter; prostate cancer cell; prostate cancer cell line; prostate cancer model; tumor growth; tumorigenesis

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.

抽象的 该提案的目的是对低分子量蛋白质进行探索性检查 酪氨酸磷酸酶（LMPTP）作为前列腺癌治疗的新靶点。前列腺癌属于 美国男性癌症死亡的主要原因，以及抑制前列腺肿瘤生长和治疗的新疗法 转移是癌症中一个未满足的主要医疗需求。 LMPTP 是一种酪氨酸磷酸酶，由 ACP1 基因。最近的几份报告表明，LMPTP 在人类前列腺中过度表达 肿瘤，并且 LMPTP 表达与术后生化复发和患者身材矮小相关 生存时间。由于对 LMPTP 在肿瘤生长中的作用知之甚少，我们决定研究 LMPTP 在前列腺癌细胞中的作用。我们生成了携带 LMPTP 敲除的前列腺癌细胞系 (KO)，并发现 LMPTP 的缺失显着损害了它们的增殖、集落形成和 体外侵袭性。我们还发现LMPTP是体内前列腺肿瘤生长的关键促进剂。我们有 其他初步数据表明 LMPTP 促进前列腺雄激素受体的激活 癌细胞。在这里，我们的目标是获得 LMPTP 作为新靶标潜力的探索性证据。 前列腺癌治疗。我们试图确定 LMPTP 促进前列腺的分子机制 癌细胞生长（目标 1）并证明药理学 LMPTP 抑制可逆转去势- 抑制前列腺肿瘤生长并损害前列腺肿瘤骨转移（目标 2）。我们的项目是探索性的， 高风险，并且对前列腺癌有明确的转化前景。我们将利用独特的方式来推进这个项目 我们开发的资源，包括一种新型的前列腺骨转移模型 癌症和新开发的 LMPTP 抑制剂具有优异的药理特性。我们是独一无二的 定位于在这项研究中取得成功，并很高兴发现 LMPTP 作为新靶点的潜力 前列腺癌治疗。