scholarly journals Tumor Microenvironment in Prostate Cancer: Toward Identification of Novel Molecular Biomarkers for Diagnosis, Prognosis, and Therapy Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Hisham F. Bahmad ◽  
Mohammad Jalloul ◽  
Joseph Azar ◽  
Maya M. Moubarak ◽  
Tamara Abdul Samad ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
Epithelial Cells ◽  
Unmet Need ◽  
Tissue Growth ◽  
Molecular Biomarkers ◽  
Castration Resistant Prostate Cancer ◽  
Reactive Stroma ◽  
Mediators Of Inflammation ◽  
Therapy Development

Prostate cancer (PCa) is by far the most commonly diagnosed cancer in men worldwide. Despite sensitivity to androgen deprivation, patients with advanced disease eventually develop resistance to therapy and may die of metastatic castration-resistant prostate cancer (mCRPC). A key challenge in the management of PCa is the clinical heterogeneity that is hard to predict using existing biomarkers. Defining molecular biomarkers for PCa that can reliably aid in diagnosis and distinguishing patients who require aggressive therapy from those who should avoid overtreatment is a significant unmet need. Mechanisms underlying the development of PCa are not confined to cancer epithelial cells, but also involve the tumor microenvironment. The crosstalk between epithelial cells and stroma in PCa has been shown to play an integral role in disease progression and metastasis. A number of key markers of reactive stroma has been identified including stem/progenitor cell markers, stromal-derived mediators of inflammation, regulators of angiogenesis, connective tissue growth factors, wingless homologs (Wnts), and integrins. Here, we provide a synopsis of the stromal-epithelial crosstalk in PCa focusing on the relevant molecular biomarkers pertaining to the tumor microenvironment and their role in diagnosis, prognosis, and therapy development.

scholarly journals Impact of Extraskeletal Metastases on Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer with Bone Metastases

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2034
Author(s):  
Soraia Lobo-Martins ◽  
Arlindo R. Ferreira ◽  
André Mansinho ◽  
Sandra Casimiro ◽  
Kim Leitzel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Unmet Need ◽  
Bone Alkaline Phosphatase ◽  
Multicenter Clinical Trial ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Therapeutic Landscape ◽  
Skeletal Related Events ◽  
The Impact

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has substantially evolved over the last decade. Nonetheless, a better understanding of bone-targeted agents (BTAs) action in mCRPC remains an unmet need. Theuse of BTAs aims to reduce the incidence of skeletal-related events (SREs) in patients with mCRPC. Less frequent BTA schedules are currently being studied to minimize adverse events. In this study, the impact of metastatic compartment (bone and extraskeletal metastases (BESM) vs. bone-only metastases (BOM)) on bone biomarker kinetics, time to first on-study SRE, and symptomatic skeletal events (SSEs) is evaluated. This is a retrospective analysis of the prospective, randomized, multicenter clinical trial of denosumab vs. zoledronic acid in patients with mCRPC and bone metastases. A total of 1901 patients were included, 1559 (82.0%) with BOM and 342 with BESM (18.0%). Bone metastases burden was balanced between groups. Baseline levels and normalization rates of corrected urinary N-terminal telopeptide and bone alkaline phosphatase did not differ between groups. However, BESM patients had a higher risk of SREs (adjusted HR 1.21; 95% CI 1.01–1.46; p = 0.043) and SSEs (adjusted HR 1.30; 95% CI 1.06–1.61; p = 0.014). This difference was more pronounced in the first 12 months of BTA treatment.In mCRPC, strategies of BTA schedule de-escalation may take into account presence of extraskeletal metastases.

scholarly journals Clinical Development of PARP Inhibitors in Treating Metastatic Castration-Resistant Prostate Cancer

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 860 ◽  
Author(s):  
Jacob J. Adashek ◽  
Rohit K. Jain ◽  
Jingsong Zhang
Keyword(s):  
Prostate Cancer ◽  
Unmet Need ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phase Ii Studies ◽  
Phase Iii Trials ◽  
Signaling Inhibitors

