[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-368352-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-368352-en":131},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","harnessing-p53-for-targeted-cancer-therapy-new-advances-and-future-directions","Harnessing p53 for targeted cancer therapy: new advances and future directions","","The transcription factor p53 is a central, frequently impaired tumor suppressor in human cancers, orchestrating stress-induced gene programs that drive cell-cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, antiviral defense, and anti-metastatic activity. About half of human tumors preserve unmutated p53, making the p53 network a strong target for precision oncology. Recent research focuses on MDM2–p53 axis inhibition, but MDM2 monotherapies yield limited apoptotic benefit and hematological toxicity. Combination regimens are summarized, emphasizing synergy with MDM2 inhibitors and covering modulators of transcriptome, translatome, and proteome, plus downstream pathway targeting and principles for future combinations.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/harnessing-p53-for-targeted-cancer-therapy-new-advances-and-future-directions/368352/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/harnessing-p53-for-targeted-cancer-therapy-new-advances-and-future-directions/368352.png","ImageObject",300,407,{"name":42,"@type":43},"Genevieve","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-24","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",11,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why is p53 considered an important target in cancer therapy?","Question",{"text":63,"@type":64},"p53 is the most frequently impaired tumor suppressor and activates transcriptional programs controlling apoptosis, cell-cycle arrest, DNA repair, metabolism, and anti-metastatic responses. About half of human tumors retain unmutated p53, enabling targeted restoration of p53 activity.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What limitations have MDM2 inhibitors shown in clinical settings?",{"text":68,"@type":64},"Small-molecule MDM2 inhibitors induce therapeutically desirable apoptosis only in limited cancer types. Clinical trials as monotherapies have not met expectations and commonly show hematological toxicity.",{"name":70,"@type":61,"acceptedAnswer":71},"How do combination treatments improve the effectiveness of MDM2 inhibitors?",{"text":72,"@type":64},"Combination strategies aim to increase efficacy while reducing adverse effects. The review highlights synergy achieved by pairing MDM2 inhibitors with drugs that modulate p53-regulated transcriptome/translatome/proteome or target downstream pathways such as apoptosis, cell-cycle arrest, DNA repair, immune response, ferroptosis, and growth factor signaling.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},368352,1790625550,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":124,"doc_module":4,"doc_module_name":25,"category_name":125,"show_sort_weight":124,"slug":126},10,"Lifestyle","lifestyle",{"id":128,"doc_module":4,"doc_module_name":25,"category_name":129,"show_sort_weight":97,"slug":130},19,"General","general",{"code":4,"msg":82,"data":132},{"doc_id":79,"user_id":133,"nickname":42,"user_avatar":134,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":140,"language":141,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":12,"update_tm":145,"read_time":146},1374391974585,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","TRANSCRIPTION  \n2025, VOL. 16, NO. 1, 3–46  \n[https://doi.org/10.1080/21541264.2025.2452711](https://doi.org/10.1080/21541264.2025.2452711)  \n| REVIEW\u003Cbr>\u003Cbr>Harnessing p53 for targeted cancer therapy: new advances and future directions\u003Cbr>Zdenek Andrysika,b,c and Joaquin M. Espinosab,c\u003Cbr>aDepartment of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; bDepartment of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; cLinda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA |  |  |\n| --- | --- | --- |\n| \u003Cbr>ABSTRACT\u003Cbr>The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumorsuppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments. |  | ARTICLE HISTORY\u003Cbr>Received 28 November 2024 Revised 7 January 2025 Accepted 8 January 2025\u003Cbr>KEYWORDS\u003Cbr>p53; nutlin; nelfinavir; integrated stress response; polytherapy; combination therapy |\n| Introduction |  |  |\n| TP53 is the most frequently mutated tumor sup- | often inactivated through alternative mechanisms, |  |\n| pressor gene in cancers. In The Cancer Genome | including viral oncoproteins or by overexpression |  |\n| Atlas (TCGA) collection [ 1], TP53 mutations | of negative regulators. The varying frequencies of |  |\n| range from 1% to 5% in papillary thyroid carcino- | TP53 mutations across different cancer types serve |  |\n| mas, renal clear cell carcinomas, renal papillary | as an important benchmark for understanding |  |\n| cell carcinomas, and cervical squamous cell carci- | p53’s role in tumor suppression. Therefore, i) |  |\n| nomas. Conversely, mutation rates reach up to | TP53 mutations provide tumors with a fitness |  |\n| 70–95% in head and neck squamous cell carcino- | advantage that surpasses all other tumor suppres- |  |\n| mas, lung squamous cell carcinomas, and ovarian | sor gene mutations. ii) Since TP53 mutations |  |\n| serous cystadenocarcinomas. TP53 mutation rates | occur in almost all cancer types, the affected |  |\n| are significantly increased in 15 out of 18 tested | mechanisms must be numerous or common to |  |\n| ","cbCaireZLisj8irA","https://ap.wps.com/l/cbCaireZLisj8irA","pdf",1944143,44,"English","# Introduction\n# Article history and abstract\n# Keywords","[{\"question\":\"Why is p53 considered an important target in cancer therapy?\",\"answer\":\"p53 is the most frequently impaired tumor suppressor and activates transcriptional programs controlling apoptosis, cell-cycle arrest, DNA repair, metabolism, and anti-metastatic responses. About half of human tumors retain unmutated p53, enabling targeted restoration of p53 activity.\"},{\"question\":\"What limitations have MDM2 inhibitors shown in clinical settings?\",\"answer\":\"Small-molecule MDM2 inhibitors induce therapeutically desirable apoptosis only in limited cancer types. Clinical trials as monotherapies have not met expectations and commonly show hematological toxicity.\"},{\"question\":\"How do combination treatments improve the effectiveness of MDM2 inhibitors?\",\"answer\":\"Combination strategies aim to increase efficacy while reducing adverse effects. The review highlights synergy achieved by pairing MDM2 inhibitors with drugs that modulate p53-regulated transcriptome/translatome/proteome or target downstream pathways such as apoptosis, cell-cycle arrest, DNA repair, immune response, ferroptosis, and growth factor signaling.\"}]","Harnessing p53 for targeted cancer therapy: new advances and future directions | PDF",1790176469,111]