SUO 2018: Adaptive Survival Pathways – AR Variants and Autophagy

Phoenix, Arizona ( Christopher Evans discussed co-targeting Adaptive Survival Pathways in mCRPC, with a specific focus on AR variants and autophagy. The basis of this lies in the wealth of opportunities that come with targeting the AR axis – it still remains the predominant target for prostate cancer management. Yet, with more research, we are learning more about concurrent pathways that affect the AR axis that can be targeted for therapeutic purposes.
In this talk, he highlights 5 bench-to-bedside examples of co-targeting, and in doing so, highlights the work going on in the field and in his own lab. The pathways he looks at are:

1. Intracrine androgen biosynthesis
2. AR-V7 splice variants via:
     a.Post-transcriptional protein degradation
     b. Expression via other nuclear receptors
     c. Expression via proteostasis pathways
3. AR pathway via suppression of stress-induced autophagy cell survival pathways

Intracrine androgen biosynthesis

Local androgen production within the tumor itself via a backdoor pathway enables some resistance to current AR-targeted therapies. Liu et al. (Cancer Research 2015) demonstrated that AKR1C3 activation conferred resistance to enzalutamide by allowing local androgen production. In the course of his lab's work, Drs. Evans and Gao identified indomethacin, a commonly used gout medication, as an inhibitor of this pathway. In that same paper, they found in vitro and in vivo that use of indomethacin significantly inhibited prostate cancer growth in enzalutamide-resistance tumors – but in conjunction with enzalutamide, enabled a synergistic response. Liu et al (Mol Cancer Therapy 2016) found the same in abiraterone resistant prostate cancer as well. Based on this, UC Davis has initiated a phase 1/2 trial of indomethacin and enzalutamide to treat CRPC in patients who have failed abiraterone therapy. Schema below:

SUO 2018 schema phase II stage

AR-V7 splice variants

AR splice variants are modifications of the Androgen receptor in which one or more of the eight exons is removed. There are numerous variants, and most of them involve loss of the ligand binding domain of the AR – leading to constitutively active AR. The most commonly identified variant and best researched is AR V7. Its expression has been associated with enzalutamide and abiraterone resistance in the well-publicized Antonarakis et al (NEJM 2014) study.

a. Post-transcriptional protein degradation
In this setting, the same group (Lie et al Clin Cancer Research) identified on a drug screen an older anti-helminthic drug niclosamide as a potent inhibitor of AR variant expression – and it does so via a proteasome-dependent pathway. It leads to AR degradation. In vitro and in vivo, they found that niclosamide inhibited tumor growth in enza-resistant tumors, but was superior when used with enzalutamide – niclosamide degraded ARV7, which allowed enzalutamide to resume its effect on full-length AR. In a phase 1b/2 trial, the authors are exploring the use of niclosamide with abiraterone in men with mCRPC. Schema is below:

SUO 2018 schema phase II stage figure 2

b. Expression via proteostasis pathways
In a very recent publication (Liu et al Nature Communications 2018), the same group identified that proteostasis by the STUB1/HSP70 complex controls sensitivity to AR-targeted therapy in advanced prostate cancer. These are cofactors to AR. They identified 2 small molecules (apo and ver) that inhibit this complex and lead to significant tumor reduction when given in conjunction with abiraterone or enzalutamide. Naturally, they will hope to take this to a clinical trial in the near future.

c. Expression via other nuclear receptors
Nuclear receptors, of which AR is one, are attractive targets. The RORs (retinoic acid receptor-related orphan receptors), and in particular, the ROR-gamma receptor was found to be overexpressed in CRPC in a few older papers and validated by this group in a more recent study (Wang J Nat Medicine 2016). Based on a small molecule screen, they were able to identified inhibitors of ROR-gamma and demonstrate significant tumor reduction in multiple advanced prostate cancer cell lines. Importantly, they identified in the same study the mechanism of action of ROR-gamma – it is to AR what AR is to PSA! By inhibiting ROR-gamma, you can inhibit AR expression.

Autophagy (AR pathway via suppression of stress-induced autophagy cell survival pathways)

Autophagy is a stress-induced process by which tumor cells can evade the therapeutic effect of different cancer treatment. By inhibiting autophagy, the tumor cells lose the ability to recover from these treatments. Therefore, by co-targeting these pathways, our traditional therapies can be enhanced. Dr. Hao Nguyen, a former UC Davis resident, and current UCSF Assistant Professor, helped establish that targeting autophagy helped overcome enzalutamide resistance in CRPC cells and improved enza response in vivo and in vitro (Nguyen HG et al Oncogene 2014). Since then, multiple agents have been identified as inhibitors of autophagy, including those with other medical uses – including metformin!

Based on this, there is a current phase 1 trial ongoing looking at concurrent metformin use with Androgen-receptor axis targeted therapies (enzalutamide).

This was a talk about the potentials for co-targeting to help enhance the treatments we currently have. In many cases, drugs that have already been developed and tested are repurposed for cancer therapeutic use. There is an amazing amount of potential here!

Presented by: Christopher P. Evans, MD, FACS, President of the Society of Urologic Oncology, chairman of the Department of Urologic Surgery at University of California, Davis School of Medicine, Sacramento, California

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, Philadelphia, Pennsylvania, @tchandra_uromd, @TjuUrology, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona