scholarly journals Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond

2019 ◽  
Vol 26 (1) ◽  
pp. R31-R52 ◽  
Author(s):  
Simon Linder ◽  
Henk G van der Poel ◽  
Andries M Bergman ◽  
Wilbert Zwart ◽  
Stefan Prekovic
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Advanced Prostate Cancer ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Treatment Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Optimal Sequence ◽  
Castration Resistant ◽  
Novel Drugs

The androgen receptor drives the growth of metastatic castration-resistant prostate cancer. This has led to the development of multiple novel drugs targeting this hormone-regulated transcription factor, such as enzalutamide – a potent androgen receptor antagonist. Despite the plethora of possible treatment options, the absolute survival benefit of each treatment separately is limited to a few months. Therefore, current research efforts are directed to determine the optimal sequence of therapies, discover novel drugs effective in metastatic castration-resistant prostate cancer and define patient subpopulations that ultimately benefit from these treatments. Molecular studies provide evidence on which pathways mediate treatment resistance and may lead to improved treatment for metastatic castration-resistant prostate cancer. This review provides, firstly a concise overview of the clinical development, use and effectiveness of enzalutamide in the treatment of advanced prostate cancer, secondly it describes translational research addressing enzalutamide response vs resistance and lastly highlights novel potential treatment strategies in the enzalutamide-resistant setting.

scholarly journals Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Yuan Liu ◽  
Cuifu Yu ◽  
Zhenlong Shao ◽  
Xiaohong Xia ◽  
Tumei Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Selective Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Selective Degradation ◽  
Castration Resistant ◽  
Novel Drugs ◽  
The Stability ◽  
Androgen Receptor Splice Variant

AbstractAndrogen receptor splice variant 7 (AR-V7), a form of ligand-independent and constitutively activating variant of androgen receptor (AR), is considered as the key driver to initiate castration-resistant prostate cancer (CRPC). Because AR-V7 lacks ligand-binding domain, the AR-targeted therapies that aim to inactivate AR signaling through disrupting the interaction between AR and androgen are limited in CRPC. Thus, the emergence of AR-V7 has become the greatest challenge for treating CRPC. Targeting protein degradation is a recently proposed novel avenue for cancer treatment. Our previous studies have been shown that the oncoprotein AR-V7 is a substrate of the proteasome. Identifying novel drugs that can trigger the degradation of AR-V7 is therefore critical to cure CRPC. Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells. Mechanically, we unravel that nobiletin selectively induces proteasomal degradation of AR-V7 (but not AR). This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.

Modern Management of Castration-resistant Prostate Cancer

2013 ◽  
Vol 09 (01) ◽  
pp. 34 ◽  
Author(s):  
Axel Heidenreich ◽  
David Pfister ◽  
Axel Merseburger ◽  
Georg Bartsch ◽  
◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Medical Treatment ◽  
Treatment Options ◽  
Treatment Strategies ◽  
New Drugs ◽  
Control Group ◽  
Daily Routine ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Radium 223

The approval or clinical evaluation of several new agents – cabazitaxel, enzalutamide, sipuleucel-T, radium-223 and abiraterone acetate – has significantly changed the management of patients with metastatic castration-resistant prostate cancer (mCRPC) prior to or after docetaxelbased chemotherapy. All of these agents have resulted in a significant survival benefit compared with their control group. However, treatment responses might differ depending on the associated comorbidities and the extent and the biological aggressiveness of the disease. Furthermore, treatment-associated side effects differ between the various drugs. As new drugs are approved, new treatment strategies and markers to best select which patients will best respond to which drug are needed. It is the aim of this article to (1) summarise the data of established treatment options in mCRPC, (2) highlight new developments of medical treatment, (3) provide clinically useful algorithms for the daily routine and to (4) point out future developments of medical treatment.

CASTRATION-RESISTANT PROSTATE CANCER: NEW PERSPECTIVES IN PHARMACOLOGICAL TREATMENT

2019 ◽  
Vol 25 (1) ◽  
pp. 49-58
Author(s):  
Dmitry A. Andreev ◽  
A. A Zavyalov ◽  
A. V Govorov ◽  
K. A. Kokushkin ◽  
M. Y Davidovskaya
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Treatment Options ◽  
Specific Treatment ◽  
Cochrane Library ◽  
Cancer Drug ◽  
Castration Resistant Prostate Cancer ◽  
Optimal Sequence ◽  
Treatment Algorithms ◽  
Castration Resistant

Prostate cancer remains one of the most actual problems in oncourology due to its high prevalence and resistance to therapy. Within 5 years of active treatment and follow-up, the castration-resistant prostate cancer (CRPC) develops in 10-20% of patients. This type of disease course resists treatments and leads to death. Medical resources distinguish two different forms of CRPC: non-metastatic and metastatic. Such separation is critically important because each of two forms requires different treatment algorithms. This paper summarizes the main outlines of foreign clinical guidelines and reviews the new treatment options for non-metastatic and metastatic CRPC as wells as the design and results of key clinical trials on drug efficiency. To prepare the review, the comprehensive literature search was conducted using PubMed/Medline, the Cochrane Library, EMBASE, CyberLeninka, e-library databases. The search line included phrases containing the following words: prostate cancer, castration-resistant prostate cancer, drug therapy, treatment algorithms, clinical studies, etc. In accordance to foreign guidelines, it is essential to determine the high risk patients with non-metastatic CRPC and promptly apply new therapeutic options including apalutamide and enzalutamide, which have proven being effective in clinical trials as therapies that attenuate the transition of the non-metastatic CRPC to the metastatic stage. Foreign medical guidelines propose to apply a wider set of treatment algorithms for patients with metastatic CRPC, for instance: considerations on possibilities to use the cabazitaxel instead of docetaxel in the 1st line therapy in patients with pre-existing mild peripheral neuropathy, etc. as well as new therapies - pembrolizumab and sipuleucel-T. The issues regarding the selection of patients with CRPC for specific treatment algorithms and defining the optimal sequence of therapeutic regimens as well as combining various regimens with minimizing toxic effects and maximizing patient benefits remain unsolved.

