Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Castration-resistant prostate cancer: potential targets and therapies.

ABSTRACT: The treatment landscape for patients with castration-resistant prostate cancer (CRPC) is undergoing significant changes with the advent of new therapies and multidisciplinary efforts by scientists and clinicians. As activation of multiple molecular pathways in the neoplastic prostate makes it impossible for single-target drugs to be completely effective in treating CRPC, this has led to combination therapy strategy, where several molecules involved in tumor growth and disease progression are targeted by a therapeutic regimen. In the present review, we provide an update on the molecular pathways that play an important role in the pathogenesis of CRPC and discuss the current wave of new treatments to combat this lethal disease.

SUBMITTER: Parray A

PROVIDER: S-EPMC3430091 | biostudies-other | 2012

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Publications

Castration-resistant prostate cancer: potential targets and therapies.

Parray Aijaz A Siddique Hifzur R HR Nanda Sanjeev S Konety Badrinath R BR Saleem Mohammad M

Biologics : targets & therapy 20120817

The treatment landscape for patients with castration-resistant prostate cancer (CRPC) is undergoing significant changes with the advent of new therapies and multidisciplinary efforts by scientists and clinicians. As activation of multiple molecular pathways in the neoplastic prostate makes it impossible for single-target drugs to be completely effective in treating CRPC, this has led to combination therapy strategy, where several molecules involved in tumor growth and disease progression are tar ...[more]

PMID: 22956858

Similar Datasets

Emerging targeted therapies for castration-resistant prostate cancer.

Project description:Until recently, few therapeutic options were available for patients with castration-resistant prostate cancer (CRPC). Since 2010, four new molecules with a demonstrated benefit (sipuleucel-T, cabazitaxel, abiraterone, and denosumab) have been approved in this setting, and to-date several other agents are under investigation in clinical trials. The purpose of this review is to present an update of targeted therapies for CRPC. Presented data are obtained from literature and congress reports updated until December 2011. Targeted therapies in advanced phases of clinical development include novel androgen signaling inhibitors, inhibitors of alternative signaling pathways, anti-angiogenic agents, inhibitors that target the bone microenvironment, and immunotherapeutic agents. Radium-223 and MDV3100 demonstrated a survival advantage in phase III trials and the road for their introduction in clinical practice is rapidly ongoing. Results are also awaited for phase III studies currently underway or planned with new drugs given as monotherapy (TAK-700, cabozantinib, tasquinimod, PROSTVAC-VF, ipilimumab) or in combination with docetaxel (custirsen, aflibercept, dasatinib, zibotentan). The optimal timing, combination, and sequencing of emerging therapies remain unknown and require further investigation. Additionally, the identification of novel markers of response and resistance to these therapies may better individualize treatment for patients with CRPC.

| S-EPMC3364443 | biostudies-literature

Castration-resistant prostate cancer: mechanisms, targets, and treatment.

Project description:Patients with castration-resistant prostate cancer (CRPC), who progress after docetaxel therapy, had until very recently, only a few therapeutic options. Recent advances in this field brought about new perspectives in the treatment of this disease. Molecular, basic, and translational research has given us a better understanding on the mechanisms of CRPC. This great investment has turned into a more rational approach to the development of new drugs. Some of the new treatments are already available to our patients outside clinical trials and may include inhibitors of androgen biosynthesis; new chemotherapy agents; bone-targeted therapy; and immunotherapy. This paper aims to review the mechanisms of prostate cancer resistance, possible therapeutic targets, as well as new options to treat CRPC.

| S-EPMC3316959 | biostudies-literature

Castration-resistant prostate cancer: targeted therapies and individualized treatment.

Project description:Various molecular mechanisms have been implicated in the progression from hormone-sensitive to castration-resistant prostate cancer (CRPC). Novel targeted agents to treat CRPC have been developed that inhibit either androgen receptor (AR)-mediated signaling (AR antagonists and inhibitors of androgen synthesis) or non-AR-mediated signaling (inhibitors of Src, mammalian target of rapamycin, chaperone proteins, insulin-like growth factor-1 receptor, vascular endothelial growth factor, and endothelin-A receptor) pathways. However, variable efficacy has been observed in clinical trials, most likely because of the biologic heterogeneity of CRPC. To account for potential differences in disease biology, a more individualized approach to treatment, based on genomic and/or proteomic analyses of individual tumors, is being investigated. By identifying tumors with a characteristic molecular subtype and assigning treatment accordingly, it is hoped that a higher proportion of patients will benefit from targeted therapy. Additionally, lessons learned through the application of these technologies to prostate cancer may subsequently influence therapeutic development in other solid tumors.

| S-EPMC3228103 | biostudies-literature

Recent progress in pharmaceutical therapies for castration-resistant prostate cancer.

