Isolation of Plasma Extracellular Vesicles for High-Depth Analysis of Proteomic Biomarkers in Metastatic Castration-Resistant Prostate Cancer Patients.

: Prostate cancer treatment has been revolutionized by targeted therapies, including PARP inhibitors, checkpoint immunotherapies, and PSMA-targeted radiotherapies. Despite such advancements, accurate patient stratification remains a challenge, with current methods relying on genomic markers, tissue staining, and imaging. Extracellular vesicle (EV)-derived proteins offer a novel non-invasive alternative for biomarker discovery, holding promise for improving treatment precision.

Systems-level liquid biopsy in advanced prostate cancer.

Treatment for castration-resistant prostate cancer (CRPC) primarily involves the suppression of androgen receptor (AR) activity using androgen receptor signaling inhibitors (ARSIs). While ARSIs have extended patient survival, resistance inevitably develops. Mechanisms of resistance include genomic aberrations at the AR locus that reactivate AR signaling, or lineage plasticity that drives emergence of AR-independent phenotypes.

AR alterations inform circulating tumor DNA detection in metastatic castration resistant prostate cancer patients.

Circulating tumor DNA (ctDNA) in plasma cell free DNA (cfDNA) of cancer patients is associated with poor prognosis, but is challenging to detect from low plasma volumes. In metastatic castration-resistant prostate cancer (mCRPC), ctDNA assays are needed to prognosticate outcomes of patients treated with androgen receptor (AR) inhibitors. We develop a custom targeted cfDNA sequencing assay, named AR-ctDETECT, to detect ctDNA in limiting plasma cfDNA available from mCRPC patients in the Alliance A031201 randomized phase 3 trial of enzalutamide with or without abiraterone.

A PSMA-targeted Tri-specific Killer Engager enhances NK cell cytotoxicity against prostate cancer.

Natural killer (NK) cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with co-activation may enhance NK cell function in mCRPC.

Integrated multi-omics assessment of lineage plasticity in a prostate cancer patient with brain and dural metastases.

Metastases to the brain are rare in prostate cancer. Here, we describe a patient with two treatment-emergent metastatic lesions, one to the brain with neuroendocrine prostate cancer (NEPC) histology and one to the dural membrane of adenocarcinoma histology. We performed genomic, transcriptomic, and proteomic characterization of these lesions and the primary tumor to investigate molecular features promoting these metastases.

Computational drug discovery pipelines identify NAMPT as a therapeutic target in neuroendocrine prostate cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive advanced subtype of prostate cancer that exhibits poor prognosis and broad resistance to therapies. Currently, few treatment options are available, highlighting a need for new therapeutics to help curb the high mortality rates of this disease. We designed a comprehensive drug discovery pipeline that quickly generates drug candidates ready to be tested.

Androgen production, uptake, and conversion (APUC) genes define prostate cancer patients with distinct clinical outcomes.

BACKGROUNDProstate cancer (PC) is driven by aberrant signaling of the androgen receptor (AR) or its ligands, and androgen deprivation therapies (ADTs) are a cornerstone of treatment. ADT responsiveness may be associated with germline changes in genes that regulate androgen production, uptake, and conversion (APUC).METHODSWe analyzed whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) data from prostate tissues (SU2C/PCF, TCGA, GETx).

Androgen receptor and estrogen receptor variants in prostate and breast cancers.

The androgen receptor (AR) and estrogen receptor alpha (ERα) are steroid receptor transcription factors with critical roles in the development and progression of prostate and breast cancers. Advances in the understanding of mechanisms underlying the ligand-dependent activation of these transcription factors have contributed to the development of small molecule inhibitors that block AR and ERα actions. These inhibitors include competitive antagonists and degraders that directly bind the ligand binding domains of these receptors, luteinizing hormone releasing hormone (LHRH) analogs that suppress gonadal synthesis of testosterone or estrogen, and drugs that block specific enzymes required for biosynthesis of testosterone or estrogen.

Evolving copy number gains promote tumor expansion and bolster mutational diversification.

The timing and fitness effect of somatic copy number alterations (SCNA) in cancer evolution remains poorly understood. Here we present a framework to determine the timing of a clonal SCNA that encompasses multiple gains. This involves calculating the proportion of time from its last gain to the onset of population expansion (lead time) as well as the proportion of time prior to its first gain (initiation time).

