Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with diverse drivers of disease progression and mechanisms of therapeutic resistance. We conducted deep phenotypic characterization of CRPC metastases and patient-derived xenograft (PDX) lines using whole-genome RNA sequencing, gene set enrichment analysis, and immunohistochemistry. Our analyses revealed 5 mCRPC phenotypes based on the expression of well-characterized androgen receptor (AR) or neuroendocrine (NE) genes: AR-high tumors (ARPC), AR-low tumors (ARLPC), amphicrine tumors composed of cells coexpressing AR and NE genes (AMPC), double-negative tumors (i.e., AR–/NE–; DNPC), and tumors with small cell or NE gene expression without AR activity (SCNPC). RE1 silencing transcription factor (REST) activity, which suppresses NE gene expression, was lost in AMPC and SCNPC PDX models. However, knockdown of REST in cell lines revealed that attenuated REST activity drives the AMPC phenotype but is not sufficient for SCNPC conversion. We also identified a subtype of DNPC tumors with squamous differentiation and generated an encompassing 26-gene transcriptional signature that distinguished the 5 mCRPC phenotypes. Together, our data highlight the central role of AR and REST in classifying treatment-resistant mCRPC phenotypes. These molecular classifications could potentially guide future therapeutic studies and clinical trial design.
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research

Related Links:

Conclusions: KSE inhibits angiogenesis in HUVECs as well as proliferation in human prostate cancer cells, suggesting KSE may be useful herbal medicine for preventing progression of prostate cancer and angiogenesis. PMID: 31608754 [PubMed - in process]
Source: Pharmaceutical Biology - Category: Drugs & Pharmacology Tags: Pharm Biol Source Type: research
Conclusion During the development of the disease, men experience bodily, social, and moral dilemmas that threaten the hegemonic masculinity. Understanding them can help professionals deal with this population.
Source: Revista da Escola de Enfermagem da USP - Category: Nursing Source Type: research
Publication date: Available online 13 October 2019Source: Seminars in Cancer BiologyAuthor(s): Vikram Shaw, Suyash Srivastava, Sanjay K. SrivastavaAbstractThe recent development of high throughput compound screening has allowed drug repurposing to emerge as an effective avenue for discovering novel treatments for cancer. FDA-approved antipsychotic drugs fluspirilene, penfluridol, and pimozide are clinically used for the treatment of psychotic disorders, primarily schizophrenia. These compounds, belong to diphenylbutylpiperidine class of antipsychotic drugs, are the potent inhibitors of dopamine D2 receptor and calcium chan...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research
This report outlines a comprehensive da...
Source: BMC Medical Research Methodology - Category: Research Authors: Tags: Research article Source Type: research
Madam — Due to the upfront use of docetaxel chemotherapy in patients with metastatic prostate cancer, there is a therapeutic conundrum for subsequent treatment at the time of progressive disease. Cabazitaxel has been established as a second-line chemotherapy option by the TROPIC trial [1], but concerns regarding toxicity mean it has not been adopted into widespread use. However, improved quality of life and modest toxicity have been reported by a recent UK early access programme [2]. There will probably be a renewed interest in both docetaxel and cabazitaxel chemotherapy in patients with metastati c castrate-resistan...
Source: Clinical Oncology - Category: Radiology Authors: Tags: Letter Source Type: research
ConclusionsThis is the first attempt to list core competencies for PC peer navigators and may offer guidance for standardizing the PC peer navigator role and training.
Source: Supportive Care in Cancer - Category: Cancer & Oncology Source Type: research
Abstract The classification of human cancers has traditionally relied on the tissue of origin, the histologic appearance and anatomical extent of disease, otherwise referred to as grade and stage. However, this system fails to explain the highly variable clinical behaviour seen for any one cancer. Molecular characterization through techniques such as next-generation sequencing (NGS) has led to an appreciation of the extreme genetic heterogeneity that underlies most human cancers. Because of the difficulties associated with fresh tissue biopsy, interest has increased in using circulating tumour material, such as ci...
Source: Cell Research - Category: Cytology Authors: Tags: Recent Results Cancer Res Source Type: research
Condition:   Prostate Cancer Intervention:   Sponsor:   Life Length SL Recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Conditions:   Hormone Sensitive Prostate Cancer;   Prostate Adenocarcinoma;   Metastasis Prostate Adenocarcinoma Interventions:   Drug: Androgen Deprivation Therapy;   Drug: Nivolumab;   Drug: Docetaxel Sponsors:   Xiao X. Wei;   Bristol-Myers Squibb Not yet recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
This article reviews the major pathways by which adrenal steroids are converted to the potent male sex hormones, testosterone (T) and 5α-dihydrotestosterone (5α-DHT) and the discrete enzyme isoforms involved in castration resistant prostate cancer. Previous studies have mainly utilized radiotracers to investigate these pathways but have not used prevailing concentrations of precursors found in castrate male human serum. In addition, the full power of stable-isotope dilution liquid chromatography tandem mass spectrometry has not been applied routinely. Furthermore, it is clear that adaptive responses occur in th...
Source: The Journal of Steroid Biochemistry and Molecular Biology - Category: Biochemistry Source Type: research
More News: Biomedical Science | Brain | Cancer | Cancer & Oncology | Clinical Trials | Genetics | Legislation | Neurology | Prostate Cancer | Study