Project description:Since 2010, six drugs have been approved for the treatment of castration-resistant prostate cancer, i.e., CYP17 inhibitor Abiraterone, androgen receptor antagonist Enzalutamide, cytotoxic agent Cabazitaxel, vaccine Sipuleucel-T, antibody Denosumab against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin. All these drugs demonstrate improvement on overall survival, expect for Denosumab, which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone-metastasis-free survival. Besides further CYP17 inhibitors (Orteronel, Galeterone, VT-464 and CFG920), androgen receptor antagonists (ARN-509, ODM-201, AZD-3514 and EZN-4176) and vaccine Prostvac, more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials, including various kinase inhibitors and platinum complexes. Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments. Under these flourishing circumstances, more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients.

| S-EPMC3742227 | biostudies-literature

MET and VEGF: synergistic targets in castration-resistant prostate cancer.

Project description:Recent advances in the treatment of prostate cancer have resulted in improved outcomes, including longer survival, but new options are needed for treating patients with castration-resistant disease, particularly in the presence of bone metastasis. Data from preclinical models and clinical biomarker studies indicate that antiangiogenic agents should be a promising treatment for this patient population, and multiple agents in this class have demonstrated activity in early-stage clinical trials. Pivotal trials in prostate cancer with agents targeting vascular endothelial growth factor (VEGF) signalling have resulted in significant improvements in tumour response and progression-free survival. However, overall survival was not significantly improved. Recent preclinical studies suggest that the limited impact on overall survival may result from the development of evasive resistance after inhibition of angiogenesis, possibly through upregulation of MET (hepatocyte growth factor receptor) signalling. MET plays important roles in angiogenesis, tumour cell invasion and bone metastasis, all of which are key factors in castration-resistant prostate cancer. Inhibition of both the MET and VEGF pathways may improve the efficacy of angiogenesis inhibitors in prostate cancer.

| S-EPMC4422050 | biostudies-literature

Current and emerging therapies for bone metastatic castration-resistant prostate cancer.

Project description:BackgroundA paucity of therapeutic options is available to treat men with metastatic castration-resistant prostate cancer (mCRPC). However, recent developments in our understanding of the disease have resulted in several new therapies that show promise in improving overall survival rates in this patient population.MethodsAgents approved for use in the United States and those undergoing clinical trials for the treatment of mCRPC are reviewed. Recent contributions to the understanding of prostate biology and bone metastasis are discussed as well as how the underlying mechanisms may represent opportunities for therapeutic intervention. New challenges to delivering effective mCRPC treatment will also be examined.ResultsNew and emerging treatments that target androgen synthesis and utilization or the microenvironment may improve overall survival rates for men diagnosed with mCRPC. Determining how factors derived from the primary tumor can promote the development of premetastatic niches and how prostate cancer cells parasitize niches in the bone microenvironment, thus remaining dormant and protected from systemic therapy, could yield new therapies to treat mCRPC. Challenges such as intratumoral heterogeneity and patient selection can potentially be circumvented via computational biology approaches.ConclusionsThe emergence of novel treatments for mCRPC, combined with improved patient stratification and optimized therapy sequencing, suggests that significant gains may be made in terms of overall survival rates for men diagnosed with this form of cancer.

| S-EPMC4673894 | biostudies-literature

Bone-targeted therapies in metastatic castration-resistant prostate cancer: evolving paradigms.

