Mitochondrial Hsp90 chaperones and prostate cancer therapy

线粒体 Hsp90 伴侣和前列腺癌治疗

• 批准号: 8526414
• 负责人: Dario C Altieri
• 金额: $ 49.75万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8526414
• 关键词: Affect; Androgens; Apoptosis; Binding; Biological Markers; Cell Survival; Chemicals; Collaborations; Cytoprotection; Development; Disease Progression; Drug resistance; Evaluation; Family; Genetic Models; Gleason Grade for Prostate Cancer; Goals; Growth; Heat-Shock Proteins 90; Heterogeneity; Histopathology; Homeostasis; Immunocompromised Host; Implant; In Vitro; Integrins; Knockout Mice; Laboratories; Lesion; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; Metastatic Prostate Cancer; Mitochondria; Mitochondrial Matrix; Molecular; Molecular Chaperones; Molecular Genetics; Molecular Models; Mus; Neoplasm Metastasis; Normal Cell; Oncogenes; Oncogenic; Organ; Organelles; Outcome; Pathologic; Pathway interactions; Patients; Permeability; Phase; Prostate; Prostate Cancer therapy; Prostatic Epithelium; Prostatic Intraepithelial Neoplasias; Regulation; Role; Safety; Staging; Testing; Therapeutic; Toxic effect; Transgenic Organisms; advanced disease; bone; cancer therapy; cell type; cyclophilin D; design; in vivo; inhibitor/antagonist; killings; mitochondrial permeability transition pore; molecular imaging; molecular modeling; mouse model; neoplastic cell; new therapeutic target; novel; preclinical efficacy; preclinical evaluation; preclinical study; prostate cancer cell; prostate carcinogenesis; protein folding; research study; small molecule; survivin; therapy resistant; tibia; tumor; tumor progression

Despite progress in the identification of cancer genes and their pathways, the development of new therapies for metastatic prostate cancer has lagged behind. This refiects the extraordinary heterogeneity of advanced disease, which makes it difficult to identify unique oncogenic lesions suitable for therapeutic intervenfion. Conversely, agents that target fundamental pathways of tumor maintenance may offer better therapeutic prospects. Recent studies have uncovered a fundamental mechanism of tumor cell survival exploited in prostate cancer. This is centered on the recruitment of Heat Shock Protein-90 (Hsp90) molecular chaperones to mitochondria ofthe transformed prostatic epithelium, but not normal prostate, in vivo. In tum, Hsp90 chaperones bind components of the mitochondrial permeability transition pore, especially Cyclophilin D, block its function, and suppress apoptosis. To target this pathway for cancer therapy, we synthesized a novel class of small molecule Hsp90 inhibitors selectively targeted to mitochondria, designated Gamitrinibs (GA Inhibitors of the mitochondrial matrix). Gamitrinibs are direct 'mitochondriotoxic' agents, kill androgendependent or -independent prostate cancer cells, but not normal prostatic epithelium, and inhibit localized and bone metastatic prostate cancer growth, in vivo, without systemic or organ toxicity. Therefore, a unifying hypothesis can be formulated that mitochondrial Hsp90 chaperones orchestrate a fundamental pathway of prostate cancer progression, and this provides a novel therapeutic target for advanced disease. Experiments in specific aim 1 will dissect the requirements of Hsp90 chaperones in maintaining mitochondrial integrity, promote drug resistance, and contribute to disease progression mediated by avpe integrin. Specific aim 2 will elucidate the mechanism(s) of differential import of Hsp90 chaperones in tumor versus normal mitochondria, map the role of survivin in orchestrating a cytoprotective chaperone network In mitochondria, and test the impact of this pathway on transformation ofthe prostatic epithelium. In specific aim 3, preclinical studies will test the activity of Gamitrinibs in molecular and genetic models of localized and metastatic prostate cancer, including prostate-specific Ren conditional knockout mice, transgenic TRAMP mice, and immunocompromised mice implanted in the bone with prostate cancer cells. The approach merges mechanistic elucidation of a novel pathway of prostate cancer progression with preclinical evaluation of its novel inhibitors. The studies have high impact as they may pave the way to the use of Gamitrinibs as novel molecular therapy for patients with advanced prostate cancer.

尽管鉴定癌症基因及其途径，但新疗法的发展 对于转移性前列腺癌，已经落后了。这重新升级了高级的非均质性 疾病，这使得难以识别适合治疗性干预的独特致癌病变。 相反，针对肿瘤维护基本途径的代理可能会提供更好的治疗性 前景。最近的研究发现了利用肿瘤细胞存活的基本机制 前列腺癌。这以热激蛋白-90（HSP90）分子的募集为中心 体内转化为前列腺上皮的线粒体，但不是正常的前列腺。在TUM中， HSP90伴侣结合线粒体通透性过渡孔的成分，尤其是环磷脂 D，阻断其功能并抑制凋亡。为了瞄准这种癌症治疗途径，我们合成了 小分子HSP90抑制剂的新颖类选择性地针对线粒体，指定为gamitrinibs （线粒体基质的GA抑制剂）。 gamitrinibs是直接的“线粒体毒性”代理，杀死且依赖于Androgendent 或独立的前列腺癌细胞，但不是正常的前列腺上皮，并抑制局部 和骨转移性前列腺癌的生长，体内，无系统性或器官毒性。因此， 可以提出统一的假设，即线粒体HSP90伴侣编排A 前列腺癌进展的基本途径，这为 晚期疾病。特定目标1中的实验将剖析HSP90伴侣的要求 维持线粒体完整性，促进耐药性并促进疾病进展 由AVPE整合素。具体目标2将阐明Hsp90伴侣在 肿瘤与正常线粒体，绘制Survivin在策划细胞保护伴侣中的作用 线粒体中的网络，并测试该途径对前列腺上皮转化的影响。在 特定的目标3，临床前研究将测试gamitrinibs在分子和遗传模型中的活性 局部和转移性前列腺癌，包括前列腺特异性的REN条件敲除小鼠， 转基因流浪汉小鼠和免疫功能低下的小鼠植入了前列腺癌细胞中的骨骼。 该方法合并了前列腺癌进展的新途径的机械阐明 对其新型抑制剂的临床前评估。研究具有很大的影响，因为它们可能为通往 使用Gamitrinibs作为晚期前列腺癌患者的新分子疗法。