期刊
MOLECULAR CANCER RESEARCH
卷 20, 期 5, 页码 782-793出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-21-1037
关键词
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资金
- Canadian Institutes of Health Research [141635, 144159, 153081, 173338]
- Terry Fox Research Institute [1062]
- Mitacs Accelerate Program [IT10125, IT06414, IT12387, IT14958]
- NCI grant pilot project award [P50CA097186]
- Canadian Foundation for Translational Immunology
- Pacific Northwest Prostate Cancer [SPORE/NCI P50 CA097186]
- NCI Drug Resistance and Sensitivity Network [NCI P50 CA186786-07S1, NCI R01 CA251245]
- Rogel Cancer Center Innovation Award [P30 CA046592]
- CDMRP Prostate Cancer Research Program
- Prostate Cancer Foundation
- Intramural Research Program of the NIH, NCI
This study aimed to develop clinically relevant models for studying ADT-induced prostate cancer dormancy. The researchers established 11 ADT-induced dormant prostate cancer models that closely mimicked the clinical courses of ADT-treated prostate cancer and identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. They also discovered transcriptomic differences in precastration PDXs that predisposed the dormancy response to ADT and developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naive prostate cancer and clinical outcome in castration-resistant prostate cancer treated with ADT or androgen-receptor pathway inhibitors.
Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced prostate cancer dormancy remains poorly understood due to the challenge in acquiring clinical dormant prostate cancer cells and the lack of representative models. In this study, we aimed to develop clinically relevant models for studying ADT-induced prostate cancer dormancy. Dormant prostate cancer models were established by castrating mice bearing patient-derived xenografts (PDX) of hormonal naive or sensitive prostate cancer. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and postcastration (dormant) PDX tissues were subjected to morphologic and transcriptome profiling analyses. As a result, we established eleven ADT-induced dormant prostate cancer models that closely mimicked the clinical courses of ADT-treated prostate cancer. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in precastration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naive prostate cancer and clinical outcome in castration-resistant prostate cancer treated with ADT or androgen-receptor pathway inhibitors.
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