Therapy Management of Metastatic Prostate Carcinoma in General Practice

2019 ◽  
pp. 12-15
Author(s):  
Alexander Meisel
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Treatment Strategies ◽  
Castration Resistant Prostate Cancer ◽  
Continuous Therapy ◽  
Castration Resistant ◽  
Literature Overview ◽  
Metastatic Prostate Carcinoma ◽  
Insight Into ◽  
Systemic Therapies

ABSTRACT In general, advanced prostate cancer is initially treated with androgen deprivation therapy (ADT). Despite high response rates to this treatment, the response is not durable and most of the patients eventually develop metastatic castration-resistant prostate cancer (mCRPC). The treatment strategies for mCRPC usually include a combination of different approaches, such as hormone therapy, chemotherapy, or radiation. Here, we discuss the case of a 78-year old patient with advanced prostate cancer who developed mCRPC after 4 years of continuous therapy with ADT. The patient was subsequently treated with analgesic radiotherapy, followed by chemotherapy, including docetaxel and cabazitaxel. The patient responded well to the treatment, with acceptable treatment-related toxicity. Three years later, however, the disease progressed, and the patient received anti-hormonal therapy with enzalutamide. In conclusion, this case report discusses the different therapy selections and outcomes. Finally, a literature overview offers a comprehensive insight into the current systemic therapies for mCRPC.

scholarly journals Novel Strategies for Treating Castration-Resistant Prostate Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 339
Author(s):  
David Ka-Wai Leung ◽  
Peter Ka-Fung Chiu ◽  
Chi-Fai Ng ◽  
Jeremy Yuen-Chun Teoh
Keyword(s):  
Prostate Cancer ◽  
Metastatic Disease ◽  
Advanced Prostate Cancer ◽  
Imaging Techniques ◽  
Treatment Strategies ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Management Options ◽  
Castration Resistant

The development of castration resistance is an inevitable pathway for the vast majority of patients with advanced prostate cancer. Recently, there have been significant breakthroughs in the understanding and management options of castration-resistant prostate cancer. Three novel hormonal agents showed survival benefits in non-metastatic patients. As for metastatic disease, there was an even wider range of management options being investigated. This review summarized advances in the management of castration-resistant prostate cancer (CRPC) including emerging data on novel imaging techniques and treatment strategies.

scholarly journals Recent Developments in the Management of Advanced Prostate Cancer

2020 ◽  
Vol 18 (7.5) ◽  
pp. 969-972
Author(s):  
Sandy Srinivas
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Treatment Options ◽  
Parp Inhibitors ◽  
Cross Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Recent Developments ◽  
Emerging Treatments ◽  
Localized Disease

Numerous new options are available for the treatment of prostate cancer when it progresses beyond localized disease. Older drugs, first developed for treatment of metastatic castration-resistant prostate cancer (CRPC), are being used to treat nonmetastatic disease based on results of large randomized controlled trials. Sequencing of available treatment options is challenging for CRPC, but there is some guidance from trial data. Cross-resistance among newer hormonal drugs is a concern, and therefore switching to another class of drug is preferred. Emerging treatments on the horizon, such as PARP inhibitors in patients with BRCA2 mutations and lutetium-177 in those with prostate-specific membrane antigen (PSMA)–positive disease, may look promising to improve outcomes among those with advanced prostate cancer.

VAL 201 — An Inhibitor of Androgen Receptor-associated Src and a Potential Treatment of Castration-resistant Prostate Cancer

2012 ◽  
Vol 08 (01) ◽  
pp. 32
Author(s):  
Ferdinando Auricchio ◽  
Antimo Migliaccio ◽  
◽  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Receptor Tyrosine Kinase ◽  
Metastatic Prostate Cancer ◽  
Treatment Options ◽  
Androgen Deprivation ◽  
Castration Resistant Prostate Cancer ◽  
Signal Transduction Protein ◽  
Castration Resistant ◽  
The Us

Prostate cancer is the second leading cause of cancer death in men in the US. The initial treatment of metastatic prostate cancer is androgen deprivation (castration) therapy and this is achieved through either surgical or medical castration, however these therapies are also associated with undesirable side effects including impotence, tumour flare and loss of bone mass. Over time, nearly all patients with metastatic disease become resistant to androgen deprivation, progressing to castration-resistant prostate cancer (CRPC), and at this stage of the disease the prognosis is extremely poor (<50 % survival at two years). Currently there are few treatment options for CRPC. Only four have been found to extend survival and none are curative. Effective treatment of CRPC is a major unmet clinical need, and the identification of alternative therapeutic targets is an active focus of research. In this article we discuss the development of a new agent, Val 201 as a potential future treatment for CRPC. VAL 201 targets the association of androgen receptor with Src, a non-receptor tyrosine kinase signal-transduction protein that is important in tumour cell proliferation, and represents a novel and exciting approach for cancer chemotherapy.

scholarly journals Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Meixia Che ◽  
Aashi Chaturvedi ◽  
Sarah A. Munro ◽  
Samuel P. Pitzen ◽  
Alex Ling ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcription Factor ◽  
Stem Cell ◽  
Androgen Receptor ◽  
Advanced Prostate Cancer ◽  
Cellular Migration ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Prostate Cancers ◽  
Cell Phenotypes

AbstractEndocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity.

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