Project description:Majority of patients with metastatic castrate resistant prostate cancer (mCRPC) develop bone metastases which results in significant morbidity and mortality as a result of skeletal-related events (SREs). Several bone-targeted agents are either in clinical use or in development for prevention of SREs. Bisphosphonates were the first class of drugs investigated for prevention of SREs and zoledronic acid is the only bisphosphonate that is FDA-approved for this indication. Another bone-targeted agent is denosumab which is a fully humanized monoclonal antibody that binds to the RANK-L thereby inhibiting RANK-L mediated bone resorption. While several radiopharmaceuticals were approved for pain palliation in mCRPC including strontium and samarium, alpharadin is the first radiopharmaceutical to show significant overall survival benefit. Contemporary therapeutic options including enzalutamide and abiraterone have effects on pain palliation and SREs as well. Other novel bone-targeted agents are currently in development, including the receptor tyrosine kinase inhibitors cabozantinib and dasatinib. Emerging therapeutics in mCRPC has resulted in great strides in preventing one of the most significant sources of complications of bone metastases.

| S-EPMC3771418 | biostudies-literature

Resistance to Novel Antiandrogen Therapies in Metastatic Castration-Resistant Prostate Cancer.

Project description:Despite the introduction of novel therapies that maximally decrease androgen-receptor (AR) signaling activity, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease. Even though abiraterone and enzalutamide represent breakthroughs in the treatment of mCRPC and have demonstrated significant survival benefits, a significant proportion of patients have primary resistance to these agents and virtually all patients develop secondary resistance. While the mechanisms of resistance to these agents are not fully understood, many hypotheses of AR-dependent and AR-independent mechanisms are emerging, including upregulation of AR and cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), induction of AR splice variants, AR point mutations, upregulation of glucocorticoid receptor, activation of alternative oncogenic signaling pathways, neuroendocrine transformation, and immune evasion via programmed death-ligand 1 upregulation. The aim of this review is to summarize the most clinically relevant mechanisms of resistance to novel androgen-directed agents, focusing on escape from enzalutamide and abiraterone.

| S-EPMC4798019 | biostudies-literature

Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer.

Project description:Prostate cancer is a heterogeneous disease where the previous concept of "hormone resistance" has been changed by a new generation of hormonal therapies that have proven efficacy in the castration-resistant setting. The fact is that androgens play a crucial role in the whole clinical course of prostate cancer, even when a patient meets castration-resistance criteria. The development of abiraterone showed how important and clinically meaningful can be to achieve the lowest possible levels of testosterone, and androgen receptor overexpression, mutation, or enhanced crosstalk with other pathways, which can also be targeted with new agents tested in the last few years. New androgen biosynthesis inhibitors have been developed, such as orteronel (TAK-700), but also new antiandrogens (enzalutamide, ARN-509, ODM-201) or even agents with a dual mechanism of action (galeterone). In this review the development of new hormonal therapies following the arrival of abiraterone for the treatment of prostate cancer will be summarized.

| S-EPMC3928129 | biostudies-literature

Nonmetastatic castration-resistant prostate cancer.

Project description:After the introduction of prostate cancer screening with the prostate-specific antigen (PSA) test, we have witnessed a dramatic stage migration. As a result, an increasing number of patients are diagnosed at earlier stages and receive local treatments including surgery or radiation. When these local treatments fail by the definition of increasing PSA levels, patients are usually treated with androgen-deprivation therapy. A fraction of these patients will finally reach a state of castration-resistant prostate cancer (CRPC) even without radiological evidence of metastasis, which is referred to as nonmetastatic CRPC (NM-CRPC). Most men with advanced or metastatic prostate cancer initially respond to various types of androgen ablation, but a considerable portion of them eventually progress to NM-CRPC. Among patients with NM-CPRC, about one-third will develop bone metastasis within 2 years. In these patients, PSA kinetics is the most powerful indicator of progression and is usually used to trigger further imaging studies and enrollment in clinical trials. Although CRPC remains largely driven by the androgen receptor, the benefit of second-line hormonal manipulations, including first-generation antiandrogens, adrenal synthesis inhibitors, and steroids, has not been investigated in men with NM-CRPC. To date, denosumab is the only agent that has been shown to delay the onset of bone metastasis. However, overall survival did not differ. In treating NM-CRPC patients, physicians should recognize the heterogeneity of the disease and acknowledge that the recently approved second-line treatments have been studied only in advanced stages of the disease.

| S-EPMC3956942 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data