Current Drug Targets (v.17, #3)

Meet Our Editorial Board Member by Patrick L. Sheets (253-253).

Editorial (Thematic Issue: New Drug Targets for Treatment of Recurrent/Metastatic Prostate Cancer) by Claudio Festuccia, Paola Negri-Cesi, Giovanni Luca Gravina (254-256).

MicroRNAs and the Response of Prostate Cancer to Anti-Cancer Drugs by Marzia Pennati, Marco Folini, Paolo Gandellini, Nadia Zaffaroni (257-265).
Despite considerable advances in early diagnosis, prostate cancer (PCa) remains the second leading cause of cancer-related deaths in men in western countries. In fact, although efficient therapies exist for early-stage disease, the treatment of advanced PCa remains unsuccessful mainly due to its poor responsiveness to anti-cancer agents. This evidence underlines the urgent need for the development of novel and more effective therapeutic approaches. In this context, the documented dysregulation of microRNAs (miRNAs) -which are short non-coding RNAs that regulate gene expression at post-transcriptional level- in PCa, together with their potential to simultaneously regulate multiple oncogenic/ tumor-suppressive pathways, has stimulated interest in defining a functional association between altered expression of specific miRNAs and the response of PCa to anti-cancer agents. The purpose of this review is to provide an overview on PCa-related miRNAs as potential novel therapeutic targets/tools, with a special focus on the role that they may play in conditioning the responsiveness of PCa to anti-cancer drugs.

Emerging Targets For Prostate Adenocarcinoma Therapy: How Molecular Biology May Drive Towards a More Tailored Approach by Maria Raffaella Ambrosio, Luigi Pirtoli, Maria Teresa del Vecchio (266-275).
Prostate adenocarcinoma is the most diagnosed male cancer in the Western world and the second leading cause of cancer-related mortality. Albeit most of the patients with prostate adenocarcinoma are currently treated by surgery and/or radiation therapy, more than 30-40% of affected subjects will eventually progress and develop advanced disease. To date, management decisions depend on the clinical stage of the patient and the histological diagnosis which unfortunately often lack to predict the real prognosis. Current therapies have shown to be insufficient, mainly in the metastatic disease. For clear-cut diagnosis and follow-up, we promptly need molecular markers also useful in predicting patient's outcome. Advances in cancer genomics have led to a plethora of biomarkers, which must now to be rigorously validated in the clinical setting. Recent insights on prostate adenocarcinoma biology which unveiled some of the biological mechanisms leading to this tumour, have managed in devising novel strategies for therapy. Immunotherapeutic agents, selective adrenal inhibitors, anti-angiogenic molecules, newly engineered androgen receptor inhibitors, compounds targeting the bone microenvironment are demonstrated to limit cancer growth by blocking specific signaling pathways. Such strategies can be complemented to existing therapeutic paradigm in improving beneficial outcome. Moreover, other emerging pharmacological compounds have shown encouraging results and several clinical trials are ongoing. This review summarizes the developing targeted therapies for prostate adenocarcinoma and discuss their potential benefit mainly in the castration- resistant forms.

Targeting the Bone Microenvironment in Metastatic Castration-Resistant Prostate Cancer by Pavlos Msaouel, Jose Nahun Galeas, Alejandro Recio Boiles, Ramiro Rancier Ruiz, Michael Koutsilieris (276-289).
Metastatic castration-resistant prostate cancer (mCRPC) is universally incurable and represents an area of substantial unmet medical need. Novel targets and therapeutic strategies have emerged based on an improved understanding of the crosstalk between prostate cancer cells and the bone microenvironment. A wide variety of signaling systems including the RANKL/RANK/OPG, IGF-I, FGF and Wnt:DKK-1 pathways can be targeted to suppress tumor growth and treatment resistance. Antisurvival factor therapy can increase the efficacy of standard antineoplastic regimens by targeting biologic molecules acting as “survival factors” within the bone microenvironment. Novel agents can also be used to mobilize the host immune system to attack prostate cancer cells. Clinical testing of these therapeutic approaches has produced encouraging objective clinical responses in subsets of patients with mCRPC. The present review summarizes data regarding the emerging strategies used to target the bone microenvironment in mCRPC.

