Role of androgen receptor splice variants, their clinical relevance and treatment options.

PURPOSE: In this review, we summarize the importance of AR variants with a particular focus on clinically relevant members of this family. METHODS: A non-systematic literature review was performed based on Medline and PubMed. RESULTS: Endocrine therapy represents the central paradigm for the management of prostate cancer. Eventually, in response to androgen ablation therapy, several resistance mechanisms against the endocrine therapy might develop that can circumvent the therapy approaches. One specific resistance mechanism that has gained increasing attention is the generation of alternatively spliced variants of the androgen receptor, with AR-V7 being the most prominent. More broadly, AR-V7 is one member of a group of alternatively spliced AR variants that share a common feature, the missing ligand-binding domain. These ΔLBD androgen receptor variants have shown the capability to induce androgen receptor-mediated gene transcription even under conditions of androgen deprivation and to drive cancer progression. CONCLUSION: The methods used for detecting AR-Vs, at least on the mRNA level, are well-advanced and harbor the potential to be introduced into clinical diagnostics. It is important to note, that the testing, especially of AR-V7 has its limitations in predicting treatment response. More promising is the great number of active clinical trials aimed at reducing the AR-Vs, and using this to re-sensitize CRPC towards endocrine treatment might provide additional treatment options for CRPC patients in the future.

Targeting the N-Terminal Domain of the Androgen Receptor: A New Approach for the Treatment of Advanced Prostate Cancer.

: Despite the recent approval and widespread use of abiraterone acetate and enzalutamide for the treatment of castration-resistant prostate cancer (CRPC), this disease still poses significant management challenges because of various tumor escape mechanisms, including those that allow androgen receptor (AR) signaling to remain active. These AR-related resistance mechanisms include AR gene amplification or overexpression, constitutively active ligand-independent AR splice variants, and gain-of-function mutations involving the AR ligand-binding domain (LBD), among others. Therefore, the development of AR-targeted therapies that function independently of the LBD represents an unmet medical need and has the potential to overcome many of these resistance mechanisms. This article discusses N-terminal domain (NTD) inhibition as a novel concept in the field of AR-directed therapies for prostate cancer. AR NTD-targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR-mediated transcriptional activity, and as a result, may affect a broader AR population including mutational and splice variant ARs. Indeed, the first clinical trial of an AR NTD inhibitor is now underway. IMPLICATIONS FOR PRACTICE: Because of emerging resistance mechanisms that involve the ligand-binding domain of the androgen receptor (AR), there is currently no effective treatment addressing tumor escape mechanisms related to current AR-targeted therapies. Many patients still demonstrate limited clinical response to current hormonal agents, and castration-resistant prostate cancer remains a lethal disease. Intense research efforts are under way to develop therapies to target resistance mechanisms, including those directed at other parts of the AR molecule. A novel small-molecule agent, EPI-506, represents a new pharmaceutical class, AR N-terminal domain inhibitors, and shows preclinical promise to overcome many known resistance mechanisms related to novel hormonal therapies.

EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor.

Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Our results can contribute to the development of more potent and less toxic novel androgen receptor antagonists for treating this disease.

Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor.

Castration-recurrent prostate cancer (CRPC) is suspected to depend on androgen receptor (AR). The AF-1 region in the amino-terminal domain (NTD) of AR contains most, if not all, of the transcriptional activity. Here we identify EPI-001, a small molecule that blocked transactivation of the NTD and was specific for inhibition of AR without attenuating transcriptional activities of related steroid receptors. EPI-001 interacted with the AF-1 region, inhibited protein-protein interactions with AR, and reduced AR interaction with androgen-response elements on target genes. Importantly, EPI-001 blocked androgen-induced proliferation and caused cytoreduction of CRPC in xenografts dependent on AR for growth and survival without causing toxicity.

An evaluation of dextranomer as a cleansing agent in the treatment of the post-phlebitic stasis ulcer.

Recent reports in the literature have indicated that dextranomer (Debrisan; Adcock-Ingram) is an effective cleansing agent for the secreting wound. To evaluate its possible use in the initial cleansing of the infected secreting stasis ulcer, 100 patients were incorporated in a single-blind randomized trial. The mean cleansing time for the Debrisan-treated ulcers was 5,9 days, compared with 15,4 days for the control group receiving standard treatment. The average healing time for ulcers treated with Debrisan and left to heal spontaneously was 4,4 weeks compared with 5,32 weeks for the controls. Debrisan, furthermore, decreased the amount of local tissue oedema and alleviated local pain in the majority of patients. It is feasible to use Debrisan for outpatient treatment and without additional staff in a busy clinic. The cost of Debrisan therapy appeared to be reasonable. A hydrophilic cleansing agent such as Debrisan has a definite place in the early treatment of the secreting infected post-phlebitic stasis ulcer.

The effect of dextranomer (Debrisan) on hand burns. A preliminary report on a new method in the treatment of hand burns.

Dextranomer (Debrisan, Pharmacia, Uppsala, Sweden) is synthetized by cross-linking of dextran chains with epichlorohydrin. It is an insoluble hydrophilic substance which is suitable for topical treatment of secreting wounds, such as burns. Thirteen patients with 17 burned hands were treated. The result of the treatment - decrease in pain, healing time and improved hand function - was registered clinically. No crust was formed. The risk of permanent restriction in range of movements decreased, since the treated hands were soft and mobile throughout the entire period of treatment. All hands treated recovered full mobility. Physiotherapy could be performed daily. No infection appeared because exudate and bacteria were continuously removed from the treated area. Pain rapidly decreased. No side reactions were observed.