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Prostate Cancer Overview - Signaling Pathway. Diagnostics Marker. Targeted Therapy and Clinical Trials.

An Introduction to Prostate Cancer

Prostate cancer (PCa) is the second leading cause of cancer death in American men, behind lung cancer and it predominately affects elderly men with higher incidence. About 1 man in 41 will die of prostate cancer. The development of PCa involves several mutations in prostate epithelial cells, usually linked to developmental changes, such as enhanced resistance to apoptotic death, constitutive proliferation, and, in some cases, to differentiation into an androgen deprivation-resistant phenotype, leading to the appearance of castration-resistant PCa (CRPCa), which leads to a poor prognosis in patients. A prostatectomy usually leads to an excellent prognosis with low risk of death from PCa after surgery. However, deregulated production and secretion of growth factors by stromal cells within the PCa microenvironment, as well as mutations in androgen signaling pathway components and further physiological modifications, including angiogenesis, local migration, invasion, intravasation, circulation, and extravasation of the tumor, potentially lead to systemic recurrence of the cancer, including the appearance of focal tumor in advanced stage. Prostate cancer can often be found early by testing for prostate-specific antigen (PSA) levels in a man's blood. Another way to find prostate cancer early is the digital rectal exam (DRE). However, neither the PSA test nor the DRE is 100% accurate. Therefore, optimizing early diagnosis and developing targeted therapy of prostate cancer are the key to improving the benefit of screening and the survival rate of patients. At present, the main molecular signaling pathways of prostate cancer including androgen receptor (AR) mediated signaling pathway, NF-κB signaling pathway, RTK signaling pathway, JAK/STAT signaling pathway and Wnt signaling pathway.

1 Main Signaling Pathways in Prostate Cancer Therapy

Fig.1 Prostate cancer signaling pathway. Targeted agents (listed in orange boxes) include those in clinical use (colored in red) and those in preclinical or early phase development (colored in green) for the treatment of advanced stage prostate cancer.

With the rapid development of molecular biology and genomics, it is known that molecular pathogenesis of prostate cancer is extremely complicated. The role of AR signaling in PCa development and progression has been well established and it influences the transition of PCa cells from androgen dependent to castration resistant (CR) stage. Activation of NF-κB pathway and subsequent downstream targets contributes to the progression and metastasis of PCa and blockade of NF-κB pathway of is associated with suppression of angiogenesis, invasion, and metastasis. EGFR/Akt or EGFR/MARP signaling pathways are critical for maintaining cell survival in PCa and disrupting the EGFR activation can inhibit tumor growth and neovascularization. Deregulation in the expression of downstream effectors of PI3K/ and RAS/mitogen-activated protein kinase (MAPK) pathways are reported to contribute significantly to PCa growth and development. Wnt5, a critical ligand that activates the β-catenin-independent pathway in Wnt signaling promotes the rapid proliferation and metastasis of PCa. Overexpression of insulin receptor IGF1R promoted tumor growth and enhanced angiogenesis in human PCa cells. Above molecular mechanisms provide multiple potential targets for the treatment of prostate cancer.

1.1 Androgen receptor (AR) mediated signaling pathway

The AR signaling is vital for normal functioning of the prostate, and initiation and maintenance of spermatogenesis. AR is a member of the steroid hormone receptor family of ligand-activated nuclear transcription factors. Under physiological conditions, both testosterone and DHT can bind to and activate AR signaling. Binding of ligand to the AR induces conformational changes in the LBD facilitating intramolecular and intermolecular interaction between NTD and CTD. This subsequently results in AR homo-dimerization, phosphorylation and nuclear translocation. Deregulated AR signaling is common during PCa development and CRPC progression due to overexpression of AR arising due to amplification/mutations, co-activator and co-repressor modifications, aberrant activation/post-translational modification, altered steroidogenesis, and generation of AR splice variants. Aberrant activation of AR also occurs via alterations in the steroidogenesis pathways which permits PCa cells to bypass testosterone and utilize adrenal androgens to generate functionally potent DHT via the 5α-dione pathway. Besides localization in the nucleus, some AR variants also exhibit exclusive cytoplasmic function that is sufficient enough for transcriptional effects. In addition, ARVs can freely enter the nucleus without association with the Hsp90 chaperone complex. Aside from the above described mechanisms that induce changes in the activity of AR, various transcription factors such as the protooncogene c-Myc, c-Jun, Sp1, FOXO3a, lymphoid enhancer binding factor 1 (LEF1), NF-κB and twist-1 also have a crucial role in promoting AR expression via gene regulation.

1.2 NF-κB signaling pathway

NF-κB is a protein complex that regulates expression of key genes required for innate and adaptive immunity, cell proliferation and survival, and lymphoid organ development. In humans, the NF-κB family comprises of five proteins namely p65 (RelA), RelB, p105/p50 (NF-κB1), p100/p52 (NF-κB2) and c-Rel. These proteins associate with each other to form homo- or heterodimeric complexes that are transcriptionally active. In the canonical pathway of activation, degradation of the IκB inhibitory protein occurs through phosphorylation at specific serine residues by IκB kinase complex (composed of the catalytic subunits IKKα and IKKβ, and the regulatory scaffolding protein NEMO). As a consequence, free NF-κB dimer enters the nucleus, binds to κB enhancer sites in the DNA and activates transcription of a wide array of genes participating in the immune and inflammatory response, cell growth, adhesion, metastasis, and apoptosis evasion. In prostate tumor cells, NF-κB is found frequently stimulated due to augmented levels of receptors such as TNF that radically increase IκB degradation. In androgen-independent prostate tumors, NF-κB expression is increased at both mRNA and protein level due to increased interleukin 6 (IL-6) expression that occurs as a result of constitutive NF-κB activation promoted by signal transduction via NF-κB inducing kinase (NIK) and IKK. NF-κB also targets a transcription regulatory element of the prostate specific antigen PSA, a vital marker for development and progression of PCa. NF-κB signaling in PCa cells also correlates with cancer progression, chemoresistance, and PSA recurrence. Reports also indicate that NF-κB activation contributes to soft-tissue or bone metastasis in prostate cancer. Furthermore, p65 of NF-κB could increase endogenous AR expression and its associated downstream target genes enhancing growth and survival in human PCa cells.

