enhance the growth of tumor cells establishing a positive feedback mechanism [43] .

Finally, it has been demonstrated that RANK is expressed not only on osteoclasts, but also on prostate cancer cells [44] suggesting that RANK allows cancer cells to migrate where RANKL is abundantly expressed, like the bone.

3.2. Denosumab

Denosumab (AMG162) is a human non-cytotoxic IgG2 monoclonal antibody with an extremely high affinity and specificity for human RANKL. It is approved for the treatment of osteoporosis, cancer treatment induced bone loss, bone metastases and other skeletal pathologies mediated by osteoclasts.

In a castration-resistant prostate cancer population presenting with bone metastases, the median time-to-first SRE for the denosumab arm was significantly prolonged (21 months) compared to the zoledronic acid arm (17 months) with no improvements in OS or progression of disease [13] .

Moreover, in a Phase III trial in men with nonmetastatic castration-resistant prostate cancer with a high risk of developing bone metastases, denosumab significantly increased bone-metastasis-free survival by a median of 4 months compared to placebo (29 vs 25 months) potentially confirming the role of RANK/RANKL in regulating cancer cell homing to the bone [13] .

3.3. Safety of Bone Target Therapies

One of the most commonly reported adverse event related to bisphosphonates and denosumab treatment is hypocalcaemia that is most often asymptomatic with these agents. In particular, hypocalcaemia occurred more frequently with denosumab than with zoledronic acid as shown in the Phase III trial in patients with CRPC and bone metastases (13% vs 6%) [13] . In an integrated analysis of 5723 patients from three randomized Phase III trials, the safety profile for denosumab was better than for zoledronic acid, demonstrating no effect on renal function and no need for dose adjustment or renal monitoring [45] . In patients receiving zoledronic acid the incidence of hypocalcaemia was lower than in patients receiving denosumab (1.3% vs 3.1% for grade 3 or grade 4 toxicities), though most cases were asymptomatic [45] . Thus, repletion of vitamin D levels before and during the therapy and monitoring of calcium levels during therapy is recommended in the prescribing information of denosumab.

3.4. Radiopharmaceuticals

Radiopharmaceuticals are other interesting agents targeting bone metastases; several studies showed how beta- emitting radiopharmaceuticals allowed bone pain relief in mCRPC patients due to their similarity to calcium, emitting radiation when they were taken up at site of osteoblastic activity.

Stronzium-89 and samarium-153 were the first radiopharmaceuticals approved for bone metastases pain relief in patients with mCRPC [46] . Although these radiopharmaceuticals are useful tool for pain palliations, no study showed impact on OS. One randomized control trial showed that stronzium-89, after six cycles of docetaxel, improved clinical PFS but frequent hematological adverse events [47] limits their use only to symptomatic patients with multiple bone metastases.

Radium-223 is an alpha emitter that differs from beta emitter agents since it delivers a highly localized radiation to the bone surface, causing double-stranded DNA breaks that lead to cell death giving less irradiation to healthy bone marrow than beta-emitters [48] . It is a calcium mimetic molecule that forms a complex with hydroxyapatite, which forms 50% of bone matrix; this linking allows radium 223 to be incorporated into the bone matrix emitting alpha particle preserving the health of bone tissue and bone marrow and limiting distribution to soft tissue [49] .

Radium-223 was recently approved by FDA for men with symptomatic mCRPC with only bone metastases showing a significant impact on OS in patients who progress with docetaxel or unfit to docetaxel. Several Phase I and II trials showed safety and tolerability of alpharadin, radium-223 chloride in solution, in mCRPC patients, with improvements in bone turnover markers such as bone alkaline phosphatase (bALP) and urine N-telopeptide (uNTX) [50] [51] . These results led investigators to conduct a randomized open-label, multicenter Phase III trial evaluating the impact on OS of radium-223 in mCRPC patients with bone metastases previously treated with docetaxel or unfit to receive docetaxel. This Phase III trial was stopped early after pre-planned efficacy interim analysis, since OS was significantly improved in the radium-223 arms versus placebo-control arm (median, 14.0 vs 11.2 months respectively); updated analyses in all 921 patients, performed before crossover from placebo to radium-223, showed a similar survival advantage for radium-223 treatment (median, 14.9 vs 11.3 months) [12] . Moreover, radium-223 showed efficacy in all secondary end points including time to the first symptomatic skeletal events (median, 15.6 months vs 9.8 months, respectively). The side effects of radium 223 can include diarrhoea and sickness but these are generally mild. Starting from these promising results, new trials are under investigation to better understand combination therapy with docetaxel and other new emergent therapies such as abiraterone acetate that will improve OS in this subset of patients.

