Mitochondrially targeted anticancer drugs (mitocans) that disrupt the energy-producing systems of cancer are emerging as new potential therapeutics. Mitochondrially targeted tamoxifen (MitoTam), an inhibitor of mitochondrial respiration respiratory complex I, is a first-in-class mitocan that was tested in the phase I/Ib MitoTam-01 trial of patients with metastatic cancer. MitoTam exhibited a manageable safety profile and efficacy; among 37% (14/38) of responders, the efficacy was greatest in patients with metastatic renal cell carcinoma (RCC) with a clinical benefit rate of 83% (5/6) of patients. This can be explained by the preferential accumulation of MitoTam in the kidney tissue in preclinical studies. Here we report the mechanism of action and safety profile of MitoTam in a case series of RCC patients. All six patients were males with a median age of 69 years, who had previously received at least three lines of palliative systemic therapy and suffered progressive disease before starting MitoTam. We recorded stable disease in four, partial response in one, and progressive disease (PD) in one patient. The histological subtype matched clear cell RCC (ccRCC) in the five responders and claro-cellular carcinoma with sarcomatoid features in the non-responder. The number of circulating tumor cells (CTCs) was evaluated longitudinally to monitor disease dynamics. Beside the decreased number of CTCs after MitoTam administration, we observed a significant decrease of the mitochondrial network mass in enriched CTCs. Two patients had long-term clinical responses to MitoTam, of 50 and 36 weeks. Both patients discontinued treatment due to adverse events, not PD. Two patients who completed the trial in November 2019 and May 2020 are still alive without subsequent anticancer therapy. The toxicity of MitoTam increased with the dosage but was manageable. The efficacy of MitoTam in pretreated ccRCC patients is linked to the novel mechanism of action of this first-in-class mitochondrially targeted drug.

中文翻译：

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线粒体靶向他莫昔芬作为抗癌疗法：在 I/Ib 期临床试验中治疗的肾细胞癌患者的病例系列。

破坏癌症能量产生系统的线粒体靶向抗癌药物（mitocans）正在成为新的潜在疗法。线粒体靶向他莫昔芬 (MitoTam) 是一种线粒体呼吸复合物 I 的抑制剂，是一种一流的线粒体抑制剂，已在转移性癌症患者的 I/Ib 期 MitoTam-01 试验中进行了测试。MitoTam 表现出可控的安全性和有效性；在 37% (14/38) 的应答者中，转移性肾细胞癌 (RCC) 患者的疗效最佳，临床受益率为 83% (5/6) 的患者。这可以通过临床前研究中 MitoTam 在肾组织中的优先积累来解释。在这里，我们报告了 MitoTam 在 RCC 患者病例系列中的作用机制和安全性概况。所有六名患者均为男性，中位年龄为 69 岁，他们之前接受过至少三线姑息性全身治疗，并且在开始 MitoTam 之前患有进展性疾病。我们记录了 4 名患者疾病稳定，1 名患者部分缓解，1 名患者疾病进展 (PD)。5 名有反应者的组织学亚型与透明细胞肾细胞癌 (ccRCC) 相匹配，无反应者的组织学亚型与具有肉瘤样特征的透明细胞癌相匹配。纵向评估循环肿瘤细胞（CTC）的数量以监测疾病动态。除了 MitoTam 给药后 CTC 数量减少之外，我们还观察到富集的 CTC 中线粒体网络质量显着减少。两名患者对 MitoTam 产生了 50 周和 36 周的长期临床反应。两名患者均因不良事件而不是 PD 停止治疗。2019年11月和2020年5月完成试验的两名患者在没有进行后续抗癌治疗的情况下仍然活着。MitoTam 的毒性随着剂量的增加而增加，但在可控范围内。MitoTam 在接受过治疗的 ccRCC 患者中的疗效与这种一流的线粒体靶向药物的新颖作用机制有关。