April 27th, 2015, Beijing, China

“A novel prostate cancer therapeutic strategy using icaritin activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants” is published on Carcinogenesis (Link: http://carcin.oxfordjournals.org/content/early/2015/04/21/carcin.bgv040.abstract?sid=8547563c-e40d-4393-9bad-f60322e9070c ). This study is completed by Prof. Eu-Leong Yong’s lab from Yong Loo Lin School of Medicine, National University of Singapore.

Prostate cancer is a hormonally fueled disease, and the most common form of cancer found in males. Consequently, there is a high incentive for drug development in this indication due to its large population size. While hormone-sensitive prostate cancer is well managed in terms of treatment options such as enzalutamide and abiraterone, unmet need persists for > 30% patients with prostate cancer that is no longer responsive to hormonal manipulation. Persistent androgen receptor (AR) signaling is the key factor driving progression and development of castration-resistant prostate cancer (CRPC). AR C-terminal truncated splice variants (ARvs) play a critical role in the resistance. AR-v7, the most abundant among ARvs, is becoming hot target for drug development. Arylhydrocarbon-receptor (AhR), a cytoplasmic transcription factor, is important in regulating auto-immunity and tumor immunity. It is demonstrated by preclinical studies and analyses of human tumor tissue that, the binding of the tryptophan (TRP) metabolite kynurenine (KYN) to AhR results in reprogramming the differentiation of na?ve CD4+ Th cells favoring Treg cells phenotype while suppressing the differentiation into IL17-producing Th17 cells.

Prof. Yong’s lab finds that icaritin, a natural prenylflavonoid, can co-target both persistent AR and ARvs (mainly AR-v7). Icaritin promotes ubiquitin-proteasomal degradation of both AR and AR-v7 by binding to arylhydrocarbon-receptor (AhR). In androgen-sensitive and castration-resistant prostate cancer murine models, icaritin showed inhibiting activity in AR signaling and tumor growth without apparent toxicity. This study indicates that icaritin may be a novel lead compound for AR-positive prostate cancer therapeutics.

Icaritin is being investigated as a Class 1 TCM/Natural Medicine sponsored by Shenogen Pharma Group. Shenogen possesses robust intellectual property rights around icaritin and got supported from National “Twelfth Five-year Plan” Special Project for “Significant New Drug Development”. Shenogen is funded by top class VCs including IDG, Qiming and Legend Capital. Icaritin treatment in advanced HCC Ph II clinical trial is completing. There’re some positive signals in MOA and biomarker exploratory studies. Shenogen plans to file icaritin as a breakthrough therapy for NDA in June 2015.

ABSTRACT

Persistent androgen receptor (AR) signaling is the key driving force behind progression and development of castration-resistant prostate cancer (CRPC). In many patients, AR COOH-terminal truncated splice variants (ARvs) play a critical role in contributing to the resistance against androgen depletion therapy. Unfortunately, clinically used antiandrogens like bicalutamide and enzalutamide, which target the ligand binding domain, have failed to suppress these AR variants. Here, we report for the first time that a natural prenylflavonoid, icaritin, can co-target both persistent AR and ARvs. Icaritin was found to inhibit transcription of key AR regulated genes, such as KLK3 (PSA) and ARvs regulated genes, such as UBE2C and induce apoptosis in AR-positive prostate cancer cells. Mechanistically, icaritin promoted the degradation of both AR and ARvs by binding to arylhydrocarbon-receptor (AhR) to mediate ubiquitin-proteasomal degradation. Therefore, icaritin impaired AR transactivation in prostate cancer cells. Knockdown of AhR gene restored AR stability and partially prevented icaritin-induced growth suppression. In clinically relevant murine models orthotopically implanted with androgen-sensitive and castration-resistant prostate cancer cells, icaritin was able to target AR and ARvs, to inhibit AR signaling, and tumor growth with no apparent toxicity. Our results provide a mechanistic framework for the development of icaritin, as a novel lead compound for AR-positive prostate cancer therapeutics, especially for those bearing AR splice variants.

About Shenogen

Shenogen Pharma Group is a drug discovery and development company based in Beijing, China, that dedicated the development of first-in-class therapeutics for cancer treatment. We possess robust intellectual property rights around a novel membrane-bound estrogen receptor, ER-alpha 36, which is related to tumor metastasis. Under the motto of “Better Medicine, Better Life” and a seasoned management team, together with our partners, Shenogen has developed an impressive product pipeline. Our pipeline consists of novel small molecule and antibody therapeutics for cancer treatment which includes liver cancer, breast cancer, other solid tumors and leukemia. Our lead molecule, icaritin, is currently in Ph II clinical trial for treatment of advanced hepatocellular carcinoma.