New Compounds Targeting the Androgen Receptor for Treatment of Advanced Prostate Cancer by Rita Assi, Sally Temraz, Ali Shamseddine, Deborah Mukherji (290-302).
The androgen receptor (AR) signalling pathway remains a key driver of prostate cancer progression despite castrate levels of testosterone in advanced disease. The androgen biosynthesis inhibitor abiraterone and the anti-androgen enzalutamide have been shown to prolong survival in randomized clinical trials both pre-and post-docetaxel chemotherapy and are now in routine clinical use. With the use of these drugs and other novel survival-prolonging therapeutics, patients with advanced prostate cancer are now living longer with better quality of life. This article will review pre-clinical and clinical data for AR-targeting therapeutics for advanced prostate cancer with a focus on mechanisms of resistance and future directions for research.

Nanoparticles-Based Treatment for Bone Metastasis by Rossana Saracino, Rosa Luciano, Giulia Battafarano, Antonio Perrotta, Maurizio Muraca, Andrea Del Fattore (303-310).
Bone is the principal site of metastasis for many carcinomas, including prostate. Once bone metastases are established, the chances of survival dramatically drop. Bone metastases place patients at increased risk of skeletal-related events, including pathologic fractures, bone pain and hypercalcemia. Indeed, skeletal metastases represent the prevalent cause of morbidity and mortality for many tumors. They are the result of interactions among tumour cells, bone marrow environment and bone cells (vicious cycle). In the last few years many efforts were undertaken to identify new therapeutic approaches for bone metastasis. Current therapies target the several players of bone vicious cycle. However many adverse effects are associated with these treatments. This review will focus on the new emerging sector of nanomedicine, that could be important to identify more specific and safe treatments for bone metastasis.

Targeting the NF-κB pathway in prostate cancer: a promising therapeutic approach? by Daniela Verzella, Mariafausta Fischietti, Daria Capece, Davide Vecchiotti, Filippo Del Vecchio, Germana Cicciarelli, Valentina Mastroiaco, Alessandra Tessitore, Edoardo Alesse, Francesca Zazzeroni (311-320).
Rel/NF-?B transcription factors are key regulators of genes implicated in inflammatory and immune activation, cell growth and protection from apoptosis. Constitutive activation of NF-?B has been observed in several types of cancers. Recently, it has been shown that inflammation and cancer are molecularly linked by means of NF-?B. During prostate cancer progression, NF-?B promotes cell survival, tumor invasion, metastasis and chemoresistance. NF-?B constitutive activation has been frequently demonstrated in primary prostate cancers and it correlates with loss of androgen receptor expression and castration-resistant phenotypes. Indeed, inhibition of NF-?B pathway may reduce the oncogenic effects mediated by chronic inflammatory response. Therefore, NF-?B represents a hopeful target for the treatment of prostate cancer due to its role in oncogenesis and chemoresistance. Here, the current knowledge about the roles of NF-?B signaling pathway in prostate tumorigenesis is discussed, taking into consideration the potentiality and effectiveness of NF-?B inhibitors as therapeutic agents for prostate cancer.

Therapeutic Value of an Integrin Antagonist in Prostate Cancer by Clément-Lacroix Philippe (321-327).
In recent decades we have seen an exponential interest in the implications of integrin receptors in cancer biology and especially in prostate tumour development. Integrins has been reported to control multiple mechanisms, such as cell survival, proliferation, differentiation, and migration. Here, we report the current understanding of the integrin signalling mechanisms in metastatic prostate tumour development, cross-talks between the primary and metastatic sites on tumour growth, interactions between tumour cells and tissue microenvironment, and epithelial-mesenchymal transition (EMT). Finally, this review presents the integrin-based chemotherapeutic agents currently under clinically consideration and provides an insight into cancer drug development using integrin as a target.

