Dear Colleagues,

Prostate cancer (PCa) incidence has been dramatically increasing these 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 go 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 the cases, leads to questions about the molecular mechanisms involving 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.

Inhibition of AR remains, however, a well-established promising drug target in CRPC. However, in spite of the improvements of current treatment for CRPC by targeting the AR, the evolution of adaptive AR-signaling leads to therapy-resistant CRPC. Treatment failure is based mostly on the inability to keep AR under long-term restraint due to adaptive responses of AR-signaling. One underlying mechanism appears to be the 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 which may improve the management of biological aggressive and resistant CRPCs. This Special Issue will provide a platform for all pharmaceutical and translational scientists to learn important breakthroughs in drug discovery and new therapeutics in this field.

 Potential topics include, but are not limit to:

1. Molecular alterations associated with prostate cancer:
   
   a) Androgen Receptor: effectiveness and resistance to current pharmacological anti AR approaches;
   b) Targeting mutated ARs and/or splicing variants;
   c) Epigenetic regulation of AR expression: methylation and histone acethylation/deacethylation status, as well as AR protein stability, as targets for the therapy of CRPC and chemotherapy-resistant prostate cancers;
   d) Intra-prostatic androgen synthesis as target for 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.
   
   a) Obesity and mesenchymal stem cells: Key players in prostate cancer progression;
   b) Lipid synthesis and metabolism: i.e., Fatty Acid synthase (FASN) and AMACR;
   c) glutathione metabolism: γ-Glutamylcyclotransferase (GGCT);
   d) Stroma-cancer cell interactions and hypoxia: Stromal niche for epithelial stem cells;
   e) Tumor associated macrophage activation;
   
   

3. Castration resistant metastatic disease (mCRPC)
   

   a) Epithelial to Mesenchymal Transition (EMT);
   b) VEGF antagonists and VEGFR inhibitors;
   c)Antagonists of integrins (avb3, avb5, a5b1, etc.) and bone metastases;
   
   
4. Mechanisms and strategies to overcome of resistance to radiotherapy or pharmacologic chemotherapy
   
   a) Radio-sensitizing agents;
   b) Modulators of intracellular trafficking of proteins and mRNA;
   c) antagonists of cell recruitment (Monocytes and granulocytes, Bone Marrow Myeloid cells, PCa stem like cells);
   d) CXCR4/CXCR7 antagonists;
   e) Ephrin/ephrin receptor antagonists or inhibitors;
   f) 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;

7. Natural compounds
   
   Papers are published upon acceptance, regardless of the Special Issue publication date.

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