“Icaritin suppresses development of neuroendocrine differentiation of prostate cancer through inhibition of IL-6/STAT3 and Aurora kinase A pathways in TRAMP mice” is published on Carcinogenesis (Link: http://carcin.oxfordjournals.org/content/early/2016/04/19/carcin.bgw044.short?rss=1 ). 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. Androgen-deprivation therapy is a mainstay of treatment for prostate cancer. But it almost inevitably leads to castrate resistant. One theory supports that anti-androgen therapy results in neuroendocrine differentiation (NED) of indolent adenocaricinoma cells. These cells are refractory to not only anti-antigen but also conventional chemotherapy. Moreover, they secrete a large numbers of chemokines, cytokines (such as IL-6) and growth factors, and overexpress proto-oncogene like Aurora kinase A, all of which eventually drive the development of neuroendocrine prostate cancer (NEPC). NEPC has a poor prognosis, with a median survival of less than one year.

Prof. Yong’s team finds that, icaritin, a natural prenylflavonoid, suppresses NED in IL-6-induced LNCaP cells and TRAMP (TRansgenic Adenocarcinoma of Mouse Prostate) model. In previous studies, the same team observed icaritin suppression of androgen receptor (AR)-positive prostate cancer cell proliferation through degradation of AR and its splice variants. Icaritin was also reported to inhibit the growth of multiple myeloma, heparocellular carcinoma through regulation of IL-6/Stat3 pathway. In this study, icaritin induces apoptosis in prostate tumor, suppresses NEPC development, and accordingly improves overall survival in TRAMP mice. From the molecular mechanistic level, icaritin inhibits expression of neuroendocrine markers (synaptophysin) and androgen receptor, as well as abnormally elevated IL-6/STAT3 and Aurora kinase A in vitro and in vivo. Furthermore, icaritin demonstrated favorable pharmacokinetic and safety profiles with marked enrichment in prostate tissues, which shows a positive signal of being a therapeutic agent against NEPC.

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. Shenogen has completed icaritin Phase II clinical trial of late-stage HCC treatment and submitted NDA application to CFDA for conditional approval. 

Abstract:

Neuroendocrine prostate cancer (NEPC) has a poor prognosis, with a median survival of less than 1 year after diagnosis. Following androgen deprivation therapy, prostate adenocarcinoma cells have been observed to develop an androgen-receptor negative, terminally differentiated, and indolent neuroendocrine-like phenotype. However several molecular events, including interleukin 6 (IL-6) stimulation, in the prostate microenvironment result in the appearance of aggressive, highly proliferative castrate-resistant NEPC. In this study, we examined the mechanistic effects of a natural prenylflavonoid, icaritin (ICT), on neuroendocrine differentiation in IL-6-induced LNCaP cells, and NEPC development in the male transgenic adenocarcinoma of the mouse prostate (TRAMP) model. TRAMP mice received daily intraperitoneal injection of ICT or vehicle. ICT induced apoptosis in prostate tumor, suppressed NEPC development, and accordingly improved overall survival in TRAMP mice. Expression of neuroendocrine markers (synaptophysin) and androgen receptor in TRAMP mice and neuroendocrine-like LNCaP cells were inhibited by ICT. Suppression of neuroendocrine and NEPC development by ICT was associated with dose-dependent inhibitory effects on abnormally elevated IL-6/STAT3 and Aurora kinase A in vitro and in vivo. Since ICT demonstrated favourable pharmacokinetic and safety profiles with marked enrichment in prostate tissues, our study provide evidence for the development this prenylflavonoid as a multi-modal therapeutic agent against NEPC.

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 completing Ph II clinical trial for treatment of advanced hepatocellular carcinoma.