Current strategies for targeting the activity of androgen receptor variants

Current therapies for advanced prostate cancer,such as enzalutamide and abiraterone,focus on inhibiting androgen receptor(AR)activity and reducing downstream signaling pathways to inhibit tumor growth.Unfortunately,cancer cells are very adaptable and,over time,these cells develop mechanisms by which they can circumvent therapeutics.One of the many mechanisms that have been discovered is the generation of AR variants.These variants are generated through alternative splicing of the full length AR and often lack the ligand binding domain.This leads to forms of the AR that are constitutively active that continue to promote prostate cancer cell growth even in the absence of ligand.The high prevalence of AR variants and their role in disease progression have prompted a number of studies investigating ways to inhibited AR variant expression and activity.Among these are the antihelminthic drug,niclosamide,which selectively promotes degradation of AR variants over full length AR and re-sensitizes anti-androgen resistant prostate cancer cells to treatment with enzalutamide and abiraterone.Other AR variant targeting mechanisms include interfering with AR variant co-activators and the development of drugs that bind to the DNA or N-terminal AR domains,which are retained in most AR variants.The clinical efficacy of treating prostate cancer by targeting AR variants is under investigation in several clinical trials.In this review,we provide an overview of the most relevant AR variants and discuss current AR variant targeting strategies.

Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer

The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit androgen signaling such as enzalutamide and abiraterone.Unfortunately,it is estimated that up to 30%of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug.Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered.Androgen receptor(AR)mutations,expression of AR-V7(or other constitutively active androgen receptor variants),intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1,Member C3(AKR1C3)are among the many mechanisms associated with resistance to anti-androgens.In regards to the taxanes,one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1(ABCB1).Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies.For instance,targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment.ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel.A more thorough understanding of how drug resistance develops will lead to improved treatment strategies.This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.

Environmental sampling of volatile organic compounds during the 2018 Camp Fire in Northern California

Trace analysis of volatile organic compounds(VOCs) during wildfires is imperative for environmental and health risk assessment. The use of gas sampling devices mounted on unmanned aerial vehicles(UAVs) to chemically sample air during wildfires is of great interest because these devices move freely about their environment, allowing for more representative air samples and the ability to sample areas dangerous or unreachable by humans. This work presents chemical data from air samples obtained in Davis, CA during the most destructive wildfire in California's history-the 2018 Camp Fire – as well as the deployment of our sampling device during a controlled experimental fire while fixed to a UAV. The sampling mechanism was an in-house manufactured micro-gas preconcentrator(μPC) embedded onto a compact battery-operated sampler that was returned to the laboratory for chemical analysis. Compounds commonly observed in wildfires were detected during the Camp Fire using gas chromatography mass spectrometry(GC–MS), including BTEX(benzene, toluene, ethylbenzene, m + p-xylene, and o-xylene), benzaldehyde, 1,4-dichlorobenzene, naphthalene, 1,2,3-trimethylbenzene and 1-ethyl-3-methylbenzene. Concentrations of BTEX were calculated and we observed that benzene and toluene were highest with average concentrations of 4.7 and 15.1 μg/m^(3), respectively. Numerous fire-related compounds including BTEX and aldehydes such as octanal and nonanal were detected upon experimental fire ignition, even at a much smaller sampling time compared to samples taken during the Camp Fire. Analysis of the air samples taken both stationary during the Camp Fire and mobile during an experimental fire show the successful operation of our sampler in a fire environment.

In honor of Dr. Donald S. Coffey-Prostate cancer biology and therapy

This special issue of the Asian Journal of Urology(AJU)is dedicated to Donald S.Coffey,Ph.D.who passed away on Nov.9,2017.Dr.Coffey,professor at Johns Hopkins University,made monumental impacts on the advancement of urological research and the lives of people around him in and out of the urological research community.Dr.Coffey played an essential role in the Society for Basic Urologic Research(SBUR)as a devoted member and former president.We have collected 11 articles written by former students,trainees,fellows and colleagues of Dr.Coffey that cover a wide range of topics considered to be of prime interest to Dr.Coffey,which include the genetics,diagnosis,and treatment of advanced prostate cancer(PCa).

What controls PTEN and what it controls （in prostate cancer）

The standard of care for metastatic prostate cancer （PCa） is androgen deprivation therapy since almost all PCa growth is initially reliant on the androgen receptor （AR）. However, almost all patients develop resistance to this therapy within 18-24 months, and current treatment for castration-resistant prostate cancer （CRPC） is extremely limited, despite the advent of new drugs that target the AR,

Transcriptional-translational conflict: a novel exploitable tumor suppressive mechanism

In a recent publication in Cancer Cell,Jana et al.uncover a phenomenon they call‘transcriptional-translational conflict’(TTC)where deletion of the ARID1A tumor suppressor elevated proliferation-associated transcripts,but up to 70% of upregulated mRNAs displayed no corresponding change in protein levels.