1.3 RTK signaling pathway

RTK signaling pathway has two major signaling pathway branches, PI3K/AKT and Ras/MAPK pathways. PI3K/AKT pathway, a chief intracellular signal transduction mechanism that links diverse classes of membrane receptors essentially plays a central role in cellular quiescence, cell growth, proliferation, differentiation, motility, survival and angiogenesis. Following stimulation by tyrosine kinase growth factor receptors, PI3K induces conscription and stimulation of the serine/threonine-specific protein kinase AKT and subsequently binds to AKT resulting in membrane translocation and its activation via phosphorylation. Activated AKT in turn phosphorylates and galvanizes several other proteins including mTOR ultimately inducing and regulating a wide array of cellular processes. PI3K/AKT pathway is often augmented due to the loss of tumor suppressor PTEN. In PCa cells, aberrant PI3K/AKT pathway disturbs the action of ERKs thereby favoring AR-independent growth. Congruently, AR target genes might impede PI3K/AKT pathway to favor AR-dependent growth, invasion and metastasis in PCa cells. Mitogen-activated protein kinases (MAPKs) comprise three distinct groups specifically ERKs, JNKs, and p38 isoforms. MAPK signaling links extracellular signals to the machinery that controls fundamental cellular processes such as growth, proliferation, differentiation, migration, apoptosis and transformation. Overexpression of EGF, FGF, IGF, and KGFs in PCa frequently results in activation of endogenous Ras and MAPK pathways. In addition, p38 signaling chiefly activated at later stages of PCa increases the expression of aquaporins which are pore-forming proteins thereby enabling PCa cells survive through hypoxia.

1.4 JAK/STAT signaling pathway

JAK/STAT pathway is an imperative and pleiotropic membrane-to-nucleus cascade that transduces multitude of signals for normal development, cellular homeostasis, cell proliferation, differentiation, migration and apoptosis following stimulation by a wide variety of stimuli including reactive oxygen species, cytokines, and growth factors. Briefly, activation of JAK/STAT pathway occurs when ligand binding induces multimerization of receptor subunits resulting in signal propagation via phosphorylation of receptor-associated JAK tyrosine kinases (JAK1, JAK2, JAK3 and Tyk2). Activated JAKs subsequently induce phosphorylation of other additional targets comprising both the receptors and STAT proteins. Phosphorylation in turn induces dimerization of STATs through conserved SH2 domain subsequently allowing their entry into the nucleus through importin α-5 and the Ran nuclear import pathway. In the nucleus, STATs bind to specific sequences in the DNA to stimulate or suppress transcription of target genes. The DNA repair gene BRAC1 can induce cell proliferation and inhibit apoptotic cell death in PCa cells through interaction with JAK1/2 and STAT3 phosphorylation. In addition, activation of STAT3 in PCa cells also stimulates various other genes that are associated with cell cycle progression, anti-apoptosis, angiogenesis and tumor invasion. STAT5a/b dimerization and ensuing nuclear translocation where the dimers binding to specific response elements of target genes promotes prostate cancer growth, tumor progression and distant metastases. Components of JAK-STAT pathway specifically pJAK-1 and pSTAT-3 function as predictors of biochemical relapse and poor prognosis of PCa.

1.5 Wnt signaling pathway

Wnt/β-catenin pathway is a highly conserved developmental signaling pathway comprising of secreted glycoproteins that play a vital role in tissue homeostasis, cell proliferation, differentiation, migration, and epithelial- mesenchymal communications, polarity and asymmetric cell division. Based on the ability to stabilize the multifunction protein β-catenin, Wnt signaling is β-catenin predominantly exists in the cytosol in complex with APC, Axin, CK1, and GSK-3β. However, free β-catenin accumulates in the perinuclear region and ultimately interact with lymphoid enhancer factor/T cell factor (LEF/TCF) in the DNA to stimulate transcription of various target genes including that of c-Myc, p300, Foxo, Bcl9-2, c-Jun, CtBP, and cyclin D1. Increased expression of β-catenin occurs quite commonly in PCa and is associated with growth, proliferation and metastasis of prostate cancer cells.

2 Prostate cancer diagnosis

Since the introduction of serum prostate-specific antigen (PSA) screening of asymptomatic populations, prostate cancer incidence rates have increased dramatically, as has the number of men undergoing radical prostatectomy and radiation therapy for this disease. However, false positives for PSA continue to be a significant problem resulting in unnecessary biopsies, and the value of broad-based PSA testing regarding predicting surgical cures has recently come into question. Currently, there are no markers that differentiate clinically relevant from clinically benign disease. Better indicators of prostate cancer presence and progression are needed to avoid unnecessary treatment, predict disease course, and develop more effective therapy. A variety of putative prostate cancer markers have been described in human serum, urine, seminal fluid, and histological specimens. These markers exhibit varying capacities to detect prostate cancer and to predict disease course.

2.1 Molecular Markers for Prostate cancer

Current advancements in proteomics, tissue microarray, DNA microarray, immunohistochemical staining, and other biotechnologies have paved the way and have significantly increased the pace at which novel biomarkers are being discovered and developed. The genetic landscape of prostate cancer was intensely explored in the last few years with NGS, whole genome expression analyses and analyses of epigenetic alterations. There is a relatively low rate of mutations in PCa compared to other tumors and prevalence of non-random copy number variations (CNV) in most PCa tumors involving well-known prostate oncogenes or tumor suppressors. Consequently, several published studies have supported the usefulness of the prostate cancer antigen 3 (PCA3 or DD3) gene as a biomarker in the diagnosis of prostate cancer stage and grading. Hypermethylation of the PDLIM4 gene has been shown to be a sensitive molecular tool in detecting prostate tumorigenesis and can be used as a biomarker to predict the biochemical, local, and systemic recurrence of prostate cancer. Patients with expression of ERG in high-grade prostatic intraepithelial neoplasia are more likely to develop prostate cancer. Homozygous loss of PTEN is causative in progression to aggressive metastatic phenotype and castration resistance and there is a strong oncogenic interaction between high levels of ERG and PTEN loss. Meanwhile, MAGI2/3 mutations and PIK3CA mutations are enriched in tumors positive. NKX3.1 is frequently mutated or lost in localized PCa, MED12 is mutated in 5% of prostate cancer, classical tumor suppressors TP53 inactivates, as well as CDKN1B (p27/KIP) and RB1 occur in primary PCa and castrate resistant disease (CRPC). miRNAs are expressed in a tissue- and function-specific manner and are protected from nuclease degradation in the bloodstream. This makes them new candidate biomarkers for detecting cancers. MiR-141 has an elevated level in the blood of patients having metastatic prostate cancer. In addition, there are several differentially expressed microRNAs (miR-200c, miR-21, miR-210, miR-205, miR-20a, miR-143∗, miR-143, and miR-16) that can be used as biomarkers.

2.2 Protein Markers for Prostate cancer

Serum prostate-specific antigen PSA, discovered in 1971, is considered the most important biomarker for detecting, staging, and monitoring cancer of the prostate in its early stage. PSA testing was initially used for monitoring prostate cancer patients and became extensively used for screening and diagnosing the disease. The main advantage of PSA testing is its superior sensitivity while its main disadvantage is that it is not very specific. In an effort to find ways of improving specificity, several variations on the basic PSA test have been proposed. Of these the prostate health index PHI, which is based on a molecular isoform of free PSA, is the most developed and has been shown to have greater specificity than use of total PSA or % free PSA. Adding the Kallikrein protein hK2 to PSA based markers has also been shown to improve the specificity of PSA based assays.