The approval of upfront abiraterone for castration-sensitive prostate cancer and the approval of enzalutamide and apalutamide for non-metastatic castration-resistant prostate cancer have led to early utilization of potent androgen receptor (AR) signaling inhibitors in treating advanced prostate cancer. There is an unmet need to develop novel therapies beyond targeting AR signaling for metastatic castration-resistant prostate cancer (mCRPC). Poly (ADP-ribose) polymerase inhibitors (PARPi) belong to a class of targeted agents being developed for the treatment of homologous recombination repair (HRR) deficient tumors. Olaparib, rucaparib, niraparib, veliparib, and talazoparib were evaluated in early phase trials as a monotherapy for HRR-deficient mCRPC. Among them, olaparib and rucaparib have breakthrough designations for BRCA1/2-mutated mCRPC. Phase II studies also reported clinical activity of the PARPi and abiraterone combination and the PARPi checkpoint inhibitor combination in HRR-intact mCRPC. Ongoing phase III trials are testing these combinations as frontline or later line treatments for mCRPC. This review summarizes the critical clinical data as well as ongoing clinical trials for developing PARPi in treating mCRPC.

scholarly journals The Current Landscape of Treatment in Non-Metastatic Castration-Resistant Prostate Cancer

2019 ◽  
Vol 13 ◽  
pp. 117955491983392 ◽  
Author(s):  
Joelle El-Amm ◽  
Jeanny B Aragon-Ching
Keyword(s):  
Prostate Cancer ◽  
Drug Administration ◽  
Advanced Prostate Cancer ◽  
Unmet Need ◽  
Early Data ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
Castration Resistant ◽  
Fda Approval ◽  
Variable Potential

Non-metastatic castration-resistant prostate cancer (nmCRPC) is a heterogeneous disease with variable potential in developing into overt metastases. It is an area of increased unmet need in advanced prostate cancer and for which there had been no great treatments until recent US Food and Drug Administration (FDA) approval of 2 novel anti-androgens apalutamide and enzalutamide, which were both approved given benefit in metastasis-free survival. Early data on the use of darolutamide, another novel anti-androgen, are also explored. This review discusses the pivotal trials that led to the approval of apalutamide and enzalutamide in the nmCRPC setting and discusses the key promises and challenges with the use of these agents.

scholarly journals Green Nanotechnology of MGF-AuNPs for Immunomodulatory Intervention in Prostate Cancer Therapy

2021 ◽  
Author(s):  
Menka Khoobchandani ◽  
Aslam Khan ◽  
Kavita Katti ◽  
Velaphi Thipe ◽  
Amal Al-Yasiri ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
M2 Macrophages ◽  
Castration Resistant Prostate Cancer ◽  
Green Nanotechnology ◽  
Splenic Macrophages ◽  
Increased Risk ◽  
Tnf Α ◽  
Prostate Cancers

Abstract Men with castration-resistant prostate cancer (CRPC) face poor prognosis and increased risk of treatment-incurred adverse effects resulting in one of the highest mortalities among patient population globally. Immune cells act as double-edged sword depending on the tumor microenvironment, which leads to increased infiltration of pro-tumor (M2) macrophages. Development of new immunomodulatory therapeutic agents capable of targeting the tumor microenvironment, and hence orchestrating the differentiation of pro-tumor M2 macrophages to anti-tumor M1, would substantially improve treatment outcomes of CRPC patients. We report, herein, Mangiferin functionalized gold nanoparticles (MGF-AuNPs) and its immunomodulatory characteristics in treating prostate cancer. We provide evidence of immunomodulatory intervention of MGF-AuNPs in prostate cancers through observations of enhanced levels of anti-tumor cytokines (IL-12 and TNF-α) with concomitant reductions in the levels of pro-tumor cytokines (IL-10 and IL-6). In the treated groups, IL-12 was elevated to ten-fold while TNF-α was elevated to about fifty-fold; while IL-10 and IL-6 were reduced by two-fold. Ability of MGF-AuNPs to target splenic macrophages is invoked via targeting of NF-kB signaling pathway. Finally, therapeutic efficacy of MGF-AuNPs, in treating prostate cancer in vivo in tumor bearing mice, is described taking into consideration various immunomodulatory interventions triggered by this green nanotechnology-based nanomedicine agent.

