Simultaneous targeting of mitochondrial metabolism and immune checkpoints as a new strategy for renal cancer therapy

Hubáčková, Soňa; Zobalova, Renata; Dubisova, Maria; Šmigová, Jana; Dvorakova, Sarka; Korinkova, Klara; Ezrova, Zuzana; Endaya, Berwini; Blažková, Kristýna; Vlčák, Erik; Brisudova, Petra; Le, Dan‐Diem Thi; Juhás, Štefan; Rösel, Daniel; Kelemen, Cristina Daniela; Sovilj, Dana; Vacurova, Eliska; Čajka, Tomáš; Filimonenko, Vlada; Dong, Lan-Feng; Anděra, Ladislav; Hozák, Pavel; Brábek, Jan; Bielčiková, Zuzana; Štursa, Jan; Werner, Lukáš; Neužil, Jiřı́

doi:10.1002/ctm2.645

Cited by 11 publications

(10 citation statements)

References 10 publications

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“…36 In addition, the high accumulation of MitoTam in kidney tissue may also contribute to its efficacy. 24 In fact, we previously reported that the accumulation of MitoTam was 2-to 10-fold greater in kidney tissue than in other tissues, and that it persisted for almost 1 week longer in the kidney than in most of the other tissues assessed. 24 We hypothesized the effect of MitoTam could be monitored by using CTCs isolated from peripheral blood of patients, and evaluating their number and the morphology of mitochondrial networks (fusion versus fission mitochondria).…”

Section: Therapeutic Advances Inmentioning

confidence: 83%

Mitochondrially targeted tamoxifen as anticancer therapy: case series of patients with renal cell carcinoma treated in a phase I/Ib clinical trial

Bielcikova,

Werner,

Stursa

et al. 2023

Ther Adv Med Oncol

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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.

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Section: Therapeutic Advances Inmentioning

confidence: 83%

Mitochondrially targeted tamoxifen as anticancer therapy: case series of patients with renal cell carcinoma treated in a phase I/Ib clinical trial

Bielcikova,

Werner,

Stursa

et al. 2023

Ther Adv Med Oncol

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“…More recently, a group of senolytic compounds, which are cardiovascular glycosides, targeting cellular membrane Na+/K+-ATPase pumps, were described to render senescent cells more susceptible to apoptosis due to a resulting electrochemical gradient imbalance. These complexes were effective ex vivo in pre-neoplastic senescent cells and in vivo in cases of lung fibrosis, treatment-triggered senescence, and old wild type mice [ 212 , 213 ].…”

Section: Converting Senescent Cells Into Apoptotic Cell By “Senolytics”mentioning

confidence: 99%

Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies

Khalil

Diab‐Assaf

Lemaı̂tre

2023

Cells

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Life expectancy has drastically increased over the last few decades worldwide, with important social and medical burdens and costs. To stay healthy longer and to avoid chronic disease have become essential issues. Organismal aging is a complex process that involves progressive destruction of tissue functionality and loss of regenerative capacity. One of the most important aging hallmarks is cellular senescence, which is a stable state of cell cycle arrest that occurs in response to cumulated cell stresses and damages. Cellular senescence is a physiological mechanism that has both beneficial and detrimental consequences. Senescence limits tumorigenesis, lifelong tissue damage, and is involved in different biological processes, such as morphogenesis, regeneration, and wound healing. However, in the elderly, senescent cells increasingly accumulate in several organs and secrete a combination of senescence associated factors, contributing to the development of various age-related diseases, including cancer. Several studies have revealed major molecular pathways controlling the senescent phenotype, as well as the ones regulating its interactions with the immune system. Attenuating the senescence-associated secretory phenotype (SASP) or eliminating senescent cells have emerged as attractive strategies aiming to reverse or delay the onset of aging diseases. Here, we review current senotherapies designed to suppress the deleterious effect of SASP by senomorphics or to selectively kill senescent cells by “senolytics” or by immune system-based approaches. These recent investigations are promising as radical new controls of aging pathologies and associated multimorbidities.

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“…In the immune compartment, OXPHOS supports function of pro-tumorigenic Tregs ( 99 ), suggesting that OXPHOS inhibition could improve anti-tumor immune responses. In line, metformin treatment suppresses Tregs in tumors ( 100 ) and CI inhibitor MitoTam improves efficacy of immune checkpoint therapy in a pre-clinical renal cancer model ( 101 ). Metformin lowers macrophage infiltration in tumors and skews TAM polarization from M2 to anti-tumor M1 phenotype ( 102 , 103 ).…”

Section: Oxidative Phosphorylationmentioning

confidence: 99%

Effects of metabolic cancer therapy on tumor microenvironment

et al. 2022

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Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly – clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.

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Simultaneous targeting of mitochondrial metabolism and immune checkpoints as a new strategy for renal cancer therapy

Cited by 11 publications

References 10 publications

Mitochondrially targeted tamoxifen as anticancer therapy: case series of patients with renal cell carcinoma treated in a phase I/Ib clinical trial

Mitochondrially targeted tamoxifen as anticancer therapy: case series of patients with renal cell carcinoma treated in a phase I/Ib clinical trial

Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies

Effects of metabolic cancer therapy on tumor microenvironment

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