Harnessing the effects of hypoxia-like inhibition on homology-directed DNA repair.

Autor: Altwerger G; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06511, USA., Ghazarian M; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06511, USA., Glazer PM; Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06511, USA. Electronic address: peter.glazer@yale.edu.
Jazyk: angličtina
Zdroj: Seminars in cancer biology [Semin Cancer Biol] 2024 Jan; Vol. 98, pp. 11-18. Date of Electronic Publication: 2023 Nov 28.
DOI: 10.1016/j.semcancer.2023.11.007
Abstrakt: Hypoxia is a hallmark feature of the tumor microenvironment which can promote mutagenesis and instability. This increase in mutational burden occurs as a result of the downregulation of DNA repair systems. Deficits in the DNA damage response can be exploited to induce cytotoxicity and treat advanced stage cancers. With the advent of precision medicine, agents such as Poly (ADP-ribose) polymerase (PARP) inhibitors have been used to achieve synthetic lethality in homology directed repair (HDR) deficient cancers. However, most cancers lack these predictive biomarkers. Treatment for the HDR proficient population represents an important unmet clinical need. There has been interest in the use of anti-angiogenic agents to promote tumor hypoxia and induce deficiency in a HDR proficient background. For example, the use of cediranib to inhibit PDGFR and downregulate enzymes of the HDR pathway can be used synergistically with a PARP inhibitor. This combination can improve therapeutic responses in HDR proficient cancers. Preclinical results and Phase II and III clinical trial data support the mechanistic rationale for the efficacy of these agents in combination. Future investigations should explore the effectiveness of cediranib and other anti-angiogenic agents with a PARP inhibitor to elicit an antitumor response and sensitize cancers to immunotherapy.
Competing Interests: Declaration of Competing Interest P.M.G. is a consultant for and has equity interests in Gennao Bio, Cybrexa Therapeutics, and pHLIP, Inc., and has equity in Patrys Ltd. None of these are related to the content of this work. The other authors declare no conflicts of interest. G.A. has no conflicts of interest. M.G. has no conflicts of interest.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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