Nature Chemical Biology<\/a>,\u00a0the study found the experimental drug zavondemstat and a closely related research compound, QC6352 \u2013 developed to treat cancers such as colorectal, pancreatic and prostate cancer \u2013 do not primarily target KDM4, a family of proteins which can help cancer cells grow and spread when it becomes overactive.<\/p>\nInstead, both compounds largely work by blocking DHODH, an enzyme cancer cells rely on to produce the molecules needed for rapid growth.<\/p>\n
The research may have implications for drugs now in development<\/p>\n
Lead author\u00a0Professor Lenka Munoz\u00a0from the University of Sydney\u00a0School of Medical Sciences\u00a0and\u00a0Charles Perkins Centre\u00a0said: \u201cWe can think of DHODH as a machine producing bricks needed to build new DNA. If you switch off the machine, the cell starts running out of bricks and can no longer efficiently copy its DNA and keep dividing.\u201d<\/p>\n
These findings could affect the interpretation of previous studies around the world that used the research compound (QC6352) to investigate the biology of the cancer protein and may have implications for the ongoing clinical development of the zavondemstat drug.<\/p>\n
The discovery emerged from research investigating whether zavondemstat and QC6352 could be repurposed for glioblastoma, the most common and aggressive form of brain cancer.<\/p>\n
\u201cWe tested these compounds to investigate whether they could potentially be repurposed for glioblastoma treatment,\u201d Professor Munoz said.<\/p>\n
\u201cWhen we tested other KDM4 inhibitors, we found they did not reproduce the anti-cancer effects observed with QC6352.<\/p>\n
\u201cIf blocking KDM4 was driving those effects, we would have expected the other inhibitors to behave similarly. Instead, the results suggested QC6352 was acting through a different mechanism.\u201d<\/p>\n
Using patient-derived glioblastoma stem cells, tumour models and a series of genetic, mechanistic and molecular experiments, the researchers traced the compounds\u2019 response to DHODH rather than KDM4.<\/p>\n
\u201cResearchers around the world have used QC6352 as a leading tool to study KDM4 biology, while the related drug zavondemstat progressed into clinical trials based on the same understanding,\u201d Professor Munoz said.<\/p>\n
\u201cOur study found much of the anti-cancer activity of these compounds is driven by blocking DHODH rather than KDM4.\u201d<\/p>\n
Study highlights broader issue facing cancer drug development<\/p>\n
Professor Munoz said the findings highlight a broader challenge in cancer drug development.<\/p>\n
\u201cGetting a drug\u2019s mechanism wrong can lead to poorly designed clinical trials, inappropriate patient selection and years of research focused on the wrong biological target,\u201d she said.<\/p>\n
\u201cThere are well-known examples of cancer drugs advancing through large clinical trials before researchers realised they were not working through the mechanism originally proposed.<\/p>\n
\u201cOur study shows this is not just a historical problem but one still happening today. Greater rigour is needed to ensure we understand exactly how potential treatments work before they move into clinical testing.<\/p>\n
\u201cEstablishing a drug\u2019s true mechanism early can protect patients<\/a>, prevent wasted research effort and help ensure what limited funding we have is directed towards genuinely promising treatments.\u201d<\/p>\nThe findings also point to DHODH inhibition as a potential new avenue for glioblastoma treatment. Several drugs targeting DHODH are already being investigated for other cancers, raising the possibility they could eventually be tested in patients with brain cancer.<\/p>\n
Beyond identifying the drug\u2019s true target, the researchers developed new compounds that inhibit KDM4 without affecting DHODH, which could help scientists study the role of KDM4 more accurately in future cancer research.<\/p>\n","protected":false},"excerpt":{"rendered":"A cancer drug currently being tested in patients may have entered clinical trials based on an incorrect understanding…\n","protected":false},"author":2,"featured_media":623262,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10],"tags":[2534,54348,134,54349,111,139,69],"class_list":["post-623261","post","type-post","status-publish","format-standard","has-post-thumbnail","category-health","tag-cancer","tag-diseases-and-conditions","tag-health","tag-medical-science","tag-new-zealand","tag-newzealand","tag-nz"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts\/623261","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=623261"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/posts\/623261\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/media\/623262"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/media?parent=623261"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/categories?post=623261"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/nz\/wp-json\/wp\/v2\/tags?post=623261"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}