4. Targeting Signal Transduction Pathways

4.1. Targeting c-MET/HGF Pathway

The receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) signaling pathway promotes stemness phenotype, tumor growth, invasion and metastases in several malignancies.

MET is expressed by primary and metastatic prostate carcinomas and its levels are higher in bone metastases compared with lymph node metastases or primary tumors [52] . Also osteoblasts and osteoclasts express MET and HGF regulating cellular responses, such as proliferation, migration and differentiation.

Cabozantinib (XL184) is an orally tyrosine kinase inhibitor that targets MET and VEGF receptor 2 (VEGFR2). In a multicenter, Phase II, nonrandomized expansion study of men with CRPC, bone metastases and disease progression despite docetaxel treatment, Cabozantinib was associated with improvements in bone scans, patient reported pain and analgesic use, circulating tumor cells, and bone biomarkers. The study was stopped because of these improvements in bone response. Patients treated with Cabozantinib showed a significant improvement in the primary end point of PFS compared with placebo group (median, 23.9 vs 5.9 weeks, respectively) [53] . Instead, in the following Phase III trial (COMET-1), Cabozantinib did not demonstrate a statistically significant increase in OS compared to prednisone. Indeed, COMET-1 showed a median OS of 11 months for treated patients and 9.8 months for the prednisone arm [54] . The most commonly reported adverse events with Cabozantinib included fatigue (13%), diarrhea (5%), and hypertension (5%) [54] .

4.2. Targeting Cellular Src Kinase

The membrane-associated tyrosine kinase Src (encoded by the c-Src gene) is a proto-oncogene involved in the onset of several pathological processes such as tumor cell proliferation, adhesion, invasion, migration and metastasis development [55] [56] .

One of the most studied Src inhibitor is dasatinib. In in vivo model of prostate cancer, it showed a synergistic effect when administered with docetaxel inhibiting the proliferation of prostate cancer cells implanted into bone [57] .

A Phase II study of dasatinib in combination with docetaxel demonstrated safety and activity becoming the subject of the Phase III READY trial [58] . This study enrolled 1500 men with chemotherapy-naive mCRPC and randomized them to docetaxel and prednisone with or without dasatinib 100 mg daily. In this trial, mCRPC men naïve for chemotherapy and treated with dasatinib plus docetaxel did not show OS improvement. Indeed, the median OS in dasatinib and placebo group was 21.5 and 21.2 months respectively [59] . The most common grade 3 - 4 adverse events included diarrhea (8%) patients in the dasatinib group vs 4% patients in the placebo group, fatigue (8% vs 6%), and asthenia (5% vs 3%) [59] .

4.3. Targeting Endothelins

Endothelins (ET-1, ET-2, ET-3) are a group of 21-amino acid peptides that are produced in a variety of tissues, where they regulates the vasomotor tone, nociception, hormone production and cell proliferation [60] . It has been demonstrated that circulating levels of endothelin-1 (ET-1) in metastatic prostate cancer patients increased compared to patients with localized disease [60] . In the bone microenvironment, ET-1 alters osteoblasts/osteoc- lasts balance driving to new bone deposition that is typical of prostate cancer metastases [61] . Indeed, malignant cells release ET-1 that binds its receptor (Endothelin receptor A), expressed by osteoblasts, stimulating their proliferation and bone apposition activity. Activated osteoblasts in turn release several growth factors promoting survival and growth of bone metastatic cancer cells.

Zibotentan (ZD4054) is an oral, specific Endothelin receptor A antagonist under investigation in ENTHUSE clinical trials. In ENTHUSE M1 study in men with mildly symptomatic CRPC zibotentan treatment compared to placebo did not significant improve OS (24.5 vs 22.5 months, respectively) [62] . Moreover, the ENTHUSE M0 study evaluating zibotentan treatment in patients with non-metastatic CRPC has been discontinued because did not meet its primary end points (OS and progression-free survival [PFS]).

Finally, randomized Phase III ENTHUSE M1C trial investigating the effect of zibotentan in combination with docetaxel versus docetaxel plus placebo showed no improvements in OS, PSA response rate, time to PSA progression, PFS, time to new bone metastases, time to new SREs, pain response, or time to pain progression [63] . The most commonly reported adverse events in zibotentan-treated patients were peripheral edema (37.7%), headache (26.2%) and nasal congestion (24.9%); each occurred with >15% higher incidence than in the placebo group [63] . In view of these results, no further investigations with zibotetan are ongoing.

4.4. Immunotherapies

Prostate cancer represents an appealing setting for immunotherapy approaches given the relatively high expression of several tumor-associated antigens (TAAs) [64] . In this regard Sipuleucel-T has recently been approved in mCRPC and alternative strategies based on the possibility of interfering with the phenomenon of tumor immune escape are currently in development phases. The most promising approach appears to be the modulation of immunosuppressive micro-environment by acting on their co-inhibitory molecule [65] . Nowadays, CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) is currently the most investigated, and the pharmacological approaches aimed at its inhibition are in advanced stages of clinical investigation also in metastatic prostate cancer [66] [67] .

