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.

Department of Anesthesiology and Intensive Care General University Hospital and 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Oncology General Faculty Hospital U Nemocnice 499 2 Prague 2 128 08 Czech Republic

Department of Oncology General University Hospital and 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Probability and Mathematical Statistics Faculty of Mathematics and Physics Charles University Prague Czech Republic

Department of Radiodiagnostics General University Hospital and 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Biotechnology Czech Academy of Sciences Prague West Czech Republic

Institute of Biotechnology Czech Academy of Sciences Prague West Czech RepublicDiabetes Centre Institute for Clinical and Experimental Medicine Prague 4 Czech Republic

Institute of Biotechnology Czech Academy of Sciences Prumyslova 595 Prague West 252 50 Czech Republic Diabetes Centre Institute for Clinical and Experimental Medicine Prague 4 Czech Republic

Institute of Pharmacology General University Hospital and 1st Faculty of Medicine Charles University Prague Czech Republic

Laboratory of Personalized Medicine Oncology Clinic Faculty Hospital Kralovske Vinohrady Prague Czech Republic

Laboratory of Personalized Medicine Oncology Clinic Faculty Hospital Kralovske Vinohrady Prague Czech Republic Urology Clinic 3rd Faculty of Medicine Charles University and Faculty Hospital Kralovske Vinohrady Prague Czech Republic

School of Pharmacy and Medical Science Griffith University Southport Qld 4222 Australia Department of Pediatrics and Inherited Metabolic Diseases General University Hospital and 1st Faculty of Medicine Charles University Prague Czech Republic Department of Physiology Faculty of Science Charles University and General University Hospital Prague Czech Republic Institute of Biotechnology Czech Academy of Sciences Prumyslova 595 Prague West 252 50 Czech Republic

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