Dear Colleagues,

Prostate cancer (PCa) incidence has been dramatically increasing in the last few years in industrialized Western countries. The androgen receptor (AR) plays a central role in the pathogenesis of this disease. Unfortunately, most PCa patients enter into an androgen-independent stage named castration-resistant prostate cancer (CRPC) in which AR signaling still is active. This more aggressive state of disease, in the vast majority of cases, leads to questions about the molecular mechanisms involved in tumor recurrence. Though localized PCa is usually treated by radical prostatectomy, androgen deprivation therapy (ADT) is preferred in locally advanced disease in combination with chemotherapy.

The inhibition of AR remains, however, a well-established promising drug target in CRPC. In spite of the improvements in the current treatment for CRPC by targeting the AR, the evolution of adaptive AR signaling leads to therapy-resistant CRPC. Treatment failure is mostly based on the inability to keep AR under long-term restraint due to adaptive responses of AR signaling. One underlying mechanism appears to be increased AR protein stability. Therefore, the regulation of AR protein stability and its degradation is another interesting path that could enhance our knowledge of carcinogenesis and tumor evolution, possibly leading to novel therapeutic targets.

The main focus of this Special Issue will be the evaluation of molecular pathways as pharmacological targets for treatment strategies that may improve the management of biologically aggressive and resistant CRPCs. This Special Issue will provide a platform for all pharmaceutical and translational scientists to research important breakthroughs in drug discovery and new therapeutics in this field.

Potential topics include, but are not limited to, those listed below.

1. Molecular alterations associated with prostate cancer.

• Androgen receptor—effectiveness and resistance to current pharmacological anti AR approaches;
• Targeting mutated ARs and/or splicing variants;
• Epigenetic regulation of AR expression—methylation and histone acetylation/deacetylation status, as well as AR protein stability, as targets for the therapy of CRPC and chemotherapy-resistant prostate cancers;
• Intra-prostatic androgen synthesis as target for the treatment of aggressive/CRPCs (i.e., inhibitors of cytochrome P450 enzyme CYP17, 17α-hydroxylase and 17,20-lyase, as well as AKR1C3).

2. Metabolic alterations and PCa progression—cellular constituents of the prostate stroma—key contributors to prostate cancer progression and therapy resistance.

• Obesity and mesenchymal stem cells—key players in prostate cancer progression;
• Lipid synthesis and metabolism, i.e., fatty acid synthase (FASN) and AMACR;
• Glutathione metabolism—γ-glutamylcyclotransferase (GGCT);
• Stroma–cancer cell interactions and hypoxia—stromal niche for epithelial stem cells;
• Tumor-associated macrophage activation.

3. Castration-resistant metastatic disease (mCRPC)

• Epithelial-to-mesenchymal transition (EMT);
• VEGF antagonists and VEGFR inhibitors;
• Antagonists of integrins (avb3, avb5, a5b1, etc.) and bone metastases.

4. Mechanisms and strategies to overcome resistance to radiotherapy or pharmacologic chemotherapy

• Radio-sensitizing agents;
• Modulators of intracellular trafficking of proteins and mRNA;
• Antagonists of cell recruitment (monocytes and granulocytes, bone marrow myeloid cells, PCa stem-like cells);
• CXCR4/CXCR7 antagonists;
• Ephrin/ephrin receptor antagonists or inhibitors;
• P21 activated kinases (PAKs).

5. Inflammation and NF-κB signaling in prostate Cancer: mechanisms and clinical implications.
6. Immunomodulators
   Immune checkpoint-mediated interactions between cancer and immune cells.

We are pleased to invite you to contribute original articles, reviews, communications, etc. We look forward to your contributions to this Special Issue.

Dr. Claudio Festuccia
Guest Editor

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• prostate cancer
• PCa progression
• molecular pathway
• treatment strategies
• immune checkpoint
• radiotherapy
• pharmacologic chemotherapy
• signaling

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