Abstract 3098: Epigenetic therapy to target neuroendocrine prostate cancer using precision medicine models
Authors: Puca Loredana , Karthaus Wouter R. , Gao Dong , Wongvipat John , Sboner Andrea , Gaudiano Marcello , Pauli Chantal , Rao Rema A. , Mosquera Juan Miguel , Cyrta Joanna , MacDonald Theresa Y. , Inghirami Giorgio Ga , Chen Yu , Rubin Mark A. , Beltran Himisha 
Published: July 2016

Background

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer that may either arise de novo or much more commonly after hormonal therapy for prostate adenocarcinoma. Patients diagnosed with NEPC are often treated with platinum chemotherapy able to produce only short duration responses underling the urgent need of identifying novel potential therapeutic targets for this lethal disease.

In the context of our Englander Institute for Precision Medicine we developed patient derived 3D NEPC tumor organoids and patient derived PDXs to test specific inhibitors on molecular targets identified by genomic analysis of native tumors. Emerging data from an integrative molecular analysis of metastatic tumors from a large cohort of castration resistant prostate cancer (CRPC) patients, including NEPC, points to a key role of the Polycomb gene EZH2 and the epigenome in the pathogenesis of NEPC.

Methods

Tumor organoids were developed according to protocols developed by our Englander Institute for Precision Medicine and other Institutes. Briefly the tissue biopsies (liver and bone biopsy) were washed, enzymatically digested and then seeded in a Matrigel (BD) droplet. Organoids were then characterized at both genomic (WES) and protein level (IHC) to confirm the expression of specific markers. Organoids were also subcutaneously injected in NSG mice to generate PDX for drug treatment in vivo.

Results

Based on the significant EZH2 overexpression in NEPC tumors by RNA-Seq and tissue microarray, we checked the expression of EZH2 and H3K273M, the readout of its activity, in NEPC organoids and we found out that both EZH2 and H3K273M were high expressed in NEPC organoids. Therefore we evaluated the effects of the EZH2 inhibitor, GSK343, in NEPC versus CRPC organoids and in the castration resistant line DU145 versus the NEPC cell line NCI-H660. We found out that GSK343 effectively inhibited H3K27me3 and resulted in a significant reduction of NEPC organoids and H660 viability while DU145 as well as CRPC organoids were insensitive to the drug. We extended our studies generating PDXs by subcutaneously injecting NEPC tumor organoids in NSG mouse. The tumor extracted from the PDXs showed a high proliferative phenotype with molecular features characteristic of NEPC as chromogranin A expression and no androgen receptor expression. NEPC PDXs were treated with the EZH2 inhibitor, GSK126, and we observed a significant reduction of tumor size along with the treatment suggesting that EZH2 is a potential therapeutic target for this highly aggressive disease.

Conclusions

In the Englander Institute for Precision Medicine we are generating NEPC patient tumor organoids and PDXs to unveil new targets to facilitate therapeutic decision at this late stage disease. Among the possible hits, EZH2 represents a promising drug target and a potential modulator of the NEPC phenotype.

Citation Format: Loredana Puca, Wouter R. Karthaus, Dong Gao, John Wongvipat, Andrea Sboner, Marcello Gaudiano, Chantal Pauli, Rema A. Rao, Juan Miguel Mosquera, Joanna Cyrta, Theresa Y. MacDonald, Giorgio Ga Inghirami, Yu Chen, Mark A. Rubin, Himisha Beltran. Epigenetic therapy to target neuroendocrine prostate cancer using precision medicine models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3098.