The DNA Repair Drugs damage response (DDR) is a sophisticated cellular network that senses and responds to genotoxic insults, including UV light, ionizing radiation and chemotherapy agents. It includes multiple mechanisms to deal with DNA lesions, including signal transduction, transcription regulation, cell-cycle checkpoints and apoptosis induction, repair through multiple pathways, and DNA damage tolerance processes. Inhibitors targeting both ATM and DNA-PK have shown promise as chemo- and radiotherapy sensitizers. Combinations of these inhibitors, such as nivolumab and rucaparib, have been shown to dramatically improve the survival rates of some patients with glioblastoma.
These drugs are aimed at targeting mitochondrial DNA Repair Drugs (mtDNA), which differs between normal and cancer cells, making them more effective chemo- and radiosensitizers than nivolumab and cytotoxic agents that directly target nDNA. Genome instability caused by deficient DNA repair is one of the 10 hallmarks of cancer. Therefore, DDR inhibitors hold great promise as anticancer agents. Cediranib works to inhibit the PDGF receptor, which promotes the growth of blood vessels that tumors need. Whereas researchers discovered that it also caused hypoxia, which weakens DNA repair. Cediranib is an oral tyrosine kinase inhibitor that blocks angiogenesis and has shown anti-tumor activity in early phase trials. It has a high specificity for the VEGFR tyrosine kinase family and targets VEGFR-1, 2, and 3, as well as c-kit. In a phase II study, patients with nongermline BRCAm recurrent platinum-resistant EOC received either cediranib alone or in combination with olaparib. The original dose was 45 mg daily, whereas due to toxicities the study was halted after 11 patients. The olaparib plus cediranib arm showed improvement in progression-free survival. Treatment-related adverse events included diarrhea and hypertension. However, aggressive intervention and proactive symptom management led to only 11% discontinuation due to toxicity in the combination arm. IlludinS is a natural compound found in mushrooms and other plants. It works by targeting DNA Repair Drugs binding proteins. It is very effective at killing tumor cells that have ERCC3 and ERCC2 mutations. Researchers hope to advance a new drug based on IlludinS into clinical trials. Isolation and chemical modification of illudins enabled the development of semisynthetic probes that retained their potent cytotoxicity. These were used in quantitative chemical proteomic profiling to identify putative targets. Promiscuous labeling of proteins suggests that illudins impact cell viability not by targeting a single protein target, rather through DNA binding and unspecific cellular responses. Illudin S and related compounds generate alkyl DNA Repair Drugs adducts that can be repaired by transcription-coupled nucleotide excision repair (TC-NER). It was discovered that NER factors XPC and CSB, regulate the sensitivity to these agents. Rucaparib is a PARP inhibitor that has been shown to improve response rates in patients with BRCA-mutant ovarian cancer. It is used to treat ovarian, fallopian tube, or primary peritoneal cancer that has returned after surgery and other chemotherapy treatments have been given. It is only approved for use in people who have a specific abnormal gene known as BRCA and who have not responded to other treatment. Nivolumab blocks the PD-1 protein on cancer cells, allowing the body’s natural immune system to recognize and attack them. It works with another immunotherapy drug, Yervoy, to prohibit cancer cells from disguising themselves, elevate T-cell activity and reduce tumor growth. It is used alone or with ipilimumab as first treatment for malignant pleural mesothelioma that has spread and cannot be removed surgically. It is also used with ipilimumab to treat squamous cell carcinoma of the esophagus and gastroesophageal junction that has spread or come back after other cancer treatments.
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November 2023
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