Project description:Informed consent was obtained to collect human mCRPC tissues and generate the patient-derived xenograft tumors as described previously (Labrecque et al., 2019; Nguyen et al., 2017). The study was approved by the University of Washington Human Subjects Division institutional review board (no. 39053). All animal studies were approved by University of Washington IACUC and performed according to NIH guidelines. Molecular characterization of AR+ mCRPC LuCaP PDXs 70CR, 78CR, 81CR, 96CR, 105CR, 136CR and 147CR was previously described (Labrecque et al., 2019; Nguyen et al., 2017). LuCaP PDX 167CR was established from a liver metastasis of 77-year-old Caucasian male who died of abiraterone-, carboplatin- and docetaxel-resistant CRPC. LuCaP 167CR expresses AR, responds to castration and is negative for synaptophysin. PDX cellular morphology recapitulates the original liver metastasis (Supplementary Figure S8A).
Project description:There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently available. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate (AA) for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line AA in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah. Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line AA in men with mCRPC. We performed a pre-specified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on AA. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line AA for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared to the homozygous wild-type group (8.9 months vs. 6.3 months, HR 0.46, 95% CI 0.23-0.94, p=0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line AA In men with mCRPC.
Project description:WNT signalling, an integral orchestrator in an assortment of developmental and pathological pathways, exhibits aberrant regulation in a variety of human malignancies, encompassing prostate cancer (PCa). Particularly, in metastatic castration-resistant prostate cancer (mCRPC), WNT signalling demonstrates dysregulated activity, albeit the precise molecular underpinnings of this ectopic signalling remain predominantly undefined. Within this investigation, we illuminate the role of the previously unidentified tumor suppressor, NLN, which serves as a molecular scaffold to facilitate KIF11 aggregation. A notable depletion of NLN was observed in approximately 30% of mCRPC cases, a deficiency that catalyzes the unleashing of KIF11-dependent cellular translocation of WNT3A, culminating in amplified WNT3A secretion into the tumor microenvironment (TME). This excessive extracellular WNT3A release augments the adaptive resilience of proximal mCRPC cells, fostering resistance against the prevailing standard-of-care AR-targeted therapies. The findings from this study delineate a hitherto uncharacterized, cancer cell-autonomous mechanism that modifies the TME via modulated WNT secretion, thereby inciting resistance to AR-targeted therapies. Moreover, these results underscore the potential clinical utility of NLN level assessments as a prognostic biomarker for mCRPC, and propose the potential efficacy of WNT3A inhibitors as a therapeutic approach to counteract resistance.
Project description:The prognosis of patients with metastatic castration-resistant prostate cancer (mCRPC) is variable. Several blood-related prognostic factors have been reported, including transcriptional profiling of whole blood and neutrophil to lymphocyte ratio. We aimed to address the contribution of distinct whole blood immune cell components to the prognosis of these patients. Subjects/Patients and Methods: Pre-treatment whole blood samples from chemotherapy-naïve mCRPC patients were prospectively collected before treatment with enzalutamide. The study consisted of a training cohort including 98 patients treated with enzalutamide in a phase 2 biomarker clinical trial (NCT02288936)
Project description:This study is aimed to explore in vivo trascriptional response of BMS-986365 and enzalutamide in mCRPC PDX models CTG-2441 and CTG-2440 which were derived from bone metastases of the same patient following progression on ADT or ADT plus abiraterone treatments, respectively.