{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T17:32:53Z","timestamp":1790530373812,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>For centuries, humans have used directed evolution to promote desired traits in domesticated animals. We hypothesized similar strategies may be employed to steer castrate resistant prostate cancer cells to a castrate sensitive phenotype allowing resumption of Androgen Deprivation therapy (ADT) and prolonging survival.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Our interdisciplinary team investigated directed evolution to restore castrate sensitivity in a patient with metastatic castrate resistant prostate cancer who could not tolerate available therapeutic agents for castrate resistant disease. Guided by an evolutionary mathematical model and using the PSA\/testosterone ratio as a biomarker for intra\u2010tumoral population dynamics, we applied a sequence of testosterone injections as evolutionary selection forces to suppress resistant androgen receptor\u2013upregulated clones and promote proliferation of ADT\u2010responsive clones.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>When the PSA\/testosterone ratio indicated successful transition to dominant castrate sensitive population, reinstitution of adaptive dosing of ADT has resulted in three stable cycles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This case suggests that evolution\u2010informed strategies using population\u2010based biomarkers to manipulate intra\u2010tumoral evolution can restore castrate sensitivity in select patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pros.70038","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T05:11:27Z","timestamp":1756444287000},"page":"1562-1567","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Directed Evolution Restored Castrate Sensitivity in a Patient With Castrate Resistant Metastatic Prostate Cancer"],"prefix":"10.1002","volume":"85","author":[{"given":"Robert A.","family":"Gatenby","sequence":"first","affiliation":[{"name":"Integrated Mathematical Oncology Department Moffitt Cancer Center Tampa Florida USA"},{"name":"Cancer Biology and Evolution Program Moffitt Cancer Center Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander R. A.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Integrated Mathematical Oncology Department Moffitt Cancer Center Tampa Florida USA"},{"name":"Cancer Biology and Evolution Program Moffitt Cancer Center Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel S.","family":"Brown","sequence":"additional","affiliation":[{"name":"Integrated Mathematical Oncology Department Moffitt Cancer Center Tampa Florida USA"},{"name":"Cancer Biology and Evolution Program Moffitt Cancer Center Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Gallaher","sequence":"additional","affiliation":[{"name":"Integrated Mathematical Oncology Department Moffitt Cancer Center Tampa Florida USA"},{"name":"Cancer Biology and Evolution Program Moffitt Cancer Center Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Krolick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn","family":"Lemanne","sequence":"additional","affiliation":[{"name":"Weil Center for Integrative Medicine University of Arizona Tucson Arizona"},{"name":"Oregon Integrative Oncology Ashland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ucl.2017.07.008"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15020461"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/bco2.116"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad7842"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-3658"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.76284"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01968-5"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14215225"},{"key":"e_1_2_7_10_1","doi-asserted-by":"crossref","unstructured":"J. A.Gallaher R. A.Gatenby J. S.Brown A. R. A.Anderson andJ.Zhang \u201cPSA\/Testosterone Ratio as a Potential Biomarker to Identify Early Progressors of Adaptive Therapy in Metastatic Castration Sensitive Prostate Cancer \u201d preprint medRxiv May 9 2025 https:\/\/doi.org\/10.1101\/2025.05.08.25327179.","DOI":"10.1101\/2025.05.08.25327179"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-52032-y"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/PPO.0000000000000216"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.24328"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44514-2"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2022.12.001"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.00647"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-3992"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-2649"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-0006"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-0806"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-2040"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1212299"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2018.09.022"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.24426"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1354"}],"container-title":["The Prostate"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pros.70038","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T09:20:01Z","timestamp":1762852801000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pros.70038"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,28]]},"references-count":24,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/pros.70038"],"URL":"https:\/\/doi.org\/10.1002\/pros.70038","archive":["Portico"],"relation":{},"ISSN":["0270-4137","1097-0045"],"issn-type":[{"value":"0270-4137","type":"print"},{"value":"1097-0045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,28]]},"assertion":[{"value":"2025-05-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}