4.5. Sipuleucel-T

Sipuleucel-T is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic CRPC. The patient’s peripheral blood mononuclear cells are treated with a prostatic acid phosphatase-granulocyte macrophage colony-stimulating factor (PAP-GM-CSF) fusion protein in addition to various other cytokines to generate PAP-specific T cells capable of recognizing and killing prostate cancer cells that express PAP. This treatment was FDA-approved in 2010 for use in patients in mCRPC, based on the results of the pivotal Phase III trial (IMPACT). In this study 512 patients with asymptomatic or minimally symptomatic chemotherapy-naive mCRPC were randomized to receive sipuleucel-T versus placebo in a 2:1 ratio showing 4.1-month improvement in median OS (25.8 vs. 21.7 months) for sipuleucel-T compared with control (HR = 0.78; 95% CI: 0.61, 0.98) [68] . Common adverse reactions reported during a safety evaluation of 601 patients who received sipuleucel-T were chills, fatigue, fever, back pain, nausea, joint ache, and headache. The majority of adverse reactions were mild or moderate in severity [68] .

4.6. Ipilimumab

Ipilimumab is a human monoclonal antibody that enhances and prolongs T-cell activation by blocking immune checkpoint CTLA-4 receptors found on the surface of T cells [65] . In a randomized Phase II trial, 108 patients with advanced prostate cancer treated with ipilimumab plus androgen-deprivation therapy showed undetectable PSA levels by 3 months compared with patients treated with endocrine therapy alone (55% vs 38%) [66] .

Recently, the results from a randomized, double-blind Phase III study (CA-184-043) comparing ipilimumab with placebo following bone-directed radiation therapy in CRPC patients previously treated with docetaxel demonstrated no improvement in OS [67] . The most frequent grade 3-4 adverse events included diarrhea (16% in the ipilimumab group vs 2% in the placebo group), fatigue (11% vs 9%, anemia (10% vs 11%), and colitis (5% vs 0) [67] .

Nevertheless, a subgroup analysis suggests that ipilimumab may be most active in patients with favorable laboratory prognostic factors (e.g., decreased alkaline phosphatase or elevated hemoglobin level) or in patients without visceral disease [66] (Table 1).

Table 1. Metastatic prostate cancer therapies currently approved or in clinical development.

5. Other Molecules

5.1. Tasquinimod

Tasquinimod is a novel immunotherapy, orally active quinoline-3-caboxamide analog that targets the tumor microenvironment exerting immunomodulatory and antiangiogenic properties [69] . In particular, tasquinimod interferes with vascular tissue homeostasis downregulating the angiogenic suppressor thrombospondin-1 and upregulating Hypoxia-inducible factor 1-alpha (HIF-1 α). At the same times it is an inhibitor of S100A9 (a protein from the family of calcium-binding S100 proteins expressed on myeloid-derived suppressor cells) modulating the local tumor immunity. Indeed, it prevents the bind of S100A9 protein with its ligand inactivating proinflammatory cascade signaling pathways [70] .

In a randomized phase II trial chemotherapy-naïve men with castrate-resistant prostate cancer showed a significant increase in progression free survival and overall survival with tasquinimod compared with placebo [71] . Tasquinimod was considered safe, with low to moderate side effects, which included mild gastrointestinal issues, muscle and joint pains, and fatigue [71] . Anyway, a phase III trial in 1245 patients did not confirm survival advantage. Even if there was a significant improvement in progression-free survival (median, 7.0 versus 4.4 months), there was no benefit in overall survival (median, 21.3 versus 24.0 months, 95%) [72] .

5.2. Custirsen

Custirsen (OGX-011) is a second-generation, 2′-methoxyethyl-modified phosphorothioate antisense oligonucleotide that inhibits clusterin expression [73] . Clusterin is an antiapoptotic protein that preserves protein during cellular stress. In prostate cancer, clusterin overexpression is associated with a high Gleason score and has been detected in patients with mCRPC after neoadjuvant hormone therapy.

Studies of clusterin have demonstrated its antiapoptotic and prosurvival activities in prostate cancer that are believed to be associated with docetaxel resistance [74] . In a phase II trial custirsen (weekly intravenous administered) plus docetaxel extended median survival rates from 16.9 months to 23.8 months compared with single-agent docetaxel [75] [76] , and a decrease of clusterin level after custirsen treatment was observed. In another Phase II trial custirsen was administered in combination with docetaxel or mitoxantrone as a second-line therapy in patients with mCRPC progressing after first-line docetaxel. Both combinations were well tolerated, but OS and PFS were better in the docetaxel arm (15.8 and 7.2 months vs 11.5 and 3.4 months, respectively) [76] .

