{"title":"碳酸酐酶 IX:癌症创新疗法的非典型靶点","authors":"Roberto Ronca , Claudiu T. Supuran","doi":"10.1016/j.bbcan.2024.189120","DOIUrl":null,"url":null,"abstract":"<div><p>Carbonic anhydrases (CAs), are metallo-enzymes implicated in several pathophysiological processes where tissue pH regulation is required. CA IX is a tumor-associated CA isoform induced by hypoxia and involved in the adaptation of tumor cells to acidosis. Indeed, several tumor-driving pathways can induce CA IX expression, and this in turn has been associated to cancer cells invasion and metastatic features as well as to induction of stem-like features, drug resistance and recurrence. After its functional and structural characterization CA IX targeting approaches have been developed to inhibit its activity in neoplastic tissues, and to date this field has seen an incredible acceleration in terms of therapeutic options and biological readouts. Small molecules inhibitors, hybrid/dual targeting drugs, targeting antibodies and adoptive (CAR-T based) cell therapy have been developed at preclinical level, whereas a sulfonamide CA IX inhibitor and an antibody entered Phase Ib/II clinical trials for the treatment and imaging of different solid tumors. Here recent advances on CA IX biology and pharmacology in cancer, and its therapeutic targeting will be discussed.</p></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":null,"pages":null},"PeriodicalIF":9.7000,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0304419X24000519/pdfft?md5=6d3ac5790309de74d9844f45f2d450f2&pid=1-s2.0-S0304419X24000519-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Carbonic anhydrase IX: An atypical target for innovative therapies in cancer\",\"authors\":\"Roberto Ronca , Claudiu T. Supuran\",\"doi\":\"10.1016/j.bbcan.2024.189120\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Carbonic anhydrases (CAs), are metallo-enzymes implicated in several pathophysiological processes where tissue pH regulation is required. CA IX is a tumor-associated CA isoform induced by hypoxia and involved in the adaptation of tumor cells to acidosis. Indeed, several tumor-driving pathways can induce CA IX expression, and this in turn has been associated to cancer cells invasion and metastatic features as well as to induction of stem-like features, drug resistance and recurrence. After its functional and structural characterization CA IX targeting approaches have been developed to inhibit its activity in neoplastic tissues, and to date this field has seen an incredible acceleration in terms of therapeutic options and biological readouts. Small molecules inhibitors, hybrid/dual targeting drugs, targeting antibodies and adoptive (CAR-T based) cell therapy have been developed at preclinical level, whereas a sulfonamide CA IX inhibitor and an antibody entered Phase Ib/II clinical trials for the treatment and imaging of different solid tumors. Here recent advances on CA IX biology and pharmacology in cancer, and its therapeutic targeting will be discussed.</p></div>\",\"PeriodicalId\":8782,\"journal\":{\"name\":\"Biochimica et biophysica acta. Reviews on cancer\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.7000,\"publicationDate\":\"2024-05-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0304419X24000519/pdfft?md5=6d3ac5790309de74d9844f45f2d450f2&pid=1-s2.0-S0304419X24000519-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochimica et biophysica acta. Reviews on cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0304419X24000519\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochimica et biophysica acta. Reviews on cancer","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0304419X24000519","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
碳酸酐酶(CA)是一种金属酶,与多种需要调节组织 pH 值的病理生理过程有关。CA IX 是一种肿瘤相关的 CA 异构体,由缺氧诱导,参与肿瘤细胞对酸中毒的适应。事实上,几种肿瘤驱动途径都能诱导 CA IX 的表达,而这反过来又与癌细胞的侵袭和转移特征以及诱导干样特征、耐药性和复发有关。在对 CA IX 进行功能和结构表征后,人们开发出了抑制其在肿瘤组织中活性的靶向方法。小分子抑制剂、混合/双靶向药物、靶向抗体和收养(基于 CAR-T 的)细胞疗法已在临床前水平开发出来,而磺胺 CA IX 抑制剂和抗体已进入 Ib/II 期临床试验,用于不同实体瘤的治疗和成像。本文将讨论癌症中 CA IX 生物学和药理学的最新进展及其治疗靶点。
Carbonic anhydrase IX: An atypical target for innovative therapies in cancer
Carbonic anhydrases (CAs), are metallo-enzymes implicated in several pathophysiological processes where tissue pH regulation is required. CA IX is a tumor-associated CA isoform induced by hypoxia and involved in the adaptation of tumor cells to acidosis. Indeed, several tumor-driving pathways can induce CA IX expression, and this in turn has been associated to cancer cells invasion and metastatic features as well as to induction of stem-like features, drug resistance and recurrence. After its functional and structural characterization CA IX targeting approaches have been developed to inhibit its activity in neoplastic tissues, and to date this field has seen an incredible acceleration in terms of therapeutic options and biological readouts. Small molecules inhibitors, hybrid/dual targeting drugs, targeting antibodies and adoptive (CAR-T based) cell therapy have been developed at preclinical level, whereas a sulfonamide CA IX inhibitor and an antibody entered Phase Ib/II clinical trials for the treatment and imaging of different solid tumors. Here recent advances on CA IX biology and pharmacology in cancer, and its therapeutic targeting will be discussed.
期刊介绍:
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer encompasses the entirety of cancer biology and biochemistry, emphasizing oncogenes and tumor suppressor genes, growth-related cell cycle control signaling, carcinogenesis mechanisms, cell transformation, immunologic control mechanisms, genetics of human (mammalian) cancer, control of cell proliferation, genetic and molecular control of organismic development, rational anti-tumor drug design. It publishes mini-reviews and full reviews.