[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-330564-105":59,"doc-detail-330564-en":134},{"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":127,"head_meta":129,"extra_data":131,"updated_unix":133},105,"en","signature-reversion-of-three-disease-associated-gene-signatures-prioritizes-cancer-drug-repurposing-candidates","Signature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates","","Drug repurposing offers a faster, lower-cost path to new oncology indications because the safety profile of existing drugs has already been established. Signature reversion computationally prioritizes compounds by finding drug-induced gene perturbations that are most inversely related to a disease-associated gene signature. This work evaluates three signature-construction approaches (limma, DESeq2, and MultiPLIER) and prioritizes candidates for four low-survival cancers. Results are enriched for PRISM screen performance and clinical-trial usage, including pamidronate and nimodipine with demonstrated activity in glioblastoma models.",{"@graph":69,"@context":126},[70,84,105],{"@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/signature-reversion-of-three-disease-associated-gene-signatures-prioritizes-cancer-drug-repurposing-candidates/330564/",{"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/signature-reversion-of-three-disease-associated-gene-signatures-prioritizes-cancer-drug-repurposing-candidates/330564.png","ImageObject",300,407,{"name":92,"@type":93},"Aurora","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118,122],{"name":109,"@type":110,"acceptedAnswer":111},"How does signature reversion prioritize cancer drug repurposing candidates?","Question",{"text":112,"@type":113},"It identifies drugs whose cell-line perturbation signatures are most inversely related to the disease-associated gene signature, suggesting reversal of disease expression patterns.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which three approaches were evaluated for constructing disease-associated gene signatures?",{"text":117,"@type":113},"The study assessed limma, DESeq2, and MultiPLIER as methods to generate disease-associated gene signatures.",{"name":119,"@type":110,"acceptedAnswer":120},"What types of evidence supported the biological relevance of the prioritized candidates?",{"text":121,"@type":113},"Prioritized candidates were enriched for compounds used in clinical trials and for those performing well in the PRISM drug screen.",{"name":123,"@type":110,"acceptedAnswer":124},"What additional glioblastoma evidence was reported for specific drug candidates?",{"text":125,"@type":113},"Pamidronate and nimodipine were predicted to be efficacious against glioblastoma and were shown to inhibit the growth of a GBM cell line and cells from a patient-derived xenograft.","https://schema.org",{"og:url":83,"og:type":128,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":130,"canonical":83},"index,follow",{"doc_id":132,"site_id":62},330564,1790161838,{"code":4,"msg":5,"data":135},{"doc_id":132,"user_id":136,"nickname":92,"user_avatar":137,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":138,"file_id":139,"file_url":140,"file_type":141,"file_size":142,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":143,"language":144,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":145,"faqs":146,"seo_title":147,"seo_description":67,"update_tm":148,"read_time":149,"preview_page_count":4},4810365810221,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","RESEARCH ARTICLE  \nSignature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates Jennifer L. Fisher, Elizabeth J. Wilk, Vishal H. Oza, Sam E. Gary , Timothy C. Howton, Victoria L. Flanary, Amanda D. Clark , Anita B. Hjelmeland and Brittany N. Lasseigne   \nDepartment of Cell, Developmental and Integrative Biology, Heersink School of Medicine, The University of Alabama at Birmingham, AL, USA  \nKeywords  \ncancer; drug repurposing; gene signature; glioblastoma; transcriptomic signature  \nCorrespondence  \nB. N. Lasseigne, Department of Cell, Developmental and Integrative Biology, Heersink School of Medicine, The University of Alabama at Birmingham, 946 Tinsley Harrison Tower, 1900 University Boulevard, Birmingham, AL 35294-0006, USA  \nE-mail: [bnp0001@uab.edu](bnp0001@uab.edu)  \n(Received 11 February 2024, revised 13 March 2024, accepted 14 March 2024)  \ndoi:10.1002/2211-5463.13796  \nDrug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient-derived xenograft (PDX) . Our results demonstrate that by applying multiple disease-associated gene signature methods, we prioritized several drug repurposing candidates for low-survival cancers.  \nNew therapeutic options are critical for improving cancer survival rates [1] . While novel drug discovery can be effective, developing these new drugs costs billions of US dollars on average and can take upwards of 13 years for FDA approval [2,3] . Additionally, 95% of phase I clinical trial oncology drug candidates are ultimately not approved due to toxicity or inefficacy [2,4] . However, drug repurposing (identifying novel indications for previously approved drugs) is a promising alternative to drug discovery. As the candidates have already passed toxicity testing in previous clinical trials, drug repurposing reduces both the time and cost  \nneeded for approval for a new indication [5,6] . This approach successfully identified oncology and non-oncology drugs for novel cancer applications. For example, imatinib, a tyrosine kinase inhibitor for chronic myeloid leukemia, has been repurposed for treating gastrointestinal stromal tumors, and rapamycin, originally used as an immunosuppressant for kidney transplants, was repurposed for the treatment of renal cell carcinoma [2,7,8] .  \nIdentifying prioritized drugs for future cancer clinical trials requires identifying both the drug target(s) associated with the disease process and the drug predicted to  \nAbbreviations  \nCORUM, The Comprehensive Resource of Mammalian Protein Complexes; CYP450, cytochrome P450; DepMap, Cancer Dependency Map; FDR, false discovery rate; GBM, glioblastoma; GO, Gene Ontology; GTEx, Genotype-Tissue Expression; LIHC, liver hepatocellular carcinoma; LINCS, The Library of Integrated Network-based Cellular Signatures; LOF, loss-of-function; LUAD, lung adenocarinoma; MET, MET  \nproto-oncogene; MOA, mechanism of action; NCS, normalized connectivity score; PAAD, pancreatic adenocarcinoma; PCA, principal component analysis; PDX, patient-derived xenograft; PLIER, pathway-level information extractor; PPI, protein–protein interaction; PRISM, Profiling Relative Inhibition Simultaneously in Mi","cbCaioJpCppWGphL","https://ap.wps.com/l/cbCaioJpCppWGphL","pdf",3109639,28,"English","# Abstract\n# Methods and signature construction approaches\n# Prioritization results and validation\n# Glioblastoma candidate findings\n# Conclusions and implications","[{\"question\":\"How does signature reversion prioritize cancer drug repurposing candidates?\",\"answer\":\"It identifies drugs whose cell-line perturbation signatures are most inversely related to the disease-associated gene signature, suggesting reversal of disease expression patterns.\"},{\"question\":\"Which three approaches were evaluated for constructing disease-associated gene signatures?\",\"answer\":\"The study assessed limma, DESeq2, and MultiPLIER as methods to generate disease-associated gene signatures.\"},{\"question\":\"What types of evidence supported the biological relevance of the prioritized candidates?\",\"answer\":\"Prioritized candidates were enriched for compounds used in clinical trials and for those performing well in the PRISM drug screen.\"},{\"question\":\"What additional glioblastoma evidence was reported for specific drug candidates?\",\"answer\":\"Pamidronate and nimodipine were predicted to be efficacious against glioblastoma and were shown to inhibit the growth of a GBM cell line and cells from a patient-derived xenograft.\"}]","Signature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates | PDF",1789989427,71]