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Targeting RAD51-Mediated Homologous Recombination as a Treatment for Advanced Solid and Hematologic Malignancies: Opportunities and Challenges Ahead.

ABSTRACT: RAD51 is integral in homologous recombination DNA damage repair and has garnered much interest as both a biomarker and potential therapeutic target in oncology. Multiple in vitro and in vivo studies have demonstrated its role as a predictive marker, particularly in the context of platinum-based therapies and poly ADP-ribose polymerase (PARP) inhibitors. In this review, we highlight the development of RAD51 inhibitors, with a focus on novel molecules and ongoing clinical trials. Despite many efforts to develop effective and tolerable direct RAD51 inhibitors, identification of these agents remains challenging. Clinically, however, there may be a role of pharmacological indirect RAD51 inhibition.

SUBMITTER: Tsang ES

PROVIDER: S-EPMC9758980 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Targeting RAD51-Mediated Homologous Recombination as a Treatment for Advanced Solid and Hematologic Malignancies: Opportunities and Challenges Ahead.

Tsang Erica S ES Munster Pamela N PN

OncoTargets and therapy 20221213

RAD51 is integral in homologous recombination DNA damage repair and has garnered much interest as both a biomarker and potential therapeutic target in oncology. Multiple in vitro and in vivo studies have demonstrated its role as a predictive marker, particularly in the context of platinum-based therapies and poly ADP-ribose polymerase (PARP) inhibitors. In this review, we highlight the development of RAD51 inhibitors, with a focus on novel molecules and ongoing clinical trials. Despite many effo ...[more]

PMID: 36536949

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Project description:Purpose of Review:Patient engagement in research is increasingly recognized as an important component of the research process and may facilitate translation of research findings. To heighten awareness on this important topic, this review presents opportunities and challenges of patient engagement in research, drawing on specific examples from 4 areas of Canadian kidney research conducted by New Investigators in the Kidney Research Scientist Core Education and National Training (KRESCENT) Program. Sources of Information:Research expertise, published reports, peer-reviewed articles, and research funding body websites. Methods:In this review, the definition, purpose, and potential benefits of patient engagement in research are discussed. Approaches toward patient engagement that may help with translation and uptake of research findings into clinical practice are highlighted. Opportunities and challenges of patient engagement are presented in both basic science and clinical research with the following examples of kidney research: (1) precision care in focal and segmental glomerulosclerosis, (2) systems biology approaches to improve management of chronic kidney disease and enhance kidney graft survival, (3) reducing the incidence of suboptimal dialysis initiation, and (4) use of patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) in kidney practice. Key Findings:Clinical research affords more obvious opportunities for patient engagement. The most obvious step at which to engage patients is in the setting of research priorities. Engagement at all stages of the research cycle may prove to be more challenging, and requires a detailed plan, along with funds and infrastructure to ensure that it is not merely tokenistic. Basic science research is several steps removed from the clinical application and involves complex scientific concepts, which makes patient engagement inherently more difficult. Limitations:This is a narrative review of the literature that has been partly influenced by the perspectives and experiences of the authors and focuses on research conducted by the authors. The evidence base to support the suggested benefits of patient engagement in research is currently limited. Implications:The formal incorporation of patients' priorities, perspectives, and experiences is now recognized as a key component of the research process. If patients and researchers are able to effectively work together, this could enhance research quality and efficiency. To effectively engage patients, proper infrastructure and dedicated funding are needed. Going forward, a rigorous evaluation of patient engagement strategies and their effectiveness will be needed.

Project description:BackgroundRAD51-dependent homologous recombination (HR) is one of the most important pathways for repairing DNA double-strand breaks (DSBs), and its regulation is crucial to maintain genome integrity. Elp1 gene encodes IKAP/ELP1, a core subunit of the Elongator complex, which has been implicated in translational regulation. However, how ELP1 contributes to genome maintenance is unclear.MethodsTo investigate the function of Elp1, Elp1-deficient mouse embryonic fibroblasts (MEFs) were generated. Metaphase chromosome spreading, immunofluorescence, and comet assays were used to access chromosome abnormalities and DSB formation. Functional roles of Elp1 in MEFs were evaluated by cell viability, colony forming capacity, and apoptosis assays. HR-dependent DNA repair was assessed by reporter assay, immunofluorescence, and western blot. Polysome profiling was used to evaluate translational efficiency. Differentially expressed proteins and signaling pathways were identified using a label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics approach.ResultsHere, we report that Elp1 depletion enhanced genomic instability, manifested as chromosome breakage and genotoxic stress-induced genomic DNA fragmentation upon ionizing radiation (IR) exposure. Elp1-deficient cells were hypersensitive to DNA damage and exhibited impaired cell proliferation and defective HR repair. Moreover, Elp1 depletion reduced the formation of IR-induced RAD51 foci and decreased RAD51 protein levels. Polysome profiling analysis revealed that ELP1 regulated RAD51 expression by promoting its translation in response to DNA damage. Notably, the requirement for ELP1 in DSB repair could be partially rescued in Elp1-deficient cells by reintroducing RAD51, suggesting that Elp1-mediated HR-directed repair of DSBs is RAD51-dependent. Finally, using proteome analyses, we identified several proteins involved in cancer pathways and DNA damage responses as being differentially expressed upon Elp1 depletion.ConclusionsOur study uncovered a molecular mechanism underlying Elp1-mediated regulation of HR activity and provides a novel link between translational regulation and genome stability.

Dataset Information

Targeting RAD51-Mediated Homologous Recombination as a Treatment for Advanced Solid and Hematologic Malignancies: Opportunities and Challenges Ahead.

Publications

Targeting RAD51-Mediated Homologous Recombination as a Treatment for Advanced Solid and Hematologic Malignancies: Opportunities and Challenges Ahead.

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