Human prostatic acid phosphatase (PAP) (or serum acid phosphatase (AP) was reportedly the first serum biomarker for prostate cancer. Although AP, with an elevated level in more than 70% of patients, was linked early with prostate cancer that had spread, both AP and prostate-specific AP (PAP, its subtype) are not sensitive enough for screening. Ki-67, a cell-proliferation associated marker, has been described as one of the most promising biomarkers of prostate cancer. Ki-67 has been suggested as a prolific predictive biomarker for men who have low-grade, low-stage prostate cancer for their PSA relapse after radical prostatectomy. Immunodetectable serum autoantibodies generated in response to the AMACR tumor-associated antigen may also be useful in preliminary diagnosis, especially if combined with PSA screening. Glutathione S-transferase π is an example of a biomarker that has been extensively studied in prostate cancer, primarily as a tissue marker. Past studies suggest GRN-A may be very useful as a prognostic factor in patients with advanced prostate cancer. PSMA has been well characterized as a diagnostic and prognostic marker, but it has limited prostate specificity. In addition, other proteins, prostate stem cell antigen (PSCA), early prostate cancer (EPCA), B7-H3, caveolin-1 (Cav-1), etc., could be the powerful candidate biomarkers for diagnosing and monitoring the status of prostate cancer.

Table 1 Candidate molecular and protein markers in prostate cancer

Marker Subcellular location Biochemical function Biological/cellular function
A2M Secreted Protease inhibitor Protein carrier
Akt-1 Nucleus/cytoplasm Protein kinase Apoptotic inhibition
AMACR Mitochondria/peroxisome Racemase Stereoisomerization
Annexin 2 Plasma membrane Calcium and lipid binding Membrane trafficking
Bax Cytoplasm/membrane Bcl-2 binding Apoptosis
Bcl-2 Mitochondrial membrane Membrane permeability Apoptosis
Cadherin-1 Plasma membrane Catenin/integrin binding Cell adhesion
Caspase 8 Cytoplasm Protease Apoptosis
Catenin Cytoskeleton Cadherin binding Cell adhesion
Cav-1 Plasma membrane Scaffolding Endocytosis/signaling
CD34 Plasma membrane Scaffolding Cell adhesion
CD44 Plasma membrane Hyaluronate binding Cell adhesion
Clar1 Nucleus SH3 binding Unknown
Cox-2 Microsomal membrane Prostaglandin synthase Inflammatory response
CTSB Lysosome Protease Protein turnover
Cyclin D1 Nucleus CDKb regulation Cell cycle
DD3 Nucleus/cytoplasm Noncoding Unknown
DRG-1 Cytoplasm GTP binding Cell growth/differentiation
EGFR Plasma membrane EGF binding Signaling
EphA2 Plasma membrane Tyrosine kinase Signaling
ERGL Plasma membrane Lectin/mannose binding Unknown
ETK/BMK Cytoplasm Tyrosine kinase Signaling
EZH2 Nucleus Transcription repressor Homeotic gene regulation
Fas Plasma membrane Caspase recruitment Apoptosis
GDEP Unknown Unknown Unknown
GRN-A Secretory granules Statin Endocrine function
GRP78 Endoplasmic reticulum Multimeric protein assembly Cell stress response
GSTP1 Cytoplasm Glutathione reduction DNA protection
Hepsin Plasma membrane Serine protease Cell growth/morphology
Her-2/Neu Plasma membrane Tyrosine kinase Signaling
HSP27 Cytoplasm Chaperone Cell stress response
HSP70 Cytoplasm Chaperone Cell stress response
HSP90 Cytoplasm Chaperone Cell stress response
Id-1 Nucleus Transcription factor Differentiation regulator
IGF-1 Secreted IGFR ligand Signaling
IGF-2 Secreted IGFR ligand Signaling
IGFBP-2 Secreted IGF binding Signaling
IGFBP-3 Secreted IGF binding Signaling/apoptosis
IL-6 Secreted Cytokine B-cell differentiation
IL-8 Secreted Cytokine Neutrophil activation
KAI1 Plasma membrane CD4/CD8 binding Signaling
Ki67 Nucleus Nuclear matrix associated Cell proliferation
KLF6 Nucleus Transcription factor B-cell development
KLK2 Secreted Protease Met-Lys/Ser-Arg cleavage
Maspin Extracellular Protease inhibitor Cell invasion suppressor
MSR1 Plasma membrane LDL receptor Endocytosis
MXI1 Nucleus Transcription factor Myc suppression
MYC Nucleus Transcription factor Cell proliferation
NF-κB Nucleus Transcription factor Immune response
NKX3.1 Nucleus Transcription factor Cell proliferation
OPN Secreted Integrin binding Cell-matrix interaction
p16 Nucleus CDK inhibitor Cell cycle
p21 Nucleus CDK inhibitor Cell cycle
p27 Nucleus CDK inhibitor Cell cycle
p53 Nucleus Transcription factor Growth arrest/apoptosis
PAP Secreted Tyrosine phosphatase Signaling
PART-1 Nucleus/cytoplasm Unknown Unknown
PATE Plasma membrane Unknown Unknown
PC-1 Nucleus RNA binding Ribosome transport
PCGEM1 Nucleus/cytoplasm Noncoding Cell proliferation/survival
PCTA-1 Cytoplasm Unknown Cell adhesion
PDEF Nucleus Transcription factor PSA promoter binding
PI3K p85 Cytoplasm Lipid kinase Signaling
PI3K p110 Cytoplasm Lipid kinase Signaling
PIM-1 Cytoplasm Protein kinase Cell differentiation/survival
PMEPA-1 Plasma membrane NEDD4 binding Growth regulation
PRAC Nucleus Choline/ethanolamine kinase Unknown
Prostase Secreted Serine protease ECM degradation
Prostasin Plasma membrane Serine protease Cell invasion suppressor
PSA Secreted Protease Semen liquification
PSCA Plasma membrane Unknown Unknown
PSDR1 Nucleus/cytoplasm Dehydrogenase reductase Steroid metabolism
PSGR Plasma membrane Odorant receptor Unknown
PSMA Plasma membrane Folate hydrolase Cell stress response
PSP94 Secreted FSH inhibitor Growth inhibition
PTEN Cytoplasm Protein/lipid phopatase Signaling
RASSF1 Cytoplasm Ras binding Signaling
RB1 Nucleus E2F-1 inactivation Cell cycle
RNAseL Cytoplasm/mitochondria RNAse Viral resistance
RTVP-1 Plasma membrane Unknown Immune response/apoptosis
ST7 Plasma membrane Unknown Cell proliferation
STEAP Plasma membrane Unknown Unknown
TERT Nucleus Reverse transcriptase Telomere synthesis
TIMP 1 Secreted Protease inhibitor Cell adhesion
TIMP 2 Secreted Protease inhibitor Cell adhesion
TMPRSS2 Plasma membrane Serine protease Unknown
TRPM2 Plasma membrane Calcium channel Ion flux
Trp-p8 Plasma membrane Calcium channel Ion flux
UROC28 Nucleus/cytoplasm Choline/ethanolamine kinase Unknown
VEGF Secreted VEGFR binding Angiogenesis

3 Targeted Therapy for Prostate Cancer

The molecular pathogenesis of prostate cancer is very complex, its occurrence, development and metastasis are closely related to the abnormality of various gene mutations and cell signaling pathways which provide a number of potential key targets for the treatment of prostate cancer. Major components of cell signaling pathways, such as the receptor tyrosine kinases (RTKs), Ras/Raf/mitogen-activated protein kinase cascade, AR pathway proteins and other major signaling cascades. In Table 2-14, selected clinical trials of novel therapeutic targets for the treatment of prostate cancer are presented.

