Heterogeneous Responses to High-Dose Testosterone in Castration-Resistant Prostate Cancer Tumors with Mixed Rb-Proficient and Rb-Deficient Cells.
| Title: | Heterogeneous Responses to High-Dose Testosterone in Castration-Resistant Prostate Cancer Tumors with Mixed Rb-Proficient and Rb-Deficient Cells. |
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| Authors: | Labaf M; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Mathematics, University of Massachusetts Boston, Boston, Massachusetts.; Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.; Han W; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Human Biology Division, Fred Hutchinson Cancer Center, Washington.; Zhang S; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Liu M; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Patten ND; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Li M; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Division of Urology, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.; Patalano S; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Macoska JA; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Balk SP; Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.; Han D; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Zarringhalam K; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.; Cai C; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts. |
| Source: | Molecular cancer therapeutics [Mol Cancer Ther] 2025 May 02; Vol. 24 (5), pp. 772-783. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| MeSH Terms: | Prostatic Neoplasms, Castration-Resistant*/drug therapy ; Prostatic Neoplasms, Castration-Resistant*/genetics ; Prostatic Neoplasms, Castration-Resistant*/pathology ; Prostatic Neoplasms, Castration-Resistant*/metabolism ; Testosterone*/pharmacology ; Testosterone*/administration & dosage ; Retinoblastoma Protein*/genetics ; Retinoblastoma Protein*/metabolism ; Retinoblastoma Protein*/deficiency; Gene Expression Regulation, Neoplastic/drug effects ; Male ; Humans ; Animals ; Mice ; Xenograft Model Antitumor Assays ; Cell Line, Tumor |
| Abstract: | Androgen deprivation therapy remains a cornerstone in managing prostate cancer. However, its recurrence often leads to the more aggressive castration-resistant prostate cancer (CRPC). Although second-line androgen receptor signaling inhibition treatments such as enzalutamide and abiraterone are available, their effectiveness against CRPC is only transient. High-dose testosterone (Hi-T) has recently emerged as a promising treatment for CRPC, primarily through the suppression of E2F and MYC signaling. However, the roles of Rb family proteins in influencing this therapeutic response remain debated. In this study, we utilized a CRPC patient-derived xenograft model that includes both Rb pathway-proficient and -deficient cell populations based on the positive or negative expression of RB family genes. Single-cell RNA sequencing analysis revealed that Rb-proficient cells displayed a robust response to Hi-T, whereas Rb-deficient cells exhibited significant resistance. Notably, our analysis indicated increased enrichment of the hypoxia signature in the Rb-deficient cell population. Further studies in RB1-silenced CRPC cell lines showed that treatment with a hypoxia-inducible factor-1α inhibitor can restore the sensitivity of Rb-deficient cells to high-dose dihydrotestosterone treatment. In conclusion, our research provides new molecular insights into CRPC tumor cell responses to Hi-T and proposes a new strategy to resensitize Rb-deficient CRPC cells to Hi-T treatment.; (©2025 The Authors; Published by the American Association for Cancer Research.) |
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| Grant Information: | R01 CA211350 United States CA NCI NIH HHS; P50 CA090381 United States CA NCI NIH HHS; R01 CA299202 United States CA NCI NIH HHS; R01 CA282906 United States CA NCI NIH HHS; R01CA211350 National Cancer Institute (NCI); W81XWH-19-1-0361 U.S. Department of Defense (DOD); HT9425-24-1-0472 U.S. Department of Defense (DOD); P50CA090381 National Cancer Institute (NCI); U54 CA156734 United States CA NCI NIH HHS; P01 CA163227 United States CA NCI NIH HHS; U54CA156734 National Cancer Institute (NCI) |
| Substance Nomenclature: | 3XMK78S47O (Testosterone); 0 (Retinoblastoma Protein) |
| Entry Date(s): | Date Created: 20250321 Date Completed: 20250502 Latest Revision: 20260307 |
| Update Code: | 20260307 |
| PubMed Central ID: | PMC12046331 |
| DOI: | 10.1158/1535-7163.MCT-24-0716 |
| PMID: | 40116305 |
| Database: | MEDLINE |
Journal Article