Anti-VEGF Therapy for Retinal Vein Occlusions by Claudio Campa, Giuseppe Alivernini, Elena Bolletta, Maurizio Battaglia Parodi, Paolo Perri (328-336).
Retinal vein occlusion (RVO) is the second most common cause of visual loss in the Western World. RVO is usually classified into branch RVO (BRVO) and central RVO (CRVO) according to the anatomical site of the vascular occlusion. The pathogenesis of RVO is not yet fully understood, however an important event is the intraluminal thrombus formation, which is usually secondary to several conditions such as hypertension, hyperlipidemia, diabetes and thrombophilia. The blockage of venous circulation causes an elevation of intraluminal pressure in the capillaries, leading to hemorrhages and leakage of fluid within the retina, increase of interstitial pressure and a consequent reduction of retinal perfusion. Ischemia may develop resulting in secretion of vascular endothelial growth factor (VEGF) that causes further vascular leakage and retinal oedema. VEGF has therefore a leading role in RVO pathogenesis and symptoms. As a consequence use of anti-VEGF agents by intravitreal injections has become very common with the aim to improve the clinical outcomes in these patients. Currently 2 anti-VEGF agents (ranimizumab and aflibercept) have been FDA (Food and Drug Administration) and EMA (European Medicine Agency) approved for the treatment of RVO, while another VEGF inhibitor (bevacizumab) is often used “off-label” in clinical practice. Many treatment regimens have been suggested in the clinical trials with these drugs, as monthly injections or injections when needed, however the ideal regimen has not been defined yet. We conducted a systematic review searching MEDLINE for the following terms: retinal vein occlusion, ranibizumab, bevacizumab, aflibercept, vascular endothelial growth factor, macular oedema. Data were extracted by one author (AG and BE) and checked by a second (BPM, CC). Aim of this article was to review available data for each drug, focusing on their efficacy and safety trying to compare their advantages and limits.

Current Perspectives on Novel Drug Delivery Systems and Approaches for Management of Cervical Cancer: A Comprehensive Review by Umme Hani, Riyaz Ali M. Osmani, Rohit R. Bhosale, Hosakote Gurumallappa Shivakumar, Parthasarathi K. Kulkarni (337-352).
Cervical cancer is uterine cervix carcinoma, the second deadly cancer and has a high incidence and mortality rate. In the developing world conventional treatment strategies such as surgical intervention and chemoradiotherapy are less widely available. Currently cancer research focuses on improving treatment of cervical cancer using various therapies such as gene therapy, recombinant protein therapy, photodynamic therapy, photothermal therapy and delivery of chemotherapeutic agents using nanoparticles, hydrogel and liposomal based delivery systems and also localized delivery systems which exist in a variety of forms such as intravaginal rings, intravaginal patches, intravaginal films, etc. in order to improve the drug delivery in a controlled manner to the diseased site thereby reducing systemic side effects. The present review encloses existing diverse delivery systems and approaches intended for treatment of cervical cancer.

New Perspectives in the Pharmacological Treatment of Non-Melanoma Skin Cancer by Paola Savoia, Ottavio Cremona, Paolo Fava (353-374).
Non-melanoma skin cancers are the most common malignancy in humans, with a basal/squamous cell carcinoma incidence ratio of 4:1 in immunocompetent patients. Basal cell carcinoma rarely metastasizes but commonly causes significant local tissue destruction and disfigurement, whereas squamous cell carcinoma is associated with a substantial risk of recurrence and metastasis; the prognosis in metastatic patients is poor. Surgical approaches give a cure rate greater than 90% if appropriately applied, on the basis of the characteristics of the primary tumors and of the patients, but in selected cases, medical treatment (5-fluorouracil, imiquimod, diclofenac and, more recently, ingenol mebutate) is preferable to invasive procedures and provides a good chance of cure, with generally excellent cosmetic outcomes. In case of advanced and metastatic non-melanoma skin cancer, newly developed molecularly targeted therapy represents a reasonably promising alternative to classical cytostatics. In particular, the monoclonal antibody cetuximab, directed against the epidermal growth factor receptor, is effective and well-tolerated in squamous cell carcinoma patients. Moreover, the recent identification of mutations in the Hedgehog signaling pathway in basal cell carcinoma lead to the development of the smoothened Hedgehog pathway inhibitor vismodegib, that was recently approved for the treatment of locally advanced or metastatic basal cell carcinoma. In this review we provide an overview of the molecular pathways involved in NMSC pathogenesis, focusing on the mechanisms of action, indications, efficacy, side effects and contraindications of new medical treatments that specifically tackle molecular targets of these pathways.