3.1 Prostate cancer therapy for AR mediated signaling pathway

In depth understanding of AR signaling and the mechanisms of castration resistance in PCa has resulted in the development of novel agents that can more efficiently retract AR signaling. Abiraterone acetate (Zytiga) is a selective, oral agent that can irreversibly inhibit the biosynthesis of testosterone. ketoconazole, a broad-spectrum antifungal agent, has been extensively used as testosterone inhibitor and second-line hormonal therapy for PCa. MDV3100 (Enzalutamide) is an inhibitor of the C-terminus ligand-binding domain with multiple effects on AR and it also prevents AR nuclear translocation, AR binding to DNA, and co-activator recruitment. Galeterone (VN/124-1, TOK-001) developed by Tokai Pharmaceuticals, which acts by disrupting the androgen receptor signaling pathway, is a 17- heteroazole steroidal analogue for men with metastatic, castration-resistant PCa or CRPC, whose prostate tumor cells express the AR-V7 splice variant.

Table 2 Clinical trials of testosterone inhibitor Abiraterone acetate

Nct id Status Lead sponsor Study first posted
NCT02608359 Recruiting Johnson & Johnson Private Limited November 18, 2015
NCT01309672 Active, not recruiting Southwest Oncology Group March 7, 2011
NCT01591122 Active, not recruiting Janssen Research & Development, LLC May 3, 2012
NCT02903368 Recruiting Dana-Farber Cancer Institute September 16, 2016
NCT02218606 Recruiting Memorial Sloan Kettering Cancer Center August 18, 2014
NCT02077634 Active, not recruiting Saarland University March 4, 2014
NCT01961843 Active, not recruiting Massachusetts General Hospital October 11, 2013
NCT02730975 Recruiting Fundación Pública Andaluza para la gestión de la Investigación en Sevilla April 7, 2016
NCT03360721 Recruiting M.D. Anderson Cancer Center December 4, 2017
NCT01751451 Active, not recruiting Memorial Sloan Kettering Cancer Center December 18, 2012
NCT01637402 Active, not recruiting Terence Friedlander, MD July 11, 2012
NCT01543776 Active, not recruiting University of Chicago March 5, 2012
NCT03458247 Recruiting Assistance Publique - Hôpitaux de Paris March 8, 2018
NCT02987543 Recruiting AstraZeneca December 9, 2016
NCT01940276 Active, not recruiting Duke University September 12, 2013
NCT03706365 Not yet recruiting Eli Lilly and Company October 16, 2018
NCT01688492 Active, not recruiting Memorial Sloan Kettering Cancer Center September 20, 2012
NCT02123758 Active, not recruiting Aragon Pharmaceuticals, Inc. April 28, 2014
NCT02217566 Active, not recruiting Janssen Research & Development, LLC August 15, 2014
NCT01792687 Active, not recruiting Aragon Pharmaceuticals, Inc. February 15, 2013
NCT02353715 Active, not recruiting Duke University February 3, 2015
NCT01717053 Active, not recruiting Duke University October 30, 2012
NCT02807805 Recruiting Chong-xian Pan June 21, 2016
NCT02787837 Recruiting Centro Nacional de Investigaciones Oncologicas CARLOS III June 1, 2016
NCT01715285 Active, not recruiting Janssen Research & Development, LLC October 26, 2012
NCT01957436 Recruiting UNICANCER October 8, 2013
NCT02257736 Active, not recruiting Aragon Pharmaceuticals, Inc. October 6, 2014
NCT03279250 Recruiting M.D. Anderson Cancer Center September 12, 2017
NCT01685125 Active, not recruiting University of Southern California September 13, 2012
NCT02975934 Recruiting Clovis Oncology, Inc. November 29, 2016
NCT02036060 Active, not recruiting Spanish Oncology Genito-Urinary Group January 14, 2014
NCT02867020 Recruiting Latin American Cooperative Oncology Group August 15, 2016
NCT02924766 Recruiting Janssen Research & Development, LLC October 5, 2016
NCT02913196 Recruiting Weill Medical College of Cornell University September 23, 2016
NCT01314118 Active, not recruiting Janssen Biotech, Inc. March 14, 2011
NCT03098836 Recruiting Daniel George, MD April 4, 2017
NCT02125357 Active, not recruiting British Columbia Cancer Agency April 29, 2014
NCT02364531 Active, not recruiting Janssen Inc. February 18, 2015
NCT02025010 Active, not recruiting Dana-Farber Cancer Institute December 31, 2013
NCT01503229 Active, not recruiting University of Washington January 2, 2012
NCT02415621 Recruiting H. Lee Moffitt Cancer Center and Research Institute April 14, 2015
NCT02960022 Recruiting Astellas Pharma Global Development, Inc. November 9, 2016
NCT02106507 Active, not recruiting Memorial Sloan Kettering Cancer Center April 8, 2014
NCT02849990 Recruiting University of Washington July 29, 2016
NCT03173859 Not yet recruiting University of Athens June 2, 2017
NCT02043678 Active, not recruiting Bayer January 23, 2014
NCT03649841 Not yet recruiting University of Washington August 28, 2018
NCT01485861 Active, not recruiting Genentech, Inc. December 6, 2011
NCT01576172 Active, not recruiting National Cancer Institute (NCI) April 12, 2012
NCT01858441 Active, not recruiting Centre Antoine Lacassagne May 21, 2013
NCT02268175 Active, not recruiting Dana-Farber Cancer Institute October 20, 2014
NCT01786265 Active, not recruiting M.D. Anderson Cancer Center February 7, 2013
NCT03356444 Not yet recruiting West China Hospital November 29, 2017
NCT02090114 Recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins March 18, 2014
NCT03449719 Not yet recruiting Lorenzo Livi February 28, 2018
NCT03732820 Not yet recruiting AstraZeneca November 7, 2018
NCT01517802 Active, not recruiting Janssen Research & Development, LLC January 25, 2012
NCT03565835 Recruiting Montefiore Medical Center June 21, 2018
NCT02485691 Recruiting Sanofi June 30, 2015
NCT02949284 Recruiting Rutgers, The State University of New Jersey October 31, 2016
NCT03587285 Not yet recruiting Guangzhou University of Traditional Chinese Medicine July 16, 2018
NCT03148795 Recruiting Pfizer May 11, 2017
NCT02160353 Recruiting Cancer Trials Ireland June 10, 2014
NCT02543255 Recruiting University Health Network, Toronto September 7, 2015
NCT01254864 Active, not recruiting M.D. Anderson Cancer Center December 7, 2010
NCT02703623 Recruiting M.D. Anderson Cancer Center March 9, 2016
NCT03009981 Recruiting Alliance Foundation Trials, LLC. January 4, 2017
NCT03016741 Recruiting Northwestern University January 11, 2017
NCT02426333 Recruiting Radboud University April 24, 2015
NCT01884285 Recruiting AstraZeneca June 24, 2013
NCT03141671 Recruiting Dana-Farber Cancer Institute May 5, 2017
NCT03419234 Recruiting ECOG-ACRIN Cancer Research Group February 1, 2018
NCT03093272 Recruiting Dana-Farber Cancer Institute March 28, 2017
NCT03436654 Recruiting Memorial Sloan Kettering Cancer Center February 16, 2018
NCT02772588 Recruiting Memorial Sloan Kettering Cancer Center May 13, 2016
NCT02903160 Recruiting Icahn School of Medicine at Mount Sinai September 16, 2016
NCT03002220 Recruiting MedSIR December 23, 2016
NCT03414437 Enrolling by invitation Carolina Research Professionals, LLC January 30, 2018
NCT03554317 Recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins June 13, 2018
NCT01995513 Active, not recruiting Pfizer November 26, 2013
NCT03568656 Recruiting CellCentric Ltd. June 25, 2018
NCT03012321 Recruiting Northwestern University January 6, 2017
NCT02429193 Active, not recruiting University Health Network, Toronto April 29, 2015
NCT02403505 Active, not recruiting Han Xu, M.D., Ph.D., Sponsor-Investigator, IRB Chair March 31, 2015
NCT03414034 Recruiting Trovagene, Inc. January 29, 2018
NCT02907372 Recruiting Centre Francois Baclesse September 20, 2016
NCT03043807 Recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins February 6, 2017
NCT03655886 Recruiting University Hospital, Ghent August 31, 2018
NCT03007732 Recruiting Lawrence Fong January 2, 2017
NCT02456571 Recruiting Duke University May 28, 2015
NCT02286921 Active, not recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins November 10, 2014
NCT01949337 Active, not recruiting Alliance for Clinical Trials in Oncology September 24, 2013
NCT01953640 Active, not recruiting Mayo Clinic October 1, 2013
NCT03298087 Recruiting VA Office of Research and Development September 29, 2017
NCT02883166 Recruiting Radboud University August 30, 2016
NCT02861573 Recruiting Merck Sharp & Dohme Corp. August 10, 2016
NCT03551782 Recruiting Janssen Research & Development, LLC June 11, 2018
NCT02813226 Recruiting Ontario Clinical Oncology Group (OCOG) June 24, 2016
NCT03176381 Recruiting Tianjin Medical University Second Hospital June 5, 2017
NCT03075735 Active, not recruiting Centro Nacional de Investigaciones Oncologicas CARLOS III March 9, 2017
NCT00268476 Recruiting Medical Research Council December 22, 2005
NCT03170960 Recruiting Exelixis May 31, 2017

