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Dear Colleagues,

Prostate cancer remains one of the top cancers diagnosed in men worldwide. While initial treatments are effective, once metastasis develops, the disease is fatal, with a 5-year survival of 30%. The last decade has led to the development and introduction of several novel agents, as well as the repurposing of others. In 2018–2019, anti-androgens abiraterone, apalutamide, and enzalutamide all received Federal Drug Administration (FDA) approval for metastatic castrate-sensitive prostate cancer (mCSPC). In addition, Relugolix, a highly selective oral gonadotropin-releasing hormone receptor antagonist, was approved for mCSPC based on the HERO (NCT03085095) trial results. The metastatic castrate-resistant prostate cancer (mCRPC) armamentarium for treatment includes docetaxel and cabazitaxel, abiraterone, enzalutamide, Radium-223, and the immunotherapy options of sipuleucel-T or prembrolizumab. More recent approvals include Olaparib for patients who previously progressed on enzalutamide or abiraterone and who carry alterations (germline and/or somatic) selected DNA damage and repair genes, as demonstrated in the PROfound (NCT02987543) trial. Another PARP inhibitor, Rucaparib, was approved in patients harboring a deleterious BRCA mutation (germline and/or somatic) who have been treated with an androgen receptor-directed therapy and taxane-based chemotherapy, following the results from the TRITON2 (NCT02952534) trial. More recently, the radioligand0based therapy, ¹⁷⁷Lu-PSMA-617, was granted priority review for patients in the post-androgen receptor pathway inhibition and post-taxane-based chemotherapy setting based on data from the VISION (NCT03511664) trial. Future research focuses on the interrogation and targeting of different molecular pathways, including PTEN-loss, DNA repair defects, autophagy, epigenetics, and inflammation, all with the potential for therapeutic intervention alone or in combination with approved agents to improve the duration of response and reduce the development of resistance. In addition, extensive research is underway to understand the immune context of prostate cancer and the identification of immune-based interventions that may benefit patients. With the increased interrogation of genomic and molecular data, the list of novel therapies being investigated for metastatic prostate cancer remains vast and ranges from early preclinical drug development through to phase III clinical trials with the goal of identification of treatments that change the paradigm for patient outcomes with metastatic disease.

In this Special Issue, we aim to highlight cutting-edge research on novel therapeutic agents and strategies for treating metastatic prostate cancer.

Dr. Melissa LaBonte LaBonte Wilson
Guest Editor

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Keywords

prostate cancer
mCSPC
mCRPC
drug resistance
androgen receptor-signaling inhibitors
bipolar androgen therapy
EZH2 inhibition
autophagy inhibition
prostate-specific membrane antigen-targeted therapy
immunotherapy
DNA repair inhibition
PI3K/AKT/mTOR inhibition
metastasis- and prostate-directed radiotherapy
inflammation
tumor microenvironment

Published Papers (2 papers)

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Research

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22 pages, 7116 KiB

Open AccessArticle

Computational Modeling to Identify Drugs Targeting Metastatic Castration-Resistant Prostate Cancer Characterized by Heightened Glycolysis

by Mei-Chi Su, Adam M. Lee, Weijie Zhang, Danielle Maeser, Robert F. Gruener, Yibin Deng and R. Stephanie Huang

Pharmaceuticals 2024, 17(5), 569; https://doi.org/10.3390/ph17050569 - 29 Apr 2024

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Abstract

Metastatic castration-resistant prostate cancer (mCRPC) remains a deadly disease due to a lack of efficacious treatments. The reprogramming of cancer metabolism toward elevated glycolysis is a hallmark of mCRPC. Our goal is to identify therapeutics specifically associated with high glycolysis. Here, we established a computational framework to identify new pharmacological agents for mCRPC with heightened glycolysis activity under a tumor microenvironment, followed by in vitro validation. First, using our established computational tool, OncoPredict, we imputed the likelihood of drug responses to approximately 1900 agents in each mCRPC tumor from two large clinical patient cohorts. We selected drugs with predicted sensitivity highly correlated with glycolysis scores. In total, 77 drugs predicted to be more sensitive in high glycolysis mCRPC tumors were identified. These drugs represent diverse mechanisms of action. Three of the candidates, ivermectin, CNF2024, and P276-00, were selected for subsequent vitro validation based on the highest measured drug responses associated with glycolysis/OXPHOS in pan-cancer cell lines. By decreasing the input glucose level in culture media to mimic the mCRPC tumor microenvironments, we induced a high-glycolysis condition in PC3 cells and validated the projected higher sensitivity of all three drugs under this condition (p < 0.0001 for all drugs). For biomarker discovery, ivermectin and P276-00 were predicted to be more sensitive to mCRPC tumors with low androgen receptor activities and high glycolysis activities (AR(low)Gly(high)). In addition, we integrated a protein–protein interaction network and topological methods to identify biomarkers for these drug candidates. EEF1B2 and CCNA2 were identified as key biomarkers for ivermectin and CNF2024, respectively, through multiple independent biomarker nomination pipelines. In conclusion, this study offers new efficacious therapeutics beyond traditional androgen-deprivation therapies by precisely targeting mCRPC with high glycolysis. Full article

(This article belongs to the Special Issue Novel Therapies for the Treatment of Metastatic Prostate Cancer)

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Review

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22 pages, 1787 KiB

Open AccessReview

The Current Therapeutic Landscape for Metastatic Prostate Cancer

by Anastasia Bernal, Alivia Jane Bechler, Kabhilan Mohan, Angie Rizzino and Grinu Mathew

Pharmaceuticals 2024, 17(3), 351; https://doi.org/10.3390/ph17030351 - 8 Mar 2024

Cited by 1 | Viewed by 1690

Abstract

In 2024, there will be an estimated 1,466,718 cases of prostate cancer (PC) diagnosed globally, of which 299,010 cases are estimated to be from the US. The typical clinical approach for PC involves routine screening, diagnosis, and standard lines of treatment. However, not all patients respond to therapy and are subsequently diagnosed with treatment emergent neuroendocrine prostate cancer (NEPC). There are currently no approved treatments for this form of aggressive PC. In this review, a compilation of the clinical trials regimen to treat late-stage NEPC using novel targets and/or a combination approach is presented. The novel targets assessed include DLL3, EZH2, B7-H3, Aurora-kinase-A (AURKA), receptor tyrosine kinases, PD-L1, and PD-1. Among these, the trials administering drugs Alisertib or Cabozantinib, which target AURKA or receptor tyrosine kinases, respectively, appear to have promising results. The least effective trials appear to be ones that target the immune checkpoint pathways PD-1/PD-L1. Many promising clinical trials are currently in progress. Consequently, the landscape of successful treatment regimens for NEPC is extremely limited. These trial results and the literature on the topic emphasize the need for new preventative measures, diagnostics, disease specific biomarkers, and a thorough clinical understanding of NEPC. Full article

(This article belongs to the Special Issue Novel Therapies for the Treatment of Metastatic Prostate Cancer)

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