scholarly journals Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential

2020 ◽  
Author(s):  
Eric T Miller ◽  
Sungyong You ◽  
Radu M Cadaneanu ◽  
Minhyung Kim ◽  
Junhee Yoon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Los Angeles ◽  
Copy Number ◽  
Chromosomal Instability ◽  
Clinical Stage ◽  
Unmet Need ◽  
Transcriptome Profiling ◽  
The Cancer Genome Atlas ◽  
Castration Resistant Prostate Cancer ◽  
Primary Tumors

Abstract Background: Metastatic prostate cancer (PC) is highly lethal. The ability to identify primary tumors capable of dissemination is an unmet need in the quest to understand lethal biology and improve patient outcomes. Previous studies have linked chromosomal instability (CIN), which generates aneuploidy following chromosomal missegregation during mitosis, to PC progression. Evidence of CIN includes broad copy number alterations (CNAs) spanning >300 base pairs of DNA, which may also be measured via RNA expression signatures associated with CNA frequency. Signatures of CIN in metastatic PC, however, have not been interrogated or well defined. We examined a published 70-gene CIN signature (CIN70) in untreated and castration-resistant prostate cancer (CRPC) cohorts from The Cancer Genome Atlas (TCGA) and previously published reports. We also performed transcriptome and CNA analysis in a unique cohort of untreated primary tumors collected from diagnostic prostate needle biopsies (PNBX) of localized (M0) and metastatic (M1) cases to determine if CIN was linked to clinical stage and outcome. Methods: PNBX were collected from 99 patients treated in the VA Greater Los Angeles (GLA-VA) Healthcare System between 2000-2016. Total RNA was extracted from high-grade cancer areas in PNBX cores, followed by RNA sequencing and/or copy number analysis using OncoScan. Multivariate logistic regression analyses permitted calculation of odds ratios for CIN status (high versus low) in an expanded GLA-VA PNBX cohort (n = 121). Results: The CIN70 signature was significantly enriched in primary tumors and CRPC metastases from M1 PC cases. An intersection of gene signatures comprised of differentially expressed genes (DEGs) generated through comparison of M1 versus M0 PNBX and primary CRPC tumors versus metastases revealed a 157-gene "metastasis" signature that was further distilled to 7-genes (PC-CIN) regulating centrosomes, chromosomal segregation, and mitotic spindle assembly. High PC-CIN scores correlated with CRPC, PC-death and all-cause mortality in the expanded GLA-VA PNBX cohort. Interestingly, approximately 1/3 of M1 PNBX cases exhibited low CIN, illuminating differential pathways of lethal PC progression. Conclusions: Measuring CIN in PNBX by transcriptome profiling is feasible, and the PC-CIN signature may identify patients with a high risk of lethal progression at the time of diagnosis.

scholarly journals Mechanisms of castration resistant prostate cancer formation and progression through neuroendocrine differentiation

2021 ◽  
Keyword(s):  
Prostate Cancer ◽  
Smooth Muscle ◽  
Epithelial Cells ◽  
Neuroendocrine Differentiation ◽  
Underlying Mechanism ◽  
Neuroendocrine Cells ◽  
Basal Cells ◽  
Castration Resistant Prostate Cancer ◽  
Normal Prostate ◽  
Castration Resistant

Normal prostate tissues consist mainly of epithelial cells, including secretory epithelial cells, basal cells, and neuroendocrine cells, and of mesenchymal cells, including smooth muscle cells and fibroblasts. The mechanisms leading to castration resistant prostate cancer (CRPC) are complex and diverse, but most involve neuroendocrine differentiation. In fact, during the development of prostate cancer, some of the tumor cells transform into neuroendocrine-like cells. This transition is a main underlying mechanism of CRPC formation.