According to statistics, a total of 102 Abiraterone acetate projects targeting prostate cancer testosterone are currently in clinical stage, of which 55 are recruiting, 46 are not recruiting and 1 is Enrolling by invitation.

Table 3 Clinical trials of testosterone inhibitor Ketoconazole

Nct id Status Lead sponsor Study first posted
NCT01036594 Active, not recruiting University of California, San Francisco December 21, 2009
NCT00859781 Recruiting Weill Medical College of Cornell University March 11, 2009
NCT01275651 Active, not recruiting Alliance for Clinical Trials in Oncology January 12, 2011
NCT00460031 Active, not recruiting Case Comprehensive Cancer Center April 13, 2007
NCT01576172 Active, not recruiting National Cancer Institute (NCI) April 12, 2012

Table 4 Clinical trials of AR inhibitor Enzalutamide

Nct id Status Lead sponsor Study first posted
NCT03674814 Not yet recruiting University of Chicago September 18, 2018
NCT02064582 Active, not recruiting University of Texas Southwestern Medical Center February 17, 2014
NCT02207504 Active, not recruiting Dana-Farber Cancer Institute August 4, 2014
NCT02125084 Active, not recruiting SCRI Development Innovations, LLC April 29, 2014
NCT02960022 Recruiting Astellas Pharma Global Development, Inc. November 9, 2016
NCT02057939 Active, not recruiting Duke University February 7, 2014
NCT03478904 Recruiting National Cancer Institute (NCI) March 27, 2018
NCT03418324 Recruiting Cedars-Sinai Medical Center February 1, 2018
NCT02384382 Active, not recruiting Pfizer March 10, 2015
NCT02495974 Active, not recruiting Astellas Pharma Europe Ltd. July 13, 2015
NCT03124615 Recruiting Macquarie University, Australia April 24, 2017
NCT02799745 Active, not recruiting Astellas Pharma Global Development, Inc. June 15, 2016
NCT03641560 Recruiting Astellas Pharma Inc August 22, 2018
NCT02294461 Active, not recruiting Astellas Pharma Inc November 19, 2014
NCT03700099 Not yet recruiting Instituto do Cancer do Estado de São Paulo October 9, 2018
NCT02339168 Active, not recruiting University of California, Davis January 15, 2015
NCT01885949 Active, not recruiting Massachusetts General Hospital June 25, 2013
NCT03196388 Recruiting Fundación Canaria de Investigación Sanitaria June 22, 2017
NCT02640534 Recruiting Swiss Group for Clinical Cancer Research December 29, 2015
NCT02588001 Active, not recruiting Translational Research Center for Medical Innovation, Kobe, Hyogo, Japan October 27, 2015
NCT01995513 Active, not recruiting Pfizer November 26, 2013
NCT02711956 Recruiting Zenith Epigenetics March 17, 2016
NCT02833883 Recruiting Memorial Sloan Kettering Cancer Center July 14, 2016
NCT02213107 Active, not recruiting University of Rochester August 11, 2014
NCT01212991 Active, not recruiting Pfizer October 1, 2010
NCT02199197 Active, not recruiting University of Utah July 24, 2014
NCT03123978 Recruiting University of California, Davis April 21, 2017
NCT02353715 Active, not recruiting Duke University February 3, 2015
NCT02677896 Active, not recruiting Astellas Pharma Global Development, Inc. February 9, 2016
NCT01942837 Active, not recruiting Dana-Farber Cancer Institute September 16, 2013
NCT03336983 Recruiting Azienda Ospedaliera Spedali Civili di Brescia November 8, 2017
NCT02407054 Active, not recruiting Eli Lilly and Company April 2, 2015
NCT01977651 Active, not recruiting Astellas Pharma Global Development, Inc. November 7, 2013
NCT02987543 Recruiting AstraZeneca December 9, 2016
NCT02607228 Active, not recruiting Gilead Sciences November 17, 2015
NCT02288247 Active, not recruiting Astellas Pharma Europe Ltd. November 11, 2014
NCT02319837 Active, not recruiting Pfizer December 18, 2014
NCT02918968 Active, not recruiting Astellas Pharma Inc September 29, 2016
NCT02028988 Active, not recruiting Dana-Farber Cancer Institute January 7, 2014
NCT02685267 Active, not recruiting Prostate Cancer Clinical Trials Consortium February 18, 2016
NCT03103724 Recruiting Fondazione IRCCS Istituto Nazionale dei Tumori, Milano April 6, 2017
NCT03531827 Recruiting National Cancer Institute (NCI) May 22, 2018
NCT02003924 Active, not recruiting Pfizer December 6, 2013
NCT02446405 Active, not recruiting University of Sydney May 18, 2015
NCT02452008 Recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins May 22, 2015
NCT02012296 Recruiting University of Chicago December 16, 2013
NCT01875250 Active, not recruiting National Cancer Institute (NCI) June 11, 2013
NCT02288936 Active, not recruiting Spanish Oncology Genito-Urinary Group November 13, 2014
NCT02814968 Recruiting The European Uro-Oncology Group June 28, 2016
NCT02446444 Active, not recruiting University of Sydney May 18, 2015
NCT03246347 Recruiting Earle Burgess August 11, 2017
NCT02254785 Active, not recruiting British Columbia Cancer Agency October 2, 2014
NCT02445976 Active, not recruiting Innocrin Pharmaceutical May 15, 2015
NCT02815033 Recruiting The European Uro-Oncology Group June 28, 2016
NCT02935205 Recruiting University of California, Davis October 17, 2016
NCT01867333 Active, not recruiting National Cancer Institute (NCI) June 4, 2013
NCT03338790 Recruiting Bristol-Myers Squibb November 9, 2017
NCT03344211 Not yet recruiting University of Southern California November 17, 2017
NCT02507570 Active, not recruiting Carolina Research Professionals, LLC July 24, 2015
NCT03110588 Recruiting University of Alabama at Birmingham April 12, 2017
NCT02225704 Active, not recruiting Cancer Trials Ireland August 26, 2014
NCT02125357 Active, not recruiting British Columbia Cancer Agency April 29, 2014
NCT02204072 Active, not recruiting Boehringer Ingelheim July 30, 2014
NCT02194842 Recruiting European Organisation for Research and Treatment of Cancer - EORTC July 18, 2014
NCT02090114 Recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins March 18, 2014
NCT03734653 Not yet recruiting University of Colorado, Denver November 8, 2018
NCT03437941 Recruiting Corcept Therapeutics February 19, 2018
