Small Molecule Activators of PP2A (SMAPs) for Prostate Cancer Therapy

用于前列腺癌治疗的 PP2A 小分子激活剂 (SMAP)

• 批准号: 9070691
• 负责人: Goutham Narla
• 金额: $ 37.43万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070691
• 关键词: Affect; Androgen Receptor; Antipsychotic Agents; Apoptosis; Bioavailable; Cancer Etiology; Cancer Patient; Cancerous; Castration; Cell Culture Techniques; Cessation of life; Development; Disease; Dose-Limiting; Drug Kinetics; Engineering; Enzymes; Exhibits; Generations; Genetic; Growth; Health; Hormone Antagonists; Human Cell Line; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular; Neuraxis; New Territories; Nuclear; Nuclear Hormone Receptors; Oncogenic; Parents; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacy (field); Phosphoric Monoester Hydrolases; Phosphotransferases; Positioning Attribute; Pre-Clinical Model; Property; Prostate Cancer therapy; Prostatic Neoplasms; Protein Phosphatase 2A Regulatory Subunit PR53; Protein Serine/Threonine Phosphatase; Protein phosphatase; Proteins; Receptor Signaling; Resistance; Series; Signal Pathway; Signal Transduction; Specimen; Testing; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor-Suppressor Gene Inactivation; United States; Xenograft Model; androgen independent prostate cancer; base; castration resistant prostate cancer; in vivo; in vivo Model; kinase inhibitor; male; man; men; mouse model; novel; novel therapeutics; phase 1 study; prostate cancer cell; prostate cancer cell line; research study; small molecule; success; tumor; tumor growth; tumorigenesis

 DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer-related death among males in the United States. Beyond the burden in lives affected and lost, more than 192,280 new cases of prostate cancer are projected in 2014. The need to define the genetic basis of this disease is clear. One of the hallmarks of oncogenesis is the aberrant activation of various cellular kinases and growth promoting nuclear hormone receptor signaling. Sustained oncogenic activation requires coordinate inactivation of tumor suppressor genes, such as protein phosphatases, to allow propagation of signaling. Although the inhibition of oncogenic signaling through the development of nuclear hormone antagonists (such as MDV3100) or kinase inhibitors has resulted in some therapeutic success, most exhibit modest efficacy, leading to eventual tumor resistance. The therapeutic activation of tumor suppressor genes has remained largely unexplored. We have developed a series of novel drugs that uniquely target protein phosphatases and possess favorable pharmacokinetics and no significant toxicity. Characterization of these compounds revealed their ability to simultaneously inhibit both the MYC and AR effector pathways in prostate cancer cell lines and mouse models. Our studies represent a first step into that new territory and highlight the potential for the development of small molecule activators of other protein phosphatases and tumor suppressor proteins for the treatment of prostate cancer specifically and other cancers more generally.

 描述（由申请人提供）：前列腺癌是美国男性癌症相关死亡的第二大原因。除了受影响和失去生命的负担外，预计2014年将有超过192，280例新的前列腺癌病例。确定这种疾病的遗传基础的必要性是明确的。肿瘤发生的标志之一是各种细胞激酶和促生长核激素受体信号传导的异常激活。持续的致癌激活需要肿瘤抑制基因（如蛋白磷酸酶）的协同失活，以允许信号传导的传播。尽管通过开发核激素拮抗剂（如MDV 3100）或激酶抑制剂抑制致癌信号传导已取得了一些治疗成功，但大多数药物表现出适度的疗效，最终导致肿瘤耐药性。肿瘤抑制基因的治疗性激活在很大程度上仍未被探索。我们已经开发了一系列独特的蛋白磷酸酶靶向药物，具有良好的药代动力学和无显着毒性。这些化合物的表征揭示了它们在前列腺癌细胞系和小鼠模型中同时抑制MYC和AR效应子途径的能力。我们的研究代表了进入这一新领域的第一步，并强调了开发其他蛋白磷酸酶和肿瘤抑制蛋白的小分子激活剂用于治疗前列腺癌和其他癌症的潜力。