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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985904%3A_____%2F22%3A00556526" target="_blank" >RIV/67985904:_____/22:00556526 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/86652036:_____/22:00556526 RIV/68378050:_____/22:00556526 RIV/67985823:_____/22:00556526 RIV/00064165:_____/22:10450733 RIV/00216208:11310/22:10450733

Výsledek na webu

<a href="https://onlinelibrary.wiley.com/doi/10.1002/ctm2.645" target="_blank" >https://onlinelibrary.wiley.com/doi/10.1002/ctm2.645</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/ctm2.645" target="_blank" >10.1002/ctm2.645</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

Mitochondrially targeted tamoxifen (MitoTam) has recently undergone phase 1/1b clinical trial in patients with various solid tumors. Since patients with clear cell renal carcinoma showed the highest response of the tested diagnoses, we studied the effect of MitoTam on renal cancer in vitro and in vivo to reveal its mechanism of action in more detail and to better understand its benefit for patients. Using primarily the murine RenCa renal cancer cell line and the derived syngeneic mouse tumor model, we studied mechanism of MitoTam toxicity including the mode of death, the role of mitochondria in the effects of the agent, and its efficacy in suppressing syngeneic tumors in mice alone and in combination with the immune checkpoint inhibitors (ICIs), monoclonal antibodies blocking PD-1 and PD-L1. Our findings show a complex effect of MitoTam on mitochondrial function and integrity of renal cancer cells. The agent inhibits complex I-dependent respiration and lowers mitochondrial potential, which results in activation of necroptosis as the major mode of cell death. As a consequence, MitoTam reduces growth of renal tumors as well as metastatic spread of tumor cells via specific targeting of malignant tissue in a mouse model. Moreover, combination of MitoTam with immunotherapy to enhance its anti-cancer efficacy shows significantly increased suppression of tumor growth as well as increased survival of experimental animals compared to single agent treatment. Our data provide a mechanistic rationale for testing of both mono and/or combinatorial therapy with MitoTam plus ICIs in renal carcinomas in Phase 2 trial.

Název v anglickém jazyce

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

Popis výsledku anglicky

Mitochondrially targeted tamoxifen (MitoTam) has recently undergone phase 1/1b clinical trial in patients with various solid tumors. Since patients with clear cell renal carcinoma showed the highest response of the tested diagnoses, we studied the effect of MitoTam on renal cancer in vitro and in vivo to reveal its mechanism of action in more detail and to better understand its benefit for patients. Using primarily the murine RenCa renal cancer cell line and the derived syngeneic mouse tumor model, we studied mechanism of MitoTam toxicity including the mode of death, the role of mitochondria in the effects of the agent, and its efficacy in suppressing syngeneic tumors in mice alone and in combination with the immune checkpoint inhibitors (ICIs), monoclonal antibodies blocking PD-1 and PD-L1. Our findings show a complex effect of MitoTam on mitochondrial function and integrity of renal cancer cells. The agent inhibits complex I-dependent respiration and lowers mitochondrial potential, which results in activation of necroptosis as the major mode of cell death. As a consequence, MitoTam reduces growth of renal tumors as well as metastatic spread of tumor cells via specific targeting of malignant tissue in a mouse model. Moreover, combination of MitoTam with immunotherapy to enhance its anti-cancer efficacy shows significantly increased suppression of tumor growth as well as increased survival of experimental animals compared to single agent treatment. Our data provide a mechanistic rationale for testing of both mono and/or combinatorial therapy with MitoTam plus ICIs in renal carcinomas in Phase 2 trial.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30109 - Pathology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Clinical and Translational Medicine

ISSN

2001-1326

e-ISSN

2001-1326

Svazek periodika

12

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

8

Strana od-do

e645

Kód UT WoS článku

000774832800001

EID výsledku v databázi Scopus

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