NCT02555189 Recruiting Sidney Kimmel Cancer Center at Thomas Jefferson University September 21, 2015
NCT03177187 Not yet recruiting Institute of Cancer Research, United Kingdom June 6, 2017
NCT03480646 Recruiting Constellation Pharmaceuticals March 29, 2018
NCT02346578 Active, not recruiting Taro Iguchi, MD, PHD January 27, 2015
NCT02058706 Active, not recruiting Barbara Ann Karmanos Cancer Institute February 10, 2014
NCT02485691 Recruiting Sanofi June 30, 2015
NCT02286921 Active, not recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins November 10, 2014
NCT02975934 Recruiting Clovis Oncology, Inc. November 29, 2016
NCT01949337 Active, not recruiting Alliance for Clinical Trials in Oncology September 24, 2013
NCT03569280 Recruiting Kangpu Biopharmaceuticals, Ltd. June 26, 2018
NCT02991911 Recruiting MedImmune LLC December 14, 2016
NCT02278185 Recruiting University of Colorado, Denver October 29, 2014
NCT02922218 Recruiting Centro Nacional de Investigaciones Oncologicas CARLOS III October 4, 2016
NCT02023463 Active, not recruiting Sidney Kimmel Cancer Center at Thomas Jefferson University December 30, 2013
NCT02268175 Active, not recruiting Dana-Farber Cancer Institute October 20, 2014
NCT03016312 Active, not recruiting Hoffmann-La Roche January 10, 2017
NCT01927627 Active, not recruiting Case Comprehensive Cancer Center August 22, 2013
NCT02522715 Recruiting OHSU Knight Cancer Institute August 13, 2015
NCT03709550 Not yet recruiting Roswell Park Cancer Institute October 17, 2018
NCT02228265 Active, not recruiting OHSU Knight Cancer Institute August 29, 2014
NCT02430480 Recruiting National Cancer Institute (NCI) April 30, 2015
NCT02215096 Recruiting GlaxoSmithKline August 13, 2014
NCT02429193 Active, not recruiting University Health Network, Toronto April 29, 2015
NCT02508636 Active, not recruiting Hao Nguyen July 27, 2015
NCT02669771 Active, not recruiting Astellas Pharma Inc February 1, 2016
NCT03314324 Recruiting Gustave Roussy, Cancer Campus, Grand Paris October 19, 2017
NCT02685397 Recruiting Sir Mortimer B. Davis - Jewish General Hospital February 18, 2016
NCT03295565 Recruiting The Netherlands Cancer Institute September 28, 2017
NCT02471469 Active, not recruiting Radboud University June 15, 2015
NCT03305224 Recruiting Taro Iguchi, MD, PHD October 9, 2017
NCT03644303 Not yet recruiting Royal Marsden NHS Foundation Trust August 23, 2018
NCT03002220 Recruiting MedSIR December 23, 2016
NCT03016741 Recruiting Northwestern University January 11, 2017
NCT02787005 Active, not recruiting Merck Sharp & Dohme Corp. June 1, 2016
NCT03148795 Recruiting Pfizer May 11, 2017
NCT02669147 Enrolling by invitation Translational Research Center for Medical Innovation, Kobe, Hyogo, Japan January 29, 2016
NCT03150056 Recruiting GlaxoSmithKline May 11, 2017
NCT01990196 Recruiting Jonsson Comprehensive Cancer Center November 21, 2013
NCT02312557 Active, not recruiting OHSU Knight Cancer Institute December 9, 2014
NCT02861573 Recruiting Merck Sharp & Dohme Corp. August 10, 2016
NCT02099864 Active, not recruiting OHSU Knight Cancer Institute March 31, 2014
NCT03275857 Recruiting University of Rochester September 8, 2017
NCT02203695 Recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins July 30, 2014
NCT02525068 Recruiting Institute of Cancer Research, United Kingdom August 17, 2015
NCT03395197 Recruiting Pfizer January 10, 2018
NCT03432949 Recruiting University Health Network, Toronto February 14, 2018
NCT03419442 Not yet recruiting Bayer February 2, 2018
NCT03556904 Recruiting University of Michigan Cancer Center June 14, 2018
NCT02403505 Active, not recruiting Han Xu, M.D., Ph.D., Sponsor-Investigator, IRB Chair March 31, 2015
NCT03554317 Recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins June 13, 2018
NCT02269982 Active, not recruiting Duke University October 21, 2014
NCT02853097 Recruiting University of Southern California August 2, 2016
NCT03568656 Recruiting CellCentric Ltd. June 25, 2018
NCT03725761 Recruiting University of Wisconsin, Madison October 31, 2018
NCT02903160 Recruiting Icahn School of Medicine at Mount Sinai September 16, 2016
NCT03236688 Recruiting Exosome Diagnostics, Inc. August 2, 2017
NCT02512185 Recruiting University Health Network, Toronto July 30, 2015
NCT02907372 Recruiting Centre Francois Baclesse September 20, 2016
NCT02856100 Recruiting Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins August 4, 2016
NCT03514836 Recruiting Sotio a.s. May 2, 2018
NCT03310541 Recruiting Memorial Sloan Kettering Cancer Center October 16, 2017
NCT02826772 Recruiting Suzhou Kintor Pharmaceutical Inc, July 11, 2016
NCT00268476 Recruiting Medical Research Council December 22, 2005
NCT03356912 Enrolling by invitation Consorzio Oncotech November 29, 2017
NCT03690141 Recruiting Effector Therapeutics October 1, 2018
NCT03526562 Recruiting University Hospital, Ghent May 16, 2018
NCT02432001 Recruiting University of California, San Francisco May 1, 2015
NCT02494921 Recruiting Rahul Aggarwal July 10, 2015
NCT02012920 Active, not recruiting Innocrin Pharmaceutical December 17, 2013
NCT02202447 Active, not recruiting Endocyte July 29, 2014
NCT03050866 Recruiting Erasmus Medical Center February 13, 2017
NCT03551782 Recruiting Janssen Research & Development, LLC June 11, 2018
NCT02008058 Active, not recruiting UNC Lineberger Comprehensive Cancer Center December 11, 2013
NCT02456571 Recruiting Duke University May 28, 2015
NCT02813226 Recruiting Ontario Clinical Oncology Group (OCOG) June 24, 2016
NCT03685591 Recruiting Pfizer September 26, 2018
NCT03075735 Active, not recruiting Centro Nacional de Investigaciones Oncologicas CARLOS III March 9, 2017
NCT02920229 Recruiting Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori September 30, 2016
NCT02398526 Active, not recruiting Bayer March 25, 2015
NCT02911467 Recruiting University of California, San Francisco September 22, 2016
NCT03170960 Recruiting Exelixis May 31, 2017