Stat5 induces androgen receptor () gene transcription in prostate cancer and offers a druggable pathway to target AR signaling.

Androgen receptor (AR) drives prostate cancer (PC) growth and progression, and targeting AR signaling is the mainstay of pharmacological therapies for PC. Resistance develops relatively fast as a result of refueled AR activity. A major gap in the field is the lack of understanding of targetable mechanisms that induce persistent AR expression in castrate-resistant PC (CRPC).

Co-occurring BRCA2/SPOP Mutations Predict Exceptional Poly (ADP-ribose) Polymerase Inhibitor Sensitivity in Metastatic Castration-Resistant Prostate Cancer.

Background And Objective: BRCA2 mutations in metastatic castration-resistant prostate cancer (mCRPC) confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. However, additional factors predicting PARP inhibitor efficacy in mCRPC are needed. Preclinical studies support a relationship between speckle-type POZ protein (SPOP) inactivation and PARP inhibitor sensitivity.

Prostate Cancer Progression Relies on the Mitotic Kinase Citron Kinase.

Unlabelled: Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression.

Co-evolution of gene copy number and structural complexity in endocrine therapy resistant prostate cancer.

Androgen receptor (AR) inhibition is standard of care for advanced prostate cancer (PC). However, efficacy is limited by progression to castration-resistant PC (CRPC), usually due to AR re-activation via mechanisms that include amplification and structural rearrangement. These two classes of alterations often co-occur in CRPC tumors, but it is unclear whether this reflects intercellular or intracellular heterogeneity of .

Targeting the Androgen Signaling Axis in Prostate Cancer.

Activation of the androgen receptor (AR) and AR-driven transcriptional programs is central to the pathophysiology of prostate cancer. Despite successful translational efforts in targeting AR, therapeutic resistance often occurs as a result of molecular alterations in the androgen signaling axis. The efficacy of next-generation AR-directed therapies for castration-resistant prostate cancer has provided crucial clinical validation for the continued dependence on AR signaling and introduced a range of new treatment options for men with both castration-resistant and castration-sensitive disease.

Basal epithelial cells in prostate development, tumorigenesis, and cancer progression.

The prostate epithelium is composed of two predominant cell populations: luminal and basal epithelial cells. Luminal cells have a secretory function that supports male fertility while basal cells function in regeneration and maintenance of epithelial tissue. Recent studies in humans and mice have expanded our knowledge of the role and regulation of luminal and basal cells in prostate organogenesis, development, and homeostasis.

Computational drug discovery for castration-resistant prostate cancers through in vitro drug response modeling.

Prostate cancer (PC) is the most frequently diagnosed malignancy and a leading cause of cancer deaths in US men. Many PC cases metastasize and develop resistance to systemic hormonal therapy, a stage known as castration-resistant prostate cancer (CRPC). Therefore, there is an urgent need to develop effective therapeutic strategies for CRPC.

ALAN is a computational approach that interprets genomic findings in the context of tumor ecosystems.

Gene behavior is governed by activity of other genes in an ecosystem as well as context-specific cues including cell type, microenvironment, and prior exposure to therapy. Here, we developed the Algorithm for Linking Activity Networks (ALAN) to compare gene behavior purely based on patient -omic data. The types of gene behaviors identifiable by ALAN include co-regulators of a signaling pathway, protein-protein interactions, or any set of genes that function similarly.

Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer.

Purpose: Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody-drug conjugates (ADC).

Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.

Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal.

Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?

Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to re-activate AR. This has led to the development of second-generation anti-androgens that more effectively antagonize AR, such as enzalutamide (ENZ).

AR gene rearrangement analysis in liquid biopsies reveals heterogeneity in lethal prostate cancer.

Castration-resistant prostate cancer (CRPC) is driven by AR gene aberrations that arise during androgen receptor (AR)-targeted therapy. AR amplification and mutations have been profiled in circulating tumor cells (CTCs), but whether AR gene rearrangements can be assessed in CTCs is unknown. In this study, we leveraged CRPC cell lines with defined AR gene rearrangements to develop and validate a CTC DNA analysis approach that utilized whole genome amplification and targeted DNA-sequencing of AR and other genes important in CRPC.