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.
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: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 examined the gene expression effects of treating androgen-deprived C4-2 prostate cancer cells with the ACLY inhibitor BMS-303141 and the AR antagonist enzalutamide.
Project description:HOXB13 is a developmentally regulated transcription factor, co-expressed along with the Androgen receptor (AR) in a majority of PCs. Previous studies have indicated context dependent roles of HOXB13 in the functional regulation of AR and enrichment of HOXB13 motifs in the AR cistrome. Our studies showed that genetic or pharmacological blockade of HOXB13 sensitized mCRPCs to Enzalutamide (ENZ, Xtandi), an anti-androgen that is currently deployed to treat mCRPC patients. To identify HOXB13-mediated mechanism of castration-resistance ChIP-sequencing was performed with the HOXB13-K13ac, or IgG antibodies in the metastatic prostate cancer cell line, C4-2B in vehicle treated as well as Enzalutamide treated cell lines. We demonstrated for the first time that BRD4, epigenetically regulates HOXB13 gene expression in PCs. Consistently, JQ1 the prototype BET inhibitor suppresses HOXB13 expression and inhibit mCRPC growth. ChIP-sequence analysis reveals that HOXB13 recruitment to the chromatin is not completely abrogated in Enzalutamide treated cells identify a subset of genes that may have potential role in CRPC proliferation, anti-androgen resistance and metastasis.
Project description:Enzalutamide, a second-generation androgen receptor inhibitor, is utilized for treating patients with metastatic castration-resistant prostate cancer (mCRPC). However, acquired resistance to enzalutamide presents a significant clinical challenge, necessitating novel strategies for overcoming this resistance. In this study, we demonstrated that PLK1 phosphorylates PDCD4 at serine 239 (S239), leading to PDCD4 degradation by enhancing its binding to βTRCP2, thereby promoting enzalutamide resistance both in vitro and in vivo. Mechanistically, phosphorylation of PDCD4 at S239 upregulates the expression of UDP-glucuronosyltransferase 2B15 (UGT2B15) through activation of the c-MYC-Hedgehog axis. This pathway circumvents the androgen receptor, thereby reducing cellular sensitivity to enzalutamide treatment. Inhibition of UGT2B15 enhances enzalutamide-induced cell apoptosis and growth arrest in a manner dependent on PDCD4-S239 phosphorylation. Our findings provide a insight into the role of PLK1-mediated PDCD4 phosphorylation in enzalutamide resistance and suggest a potential therapeutic strategy to overcome resistance in prostate cancer.
Project description:Prostate cancer C4-2B cells were cultured in enzalutamide in a dose-escalation manner. After sixty passages cells were resistant to enzalutamide, with a specific sets of genes been deregulated. We performed global gene expression analysis by cDNA microarrays to identify genes responsible for enzalutamide resistance in C4-2B-MDVR cells. Enzalutamide resistant C4-2B-MDVR cells were selected from C4-2B cells during long time enzalutamide treatment. Genes responsible for enzalutamide resistance were identified using C4-2B vs. C4-2B-MDVR RNA extraction and hybridization on Affymetrix microarrays.