According to statistics, a total of 148 Abiraterone acetate projects targeting prostate cancer testosterone are currently in clinical stage, of which 77 are recruiting, 69 are not recruiting and 2 is Enrolling by invitation.

3.2 Prostate cancer therapy for NF-κB signaling pathway

Preclinical studies in prostate cancer xenografts have firmly established that blockade of receptor activator of NF-κB (RANK) signal instigated by binding of RANK ligands (RANK-L) impairs the establishment and progression of bone metastasis. Denosumab, a fully human monoclonal antibody, binds to RANK-L and directly inhibits osteoclasts to abrogate bone reabsorption. BMS-345541 selectively inhibits the catalytic subunit of IKK and can suppress tumor growth. The small molecule inhibitor, bindarit, an indazolic derivative, which may down-regulate NF-κB through reduced phosphorylation of IκBα and p65. The NF-κB specific inhibitor DHMEQ, prevents the nuclear translocation of the transcription factor, and has been shown to have anti-cancer effects in numerous different cancer subtypes. Amlexanox effectively represses PCa cell migration and tumor metastasis in vitro and in vivo by inhibition of the NF-κB signal pathway through specifically targeting IKKɛ and TBK1.

Table 5 Clinical trials of RANK-L mAb Ketoconazole

Nct id Status Lead sponsor Study first posted
NCT02051218 Recruiting Swiss Group for Clinical Cancer Research January 31, 2014
NCT02274623 Active, not recruiting OPKO Ireland Global Holdings Ltd. October 24, 2014
NCT02721433 Active, not recruiting Ottawa Hospital Research Institute March 29, 2016
NCT02398526 Active, not recruiting Bayer March 25, 2015

3.3 Prostate cancer therapy for RTK signaling pathway

Several inhibitors of RTK signaling are also being actively investigated either as single agents or in combination for PCa treatment and therapy. Many drugs that inhibit VEGF signaling have been tested in prostate cancer. The most well-known is bevacizumab, a humanized monoclonal antibody to VEGF. There are other monoclonal antibodies and small molecule inhibitors that target VEGF signaling, including aflibercept, sunitinib, sorafenib and cediranib (AZD2171). The c-Met receptor tyrosine kinase has received considerable attention as a potential therapeutic target for many solid tumors, including prostate cancer. Rilotumumab, cabozantinib (XL184), tivantinib (ARQ197) are promising c-Met inhibitors or monoclonal antibodies in clinical development for the treatment of prostate cancer. Studies of the mTOR inhibitors rapamycin, everolimus, and temsirolimus as single agents and in combination with the androgen receptor antagonist bicalutamide are in progress. Monoclonal antibodies specific to the IGF-1R and small molecules that aim to inhibit its tyrosine kinase activity have been developed, such as cixutumumab (IMC-A12) and linsitinib (fOSI-906). In prostate cancer, Src appears to be involved in the transition to the castration-resistant phenotype. Dasatinib and saracatinib, the Src inhibitors, suppress growth of prostate cancer in cell lines.

