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: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 dataset contains 29 paired FASTQ files from whole-genome bisulfite sequencing (WGBS) assay performed on mCRPC tumors. Sequencing was performed using 150nt paired reads generated by a Novaseq 6000 instrument. It also contains whole-genome sequencing bam files aligned to hg38 using BWA from
36 patients, with tumor and matched tumor-adjacent normal samples. Sequencing was generated using HiSeq X Ten.
Project description:Prostate cancer is a heterogenous disease and can be broadly categorized into androgen responsive and androgen indifferent groups. Robust biomarkers to identify them and enable the development of therapeutic strategies specific to each, remain to be defined. We conducted a dynamic, modular clinical trial ("DynAMo") in which 192 men with mCRPC were segregated based on Satisfactory (≥ 50% PSA decline from baseline and <5 CTC/7.5mL) versus Unsatisfactory marker status after 8-weeks of abiraterone, prednisone and apalutamide (ApA). Those with Satisfactory status (n=128, 67%) were randomized to continue ApA alone (Module 2A) or with ipilimumab (Module 2B). Median overall survival (OS) and 95% CI was 46.4 (39.2, 68.2) months and 41.4 (33.3, 49.9) months respectively. Patients with Unsatisfactory marker status (n=64, 33%) had carboplatin+cabazitaxel chemotherapy added to ApA (Module 3) and had an OS and 95% CI of 18.7 (14.3, 26.3) months. As part of this study, poly(A) RNA was extracted from 140 fresh frozen cores obtained from 136 patients during pre-treatment biopsies of metastatic sites. Of these, 21 (15.0%) yielded insufficient or poor-quality RNA. Of the 119 cores that were subject to bulk RNA sequencing, 56 (47.1%) from 56 patients passed quality control filters (i.e., RNA total reads ≥60 million, exonic rates ≥0.7, and ≥20,000 genes detected). The sequencing results from these 56 patient samples are provided here.