{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:06:03Z","timestamp":1789563963877,"version":"build-2803163510"},"reference-count":52,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20231504"],"award-info":[{"award-number":["BK20231504"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp;amp; Cancer"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The PIK3CA\u2010related overgrowth spectrum (PROS) encompasses a group of rare, somatic disorders caused by somatic activating mutations in PIK3CA, resulting in a dysregulated PI3K\/AKT\/mTOR pathway and consequent segmental tissue overgrowth and vascular malformations affecting multiple tissue types. This review synthesizes advances in targeted therapy for PROS, focusing on molecular rationale, clinical evidence, limitations, and future perspectives of targeting the PI3K\/AKT\/mTOR pathway. Overall, the selective PI3K\u03b1 inhibitor alpelisib has shown reductions in lesion burden and improvements in functional outcomes, with a generally manageable safety profile. Other agents, including taselisib and miransertib, have shown limited clinical benefits, and their further development has been constrained by safety concerns and insufficient efficacy. Although mTOR inhibitors, such as sirolimus, have shown partial efficacy in symptom control, durable responses remain uncommon, and recurrence after treatment discontinuation has been observed. Long\u2010term safety, particularly in pediatric populations, remains to be fully established. In conclusion, targeted therapies, particularly alpelisib, represent a significant advancement in the management of PROS, although optimization of patient selection, long\u2010term risk assessment, and strategies to minimize recurrence remain important unmet needs.<\/jats:p>","DOI":"10.1002\/1545-5017.70697","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T12:24:58Z","timestamp":1789561498000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Advances in the Targeted Therapy for PIK3CA\u2010Related Overgrowth Spectrum (PROS): From Molecular Mechanisms to Clinical Translation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2671-0740","authenticated-orcid":false,"given":"Zhu","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Plastic Surgery and Vascular Biology Lab Nanjing Jinling Hospital Southeast University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1380-5425","authenticated-orcid":false,"given":"Si\u2010Ming","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery and Vascular Biology Lab Nanjing Jinling Hospital Southeast University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436\u2010021\u201001290\u2010y"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2014.00064"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2008.245"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2012.00109"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41065\u2010021\u201000184\u2010y"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010021\u201001929\u20108"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1104017"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2332"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2331"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.05.006"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36552"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34402"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31531"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldab023"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202523139"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010018\u20100217\u20109"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010genom\u2010121222\u2010114518"},{"key":"e_1_2_10_20_1","unstructured":"\u201cA Phase II Study to Evaluate the Long\u2010term Safety and Efficacy of Alpelisib in Patients with PIK3CA\u2010Related Overgrowth Spectrum (PROS) Who Previously Participated in Study CBYL719F12002 (EPIK\u2010P1) \u201dOrphanet 2021."},{"issue":"1","key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"8227","DOI":"10.1182\/blood-2025-8227","article-title":"Study Assessing the Efficacy, Safety and Pharmacokinetics of Alpelisib in Pediatric and Adult Patients With PIK3CA\u2010Related Overgrowth Spectrum (PROS): Epik\u2010P4, a Phase II Study","volume":"146","author":"Borst A. 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