[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-333100-105":59,"doc-detail-333100-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","molecular-and-cellular-mechanisms-underlying-the-failure-of-mitochondrial-metabolism-drugs-in-cancer-clinical-trials-viewpoint","Molecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials - Viewpoint","","Explores why clinical trials targeting mitochondrial metabolism in cancer—including drugs such as metformin—have largely failed, despite strong mechanistic rationale. Details how mitochondrial electron transport chain (ETC) function supports oxidative phosphorylation and tumor bioenergetics through links to the TCA cycle and metabolite production. Describes major limitations from toxicity and narrow therapeutic indices of ETC/TCA inhibitors (e.g., CPI-613, CB-839, IACS-010759), and explains why effective yet safe dosing is difficult because ETC activity is required for normal tissues. Also highlights translational strategies using mitochondrial metabolism modulators.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/molecular-and-cellular-mechanisms-underlying-the-failure-of-mitochondrial-metabolism-drugs-in-cancer-clinical-trials-viewpoint/333100/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/molecular-and-cellular-mechanisms-underlying-the-failure-of-mitochondrial-metabolism-drugs-in-cancer-clinical-trials-viewpoint/333100.png","ImageObject",300,407,{"name":92,"@type":93},"Himbo","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-01","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",15,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why do drugs targeting mitochondrial metabolism fail in many cancer clinical trials?","Question",{"text":113,"@type":114},"Clinical translation is hindered by toxic side effects that limit effective antineoplastic dosing, and by mechanisms that prevent adequate therapeutic benefit in trial settings.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does the mitochondrial ETC support tumor growth?",{"text":118,"@type":114},"The ETC enables oxidative phosphorylation, generating ATP and supporting biosynthetic programs by coupling to the oxidative TCA cycle that supports macromolecule production.",{"name":120,"@type":111,"acceptedAnswer":121},"What role does metformin play in this discussion?",{"text":122,"@type":114},"Metformin is highlighted as an example of a mitochondrial metabolism-targeting drug, with laboratory anticancer effects and retrospective clinical observations suggesting reduced cancer incidence and related deaths.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},333100,1790211221,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":19,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":52,"preview_page_count":4},687197100911,"https://ap-avatar.wpscdn.com/avatar/a000239b6f1da00475?x-image-process=image/resize,m_fixed,w_180,h_180&k=1785132997149421697","The Journal of Clinical Investigation VIEWPOINT  \nMolecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials  \nKarthik Vasan and Navdeep S. Chandel  \nDepartment of Medicine, Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.  \nThe majority of cancer cells have a functional mitochondrial electron transport chain (ETC) . Mitochondrial complex Iis the primary entry point into the ETC, where oxidative phosphorylation occurs, generating ATP as an energy source for powering the cell. Electrons are transferred through a chain of mitochondrial protein complexes (complex I, II, III, and IV) to the final electron acceptor, molecular oxygen, while protons are pumped by complexes I, III, and IV to create an electrochemical proton gradient, ultimately driving ATP synthesis through complex V. The ETC can function optimally even in hypoxic conditions, allowing solid tumors, which often have limited oxygen availability, to maintain mitochondrial respiration. Mitochondrial ETC function is intrinsically linked to the oxidative tricyclic acid (TCA) cycle, which supports tumor growth by enabling macromolecule biosynthesis (1). Genetic and pharmacologic inhibition of the ETC prevents de novo pyrimidine synthesis and oxidative TCA cycle flux, supporting lipid, heme, aspartate, and asparagine production, all of which act together to decrease primary tumor growth and metastasis (2). Furthermore, mutations in ETC genes are generally selected against across various types of cancer (3) . Thus, mitochondrial metabolism is an essential, dynamic process throughout tumorigenesis, with metabolic flexibility serving the tumor’s needs at every stage, from initiation to metastasis. Ultimately, the metabolic demand imposed by driver mutations on specific tissue lineages, coupled with nutrient or metabolite availability of tissue microenvironment, determines the dependency  \non any intracellular metabolic pathways, including ETC-linked pathways. Owing to the critical role of mitochondria in tumor growth, there is considerable interest in translating inhibition of mitochondrial ETC or TCA cycle metabolism into clinical practice (1). However, clinical trials with drugs targeting mitochondrial metabolism, including metformin, have largely failed (4). Here, we discuss the mechanisms underlying why these trials have failed and a possible path forward to successfully targeting mitochondria metabolism, using metformin as an example, for cancer therapy.  \nToxicity of mitochondrial metabolism–targeting drugs Multiple inhibitors that target mitochondrial metabolism have been tried in clinical trials, including CPI-613 (also known as devimistat), CB-839 (also known as telaglenastat), ONC201, and IACS- 010759. CPI-613 is a lipoate analog that purportedly inhibits 2 tricyclic acid (TCA) cycle enzyme complexes, α-ketoglutarate dehydrogenase and pyruvate dehydrogenase. Although the exact mechanism of CPI-613’s anticancer activity is unclear, promising phase I outcomes in pancreatic cancer and acute myeloid leukemia (AML) trials have been reported (NCT01835041 and NCT01034475) . However, CPI-613 in combination with FOLFIRINOX did not have a survival benefit compared with FOLFIRINOX alone for patients with previously untreated metastatic pancreatic ductal adenocarcinoma (AVENGER 500 trial, NCT03504423). CB-839 is aglutaminase inhibitor that prevents glu-  \nConflict of interest: NSC was on the scientific advisory board of Cornerstone Pharmaceuticals and is on the scientific advisory board of Asha Therapeutics.  \nCopyright: © 2024, Vasan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.  \nReference information: J Clin Invest. 2024;134(3):e176736 . [https://doi.org/10.1172/JCI176736](https://doi.org/10.1172/JCI176736) .  \ntaminolysis from feeding the TCA cycle. In a phase II clinical tria","cbCaihEwxmhBH4QY","https://ap.wps.com/l/cbCaihEwxmhBH4QY","pdf",1100837,"English","# Molecular and cellular rationale\n## ETC function and oxidative TCA coupling\n## Metabolic flexibility across tumorigenesis\n# Clinical failure of mitochondrial metabolism drugs\n## Toxicity and dosing limitations\n## Examples of trial drugs and outcomes\n# Metformin as a translational example","[{\"question\":\"Why do drugs targeting mitochondrial metabolism fail in many cancer clinical trials?\",\"answer\":\"Clinical translation is hindered by toxic side effects that limit effective antineoplastic dosing, and by mechanisms that prevent adequate therapeutic benefit in trial settings.\"},{\"question\":\"How does the mitochondrial ETC support tumor growth?\",\"answer\":\"The ETC enables oxidative phosphorylation, generating ATP and supporting biosynthetic programs by coupling to the oxidative TCA cycle that supports macromolecule production.\"},{\"question\":\"What role does metformin play in this discussion?\",\"answer\":\"Metformin is highlighted as an example of a mitochondrial metabolism-targeting drug, with laboratory anticancer effects and retrospective clinical observations suggesting reduced cancer incidence and related deaths.\"}]","Molecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials - Viewpoint | PDF",1790000849]