Table 6 Clinical trials of VEGF mAb Bevacizumab

Nct id Status Lead sponsor Study first posted
NCT00942331 Active, not recruiting National Cancer Institute (NCI) July 20, 2009

Table 7 Clinical trials of VEGFR inhibitor Sunitinib

Nct id Status Lead sponsor Study first posted
NCT00329043 Active, not recruiting M.D. Anderson Cancer Center May 24, 2006
NCT01254864 Active, not recruiting M.D. Anderson Cancer Center December 7, 2010
NCT02616185 Recruiting Pfizer November 26, 2015
NCT02044354 Active, not recruiting Gustave Roussy, Cancer Campus, Grand Paris January 24, 2014
NCT01858441 Active, not recruiting Centre Antoine Lacassagne May 21, 2013
NCT02465060 Recruiting National Cancer Institute (NCI) June 8, 2015

Table 8 Clinical trials of VEGFR inhibitor Cediranib

Nct id Status Lead sponsor Study first posted
NCT02893917 Recruiting National Cancer Institute (NCI) September 9, 2016
NCT02484404 Recruiting National Cancer Institute (NCI) June 29, 2015

Table 9 Clinical trials of c-Met inhibitor Cabozantinib

Nct id Status Lead sponsor Study first posted
NCT01630590 Active, not recruiting M.D. Anderson Cancer Center June 28, 2012
NCT01574937 Active, not recruiting Dana-Farber Cancer Institute April 10, 2012
NCT01683994 Active, not recruiting National Cancer Institute (NCI) September 12, 2012
NCT01812668 Active, not recruiting Barbara Ann Karmanos Cancer Institute March 18, 2013
NCT01599793 Active, not recruiting University of Chicago May 16, 2012
NCT01588821 Active, not recruiting Massachusetts General Hospital May 1, 2012
NCT03170960 Recruiting Exelixis May 31, 2017

Table 10 Clinical trials of mTOR inhibitor Rapamycin

Nct id Status Lead sponsor Study first posted
NCT02125084 Active, not recruiting SCRI Development Innovations, LLC April 29, 2014
NCT00976755 Active, not recruiting Swiss Group for Clinical Cancer Research September 14, 2009
NCT03618355 Recruiting Rapamycin Holdings Inc. August 7, 2018
NCT02106507 Active, not recruiting Memorial Sloan Kettering Cancer Center April 8, 2014
NCT03580239 Not yet recruiting Tianjin Medical University Second Hospital July 9, 2018
NCT02565901 Recruiting University of Washington October 1, 2015
NCT02407054 Active, not recruiting Eli Lilly and Company April 2, 2015
NCT02646319 Active, not recruiting Mayo Clinic January 5, 2016
NCT02913131 Recruiting Rahul Aggarwal September 23, 2016

Table 11 Clinical trials of mTOR inhibitor Everolimus

Nct id Status Lead sponsor Study first posted
NCT02125084 Active, not recruiting SCRI Development Innovations, LLC April 29, 2014
NCT00976755 Active, not recruiting Swiss Group for Clinical Cancer Research September 14, 2009
NCT03580239 Not yet recruiting Tianjin Medical University Second Hospital July 9, 2018
NCT02106507 Active, not recruiting Memorial Sloan Kettering Cancer Center April 8, 2014
NCT03618355 Recruiting Rapamycin Holdings Inc. August 7, 2018
NCT02565901 Recruiting University of Washington October 1, 2015
NCT02407054 Active, not recruiting Eli Lilly and Company April 2, 2015
NCT02646319 Active, not recruiting Mayo Clinic January 5, 2016
NCT02913131 Recruiting Rahul Aggarwal September 23, 2016

Table 12 Clinical trials of mTOR inhibitor Temsirolimus

Nct id Status Lead sponsor Study first posted
NCT02125084 Active, not recruiting SCRI Development Innovations, LLC April 29, 2014
NCT00976755 Active, not recruiting Swiss Group for Clinical Cancer Research September 14, 2009
NCT02106507 Active, not recruiting Memorial Sloan Kettering Cancer Center April 8, 2014
NCT03580239 Not yet recruiting Tianjin Medical University Second Hospital July 9, 2018
NCT03618355 Recruiting Rapamycin Holdings Inc. August 7, 2018
NCT02407054 Active, not recruiting Eli Lilly and Company April 2, 2015
NCT02565901 Recruiting University of Washington October 1, 2015
NCT02646319 Active, not recruiting Mayo Clinic January 5, 2016
NCT02913131 Recruiting Rahul Aggarwal September 23, 2016

Table 13 Clinical trials of Src inhibitor Dasatinib

Nct id Status Lead sponsor Study first posted
NCT01685125 Active, not recruiting University of Southern California September 13, 2012
NCT01990196 Recruiting Jonsson Comprehensive Cancer Center November 21, 2013
NCT01254864 Active, not recruiting M.D. Anderson Cancer Center December 7, 2010
NCT02465060 Recruiting National Cancer Institute (NCI) June 8, 2015

3.4 Prostate cancer therapy for JAK/STAT signaling pathway

The evidence that the JAK/STAT pathway is activated in a large proportion of solid tumors and that its activation contributes to the malignant properties of cancer cells makes the JAK/STAT pathway a promising target for the development of new therapies. The JAK1/2 inhibitor ruxolitinib improves symptoms and prolongs survival. Blockade of activated STAT3, by either siltuximab (CNTO 328) or LLL12, a specific pSTAT3 inhibitor, suppresses the clonogenicity of the stem-like cells in patients with high-grade disease.

Table 14 Clinical trials of JAK1/2 inhibitor Ruxolitinib

Nct id Status Lead sponsor Study first posted
NCT03274778 Recruiting Oncology Institute of Southern Switzerland September 7, 2017
NCT02711137 Active, not recruiting Incyte Corporation March 17, 2016

3.5 Prostate cancer therapy for Wnt signaling pathway

Activation of the Wnt pathway also contributes to the tumorigenicity of cancer stem cells (CSCs). Therefore, inhibiting this pathway has been a recent focus for cancer research with multiple targetable candidates in development. OMP-54F28 acts as a decoy receptor by sequestering WNT ligands and selectively reduces cancer stem cells. IWR-1, an inhibitor of tankyrase, can stabilize Axin leading to enhancement of β-catenin destruction. 3289-8625 has a binding affinity to DVL and it may be useful for blocking the Wnt signaling pathway at the Fz-Dvl interaction point.

Reference

  1. Ramalingam, S.; et al. Dissecting major signaling pathways in prostate cancer development and progression: Mechanisms and novel therapeutic targets. J Steroid Biochem Mol Biol. 2017 Feb; 166: 16-27.
  2. da Silva, HB.; et al. Dissecting Major Signaling Pathways throughout the Development of Prostate Cancer. Prostate Cancer. 2013; 2013: 920612.
  3. Tricoli, JV.; et al. Detection of Prostate Cancer and Predicting Progression: Current and Future Diagnostic Markers. Clin Cancer Res. 2004 Jun 15; 10: 3943-53.
  4. Prensner, JR.; et al. Beyond PSA: the next generation of prostate cancer biomarkers. Sci Transl Med. 2012 Mar 28; 4(127): 127rv3.
  5. Van Neste, L.; et al. The epigenetic promise for prostate cancer diagnosis. The Prostate. 2012 Aug 1; 72(11): 1248-61.
  6. Le, PN.; et al. Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther. 2015 Feb; 146: 1-11.
  7. Wozney, JL.; Antonarakis, ES. Growth factor and signaling pathways and their relevance to prostate cancer therapeutics. Cancer Metastasis Rev. 2014 Sep; 33(2-3): 581-94.
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