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)

基本信息

批准号：
9280615
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
项目类别：
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/9280615
关键词：
Affect Androgen Receptor Antipsychotic Agents Apoptosis Bioavailable Cancer Etiology Cancer Patient Cancerous Castration Cell Culture Techniques Cell Line Cessation of life Development Disease Dose-Limiting Drug Kinetics Engineering Enzymes Exhibits Generations Genetic Growth Hormone Antagonists Human Lead Malignant Neoplasms Malignant neoplasm of prostate Molecular Neuraxis New Territories Nuclear Nuclear Hormone Receptors Oncogenic Oral 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 Therapeutic Therapeutic Index Tissues Toxic effect Tumor Suppressor Genes Tumor Suppressor Proteins Tumor-Suppressor Gene Inactivation United States Xenograft Model androgen independent prostate cancer c-myc Genes castration resistant prostate cancer experimental study 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 prostate cancer model protein activation public health relevance small molecule success therapeutic evaluation tumor tumor growth tumorigenesis

项目摘要

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，除了受影响和死亡的生命负担之外，预计 2014 年将有超过 192,280 例新的前列腺癌病例。定义这种疾病的遗传基础是明确的，肿瘤发生的标志之一是各种细胞激酶和生长促进核激素受体信号传导的异常激活，持续的致癌激活需要协调。肿瘤抑制基因（例如蛋白磷酸酶）失活，以允许信号传播虽然通过开发核激素拮抗剂（例如MDV3100）或激酶抑制剂来抑制致癌信号已经取得了一些治疗成功，但大多数效果有限。导致最终的肿瘤耐药性的肿瘤抑制基因的治疗激活在很大程度上尚未被探索。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 效应通路的能力，我们的研究代表了进入这一新领域的第一步，并强调了开发小分子激活剂的潜力。其他蛋白磷酸酶和肿瘤抑制蛋白用于治疗前列腺癌和更广泛的其他癌症。