Prostate Cancer Discovery and Development Program, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Br J Cancer. 2011 Feb 15;104(4):629-34. doi: 10.1038/bjc.2011.9. Epub 2011 Feb 1.
The molecular chaperone heat shock protein-90 (Hsp90) is a promising cancer drug target, but current Hsp90-based therapy has so far shown limited activity in the clinic.
We tested the efficacy of a novel mitochondrial-targeted, small-molecule Hsp90 inhibitor, Gamitrinib (GA mitochondrial matrix inhibitor), in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. The TRAMP mice receiving 3-week or 5-week systemic treatment with Gamitrinib were evaluated for localised or metastatic prostate cancer, prostatic intraepithelial neoplasia (PIN) or localised inflammation using magnetic resonance imaging, histology and immunohistochemistry. Treatment safety was assessed histologically in organs collected at the end of treatment. The effect of Gamitrinib on mitochondrial dysfunction was studied in RM1 cells isolated from TRAMP tumours.
Systemic administration of Gamitrinib to TRAMP mice inhibited the formation of localised prostate tumours of neuroendocrine or adenocarcinoma origin, as well as metastatic prostate cancer to abdominal lymph nodes and liver. The Gamitrinib treatment had no effect on PIN or prostatic inflammation, and caused no significant animal weight loss or organ toxicity. Mechanistically, Gamitrinib triggered acute mitochondrial dysfunction in RM1 cells, with loss of organelle inner membrane potential and release of cytochrome-c in the cytosol.
The Gamitrinib has pre-clinical activity and favourable tolerability in a genetic model of localised and metastatic prostate cancer in immunocompetent mice. Selective targeting of mitochondrial Hsp90 could provide novel molecular therapy for patients with advanced prostate cancer.
分子伴侣热休克蛋白 90（Hsp90）是一种很有前途的癌症药物靶点，但目前基于 Hsp90 的治疗在临床上的活性有限。
我们测试了一种新型线粒体靶向小分子 Hsp90 抑制剂 Gamitrinib（GA 线粒体基质抑制剂）在 Transgenic Adenocarcinoma of the Mouse Prostate（TRAMP）模型中的疗效。接受 3 周或 5 周系统 Gamitrinib 治疗的 TRAMP 小鼠，通过磁共振成像、组织学和免疫组织化学评估局部或转移性前列腺癌、前列腺上皮内瘤变（PIN）或局部炎症。在治疗结束时通过组织学评估治疗的安全性。在从 TRAMP 肿瘤中分离的 RM1 细胞中研究了 Gamitrinib 对线粒体功能障碍的影响。
系统给予 Gamitrinib 可抑制起源于神经内分泌或腺癌的局部前列腺肿瘤、以及向腹部淋巴结和肝脏转移的前列腺癌的形成。Gamitrinib 治疗对 PIN 或前列腺炎症没有影响，也没有导致明显的动物体重减轻或器官毒性。机制上，Gamitrinib 在 RM1 细胞中引发急性线粒体功能障碍，导致细胞器内膜电位丧失和细胞色素-c 释放到细胞质中。
Gamitrinib 在免疫功能正常的小鼠局部和转移性前列腺癌的遗传模型中具有临床前活性和良好的耐受性。线粒体 Hsp90 的选择性靶向可能为晚期前列腺癌患者提供新的分子治疗。