A randomized open-label phase III trial (SYNERGY) evaluated first-line therapy with custirsen in combination with docetaxel-prednisone versus docetaxel-prednisone alone in chemotherapy-naive mCRPC patients [77] . In particular, CRPC patients with a poor prognosis appeared to benefit from custirsen when added to docetaxel as 1st-line therapy. The poor prognosis group was analyzed separately for treatment effect (n = 492). The median OS was 17.0 m in the custirsen arm vs. 14.0 m in the control arm. PSA progression in the poor prognosis group also favored custirsen. Side effects included febrile neutropenia, fever, pleural effusion, and dyspnea [77] .

Currently another randomized open-label phase III trial is ongoing in order to evaluate the OS, as first end point. In particular, AFFINITY trial, investigates the survival benefit in docetaxel-pretreated patients of second-line chemotherapy with cabazitaxel 25 mg/m2 and prednisone 10 mg/day with or without custirsen [78] .

6. Conclusions

The treatment of prostate cancer, in particular of its most malignant hormone independent and castration resistant forms, has been improved thanks to the develop of new strategies.

In the last few years, many different therapeutic strategies for CRPC have been developed and evaluated in clinical studies. Several strategies showed objective clinical benefit and have been approved for clinical use. These include the androgen inhibitors such as enzalutamide and abiraterone, radium-223 and sipuleucel-T. Although enzalutamide, abiraterone and radium-223 represent the standard care for the treatment of bone metastatic CRPC, sipuleucel-T has not widely used in clinical practice because, rarely, patients responded to therapy. The identification of biomarkers could help to select patients that may (or may not) benefit from sipuleucel-T therapy.

In the near future, it will be crucial to test these agents together or sequentially. In this regard a Phase II study on CRPC bone metastatic patients in which abiraterone and enzalutamide were administered simultaneously showed promising results [73] . Moreover, recent evidence has demonstrated that anti-androgens are able to target both prostate cancer cells and the bone microenvironment. This could influence future therapeutic approaches evaluating the possibility of combining anti-androgen treatment with bone-targeted agents (biphosphonates, denosumab) in order to achieve better control of prostate cancer bone metastases. In recent years, the simultaneous development of novel and more potent classes of drugs targeting androgen pathway has emerged such as ortonel, ARN-509 and galeterone.

On the other hand, there are several examples of new molecular targeting drugs that showed promising results in preclinical PCa models but showed insufficient effects in clinical phase III studies. These targets include the endothelin A receptor antagonist zibotentan, the Src inhibitor dasatinib, and the c-MET inhibitor cabozantinib, although some of the initial excitement failed to materialize.

In spite of the development and consequent approval of a number of new drugs active against mCRPC, no great improvement in overall was found and several patients have disease progression and early mortality. The discovery of new drug resistance mechanisms, the genomic and proteomic analysis to classify different prostate cancer molecular subtypes, as well as the set-up of new prognostic and predictive biomarkers, may further improve mCRPC treatment.

In order to make a great deal of progress in prostate cancer treatment, it is imperative that both basic and clinical investigators cooperate to reach this common goal.

Abbreviations

PCa: Prostate Cancer

PIN: Prostatic Intraepithelial Neoplasia

HGPIN: High Grade Prostatic Intraepithelial Neoplasia

ADT: Androgen Deprivation Therapies

PSA: Prostate Specific Antigen

SRE: Skeletal Related Event

mCRPC: metastatic Castration Resistant Prostate Cancer

OS: Overall Survival

AR: Androgen Receptor

CYP17: Cytocrome P450 17 alpha hydroxysteroid dehydrogenase

PFS: Progression Free Survival

RANK: Receptor Activator of Nuclear Factor-Kb

RANKL: Receptor Activator of Nuclear Factor-kB Ligand

OPG: Osteoprotegerin

TNF: Tumor Necrosis Factor

TGF-b: Tumor Growth Factor-b Factor

PDGF: Platelet-Derived Growth Factor

bALP: bone alkaline phosphatase

uNTX: urine N-telopeptide

HGF: Hepatocyte Growth Factor

VEGF: Vascular Endothelial Growth Factor

VEGFR: Vascular Endothelial Growth Factor Receptor

ET: Endothelin

TAAs: Tumor Associated Antigens

CTLA-4: Cytotoxic T-lymphocyte associated antigen 4

PAP-GM-CSF: Phosphatase-granulocyte macrophage colony-stimulating factor

HIF-1α: Hypoxia-Inducible Factor 1-alpha

NOTES

*Corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

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