The laboratories of Gavande<\/a> and Turchi were among the first to advance the concept of targeting the Ku70\/80 DNA-binding complex \u2014 a central DNA damage sensor in the NHEJ pathway \u2014 as a novel therapeutic strategy for cancer treatment. Building on this foundation, the researchers continue to lead medicinal chemistry optimization and mechanistic studies focused on targeting Ku70\/80 for cancer therapy.<\/p>\nFixing the flaws of current cancer treatments<\/p>\n
The research focuses on DNA-dependent protein kinase, or DNA-PK, a critical enzyme that cancer cells use to repair DNA double-strand breaks caused by radiation, chemotherapy and other cellular stresses. DNA-PK has long been considered an attractive therapeutic target in cancer, and several DNA-PK inhibitors are currently being evaluated clinically by pharmaceutical companies. However, many current approaches target the catalytic activity of DNA-PK directly, which can raise concerns about toxicity and effects on normal tissues.<\/p>\n
Gavande\u2019s and Turchi\u2019s team are pursuing a different strategy. Instead of targeting DNA-PK directly, their compounds, called\u00a0Ku-DNA binding inhibitors (Ku-DBi) are designed to block Ku70\/80, the DNA damage sensor that recognizes broken DNA ends and recruits DNA-PK to initiate repair. Without Ku binding to damaged DNA, DNA-PK cannot be properly activated. In this way, Ku-DBi\u2019s act like a precision \u201coff-switch\u201d for a key DNA repair pathway that cancer cells depend on for treatment resistance.<\/p>\n
A new weapon against hard-to-treat solid tumors<\/p>\n
During the initial phase of funding, the team discovered and optimized Ku-targeted small molecules that enter cells, inhibit DNA-PK activation, disrupt NHEJ-mediated DNA repair, and sensitize cancer cells to radiation and radiomimetic agents in preclinical models. With renewed NIH support, the investigators will move the program into its next critical phase: defining the DNA damage contexts and cancer vulnerabilities where Ku-DBi\u2019s may have the greatest therapeutic impact.<\/p>\n
\u201cIn this next phase of our research, we will investigate various DNA double-strand break repair contexts to identify novel therapeutic combinations with Ku-DBi\u2019s,\u201d said Gavande. \u201cWe will also work to discover where Ku-DBi\u2019s can create new synthetic lethal interactions in cancers that are currently difficult to target with precision therapies, while continuing our medicinal chemistry efforts to optimize in vivo activity and delivery of these compounds.<\/p>\n
Working on this project has been an exciting opportunity to contribute to the development of first-in-class Ku70\/80 DNA-binding inhibitors and to better understand how targeting DNA repair can improve radiotherapy for lung cancer and other difficult-to-treat tumors,\u201d said Dr. Narva Kushwaha, a postdoctoral researcher in Gavande\u2019s laboratory.<\/p>\n
\u201cOur innovative approach of targeting the structure-specific DNA-binding protein Ku aims to significantly enhance our understanding of the DNA damage response and mechanisms of DNA repair,\u201d said Gavande. \u201cBy targeting the earliest step in DNA-PK activation, we hope to create more selective therapeutic opportunities for cancers that depend heavily on DNA repair for survival.\u201d<\/p>\n
Why it matters<\/p>\n
For lung cancer patients, the ability to sensitize tumors to radiotherapy could help improve tumor control while reducing the dose-related toxicities that limit treatment. The development of these new chemical entities represents a major leap forward in precision medicine, offering new hope for safer, more effective treatments across a wide range of human cancers.<\/p>\n
Research reported in this press release was supported by the\u00a0National Cancer Institute of the National Institutes of Health under award\u00a0number\u00a0R01CA247370.\u00a0The content of this press release is solely the responsibility of the authors and does not necessarily\u00a0represent\u00a0the official views of the National Institutes of Health.\u00a0\u00a0<\/p>\n
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Wayne State University is one of the nation\u2019s pre-eminent public research universities in an urban setting. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world. For more information about research at Wayne State University, visit research.wayne.edu.<\/p>\n","protected":false},"excerpt":{"rendered":"Newswise \u2014 DETROIT \u2014 Cancer treatments like radiation and chemotherapy work by doing one main thing: shredding the…\n","protected":false},"author":2,"featured_media":364143,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10],"tags":[5299,2534,261565,12690,11741,39680,134,527,111,2055,139,69,1674,261566],"class_list":["post-529980","post","type-post","status-publish","format-standard","has-post-thumbnail","category-health","tag-biotech","tag-cancer","tag-cancerwayne-state-universitydnadna-pkcancer-treatment","tag-clinical-trials","tag-ethics-and-research-methods","tag-grant-funded-news","tag-health","tag-healthcare","tag-new-zealand","tag-newswise","tag-newzealand","tag-nz","tag-pharmaceuticals","tag-wayne-state-university-division-of-research"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts\/529980","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/comments?post=529980"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts\/529980\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/media\/364143"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/media?parent=529980"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/categories?post=529980"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/tags?post=529980"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}