scholarly journals The Role of Androgen Receptor in Cross Talk Between Stromal Cells and Prostate Cancer Epithelial Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Qianyao Tang ◽  
Bo Cheng ◽  
Rongyang Dai ◽  
Ronghao Wang
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Tumor Microenvironment ◽  
Epithelial Cells ◽  
Cross Talk ◽  
Cell Invasion ◽  
Stromal Cells ◽  
Neuroendocrine Cells ◽  
Stromal Fibroblasts ◽  
Biological Regulation

Prostate cancer (PCa) lists as the second most lethal cancer for men in western countries, and androgen receptor (AR) plays a central role in its initiation and progression, which prompts the development of androgen deprivation therapy (ADT) as the standard treatment. Prostate tumor microenvironment, consisting of stromal cells and extracellular matrix (ECM), has dynamic interactions with PCa epithelial cells and affects their growth and invasiveness. Studies have shown that both genomic and non-genomic AR signaling pathways are involved in the biological regulation of PCa epithelial cells. In addition, AR signaling in prostate stroma is also involved in PCa carcinogenesis and progression. Loss of AR in PCa stroma is clinically observed as PCa progresses to advanced stage. Especially, downregulation of AR in stromal fibroblasts dysregulates the expression levels of ECM proteins, thus creating a suitable environment for PCa cells to metastasize. Importantly, ADT treatment enhances this reciprocal interaction and predisposes stromal cells to promote cell invasion of PCa cells. During this process, AR in PCa epithelium actively responds to various stimuli derived from the surrounding stromal cells and undergoes enhanced degradation while elevating the expression of certain genes such as MMP9 responsible for cell invasion. AR reduction in epithelial cells also accelerates these cells to differentiate into cancer stem-like cells and neuroendocrine cells, which are AR-negative PCa cells and inherently resistant to ADT treatments. Overall, understanding of the cross talk between tumor microenvironment and PCa at the molecular level may assist the development of novel therapeutic strategies against this disease. This review will provide a snapshot of AR’s action when the interaction of stromal cells and PCa cells occurs.

Molecular and metabolic imaging of castration-resistant prostate cancer: state of art and future prospects

2021 ◽  
Vol 21 ◽  
Author(s):  
Luca Filippi ◽  
Agostino Chiaravalloti ◽  
Pietro Basile ◽  
Orazio Schillaci ◽  
Oreste Bagni
Keyword(s):  
Prostate Cancer ◽  
Unmet Need ◽  
Response Assessment ◽  
Cellular Level ◽  
Molecular Probes ◽  
Metabolic Imaging ◽  
Imaging Biomarkers ◽  
Castration Resistant Prostate Cancer ◽  
Future Prospects ◽  
Castration Resistant

: Prostate cancer (PCa) represents the most common tumor in male and one of the most relevant causes of death in Western countries. Androgen deprivation therapy (ADT) constitutes a widely used approach in advanced PCa. When PCa progresses in spite of ADT and castrate levels of testosterone, the severe clinical condition termed as metastatic castration-resistant prostate cancer (mCRPC) takes place. The only approach to mCRPC has been represented by chemotherapy with taxanes for many years. Nevertheless, recently introduced treatments such as 2nd generation antiandrogens (i.e. enzalutamide and abiraterone), cell immunotherapy with sipuleucel-T or targeted alpha therapy with 223Ra-dichloride, have dramatically changed mCRPC prognosis. These novel therapies call for an unmet need for imaging biomarkers suitable for patients’ pre-treatment stratification and response assessment. In this scenario, nuclear medicine can provide several metabolic and molecular probes for investigating pathological processes at a cellular and sub-cellular level. The aim of this paper is to review the most relevant findings of the literature published to date on this topic, giving particular emphasis to the pros and cons of each tracer and also covering future prospects for defining personalized therapeutic approaches.

Sign in / Sign up

Export Citation Format

Share Document