Abstract B29: Targeting EZH2 and PI3K/mTOR for a novel combination therapeutic strategy in aggressive variant prostate cancer

Abstract

Abstract Androgen-deprivation therapy (ADT) is the current standard of care for metastatic prostate cancer; however, ADT fails to provide a durable response in 90% of patients due to acquired resistance and progression to castration-resistance prostate cancer. Aggressive-variant prostate cancer (AVPC) is a lethal phenotype that arises upon treatment with ADT, resulting in a lineage switch to a neuroendocrine morphology and the acquisition of molecular alterations that enable the cells to survive independent of AR signaling. Our work, and the work of others, has established that combinatorial loss/mutation of tumor suppressor genes—PTEN, TP53 and RB1—drive lineage plasticity and therapeutic resistance to ADT. Further, epigenetic regulators, including EZH2, are indicated as driver effectors of lineage plasticity downstream of these key combinatorial genetic events. With the known activation PI3K/AKT/mTOR signaling due to PTEN loss and the data supporting epigenetic targeting of EZH2, it remains to be determined if co-inhibition of PI3K/AKT/mTOR and EZH2 will provide a significant response in AVPC patients. GEMMs and GEMM-derived 3D organoid models representing either prostate-specific PTEN and RB1 loss (PbCre4:Ptenfl/fl:Rb1fl/fl), or PTEN and P53 loss (PbCre4:Ptenfl/fl:p53fl/fl), were used to determine if inhibition of PI3K/AKT/mTOR and EZH2 provides lineage reversal and novel therapeutic directions to treat AVPC phenotypes. Tumor organoids were treated in vitro and in vivo with PI3K/AKT/mTOR and EZH2 inhibitors as 1) a monotherapy, 2) each in combination with ADT, and 3) both in combination with ADT. Tumors were interrogated in either androgen-sensitive or androgen-resistant conditions to identify if the combination-therapy approach is more beneficial to prevent progression to AVPC and ADT-resistance or to reverse the AVPC phenotype and restore hormone sensitivity. Quantitative determination of therapeutic response was carried out in vitro in 3D using fluorescent cytotoxicity and proliferation assays. In vivo, tumor response will be assessed by histologic analysis and RNA sequencing. Protein and mRNA expression was measured by qPCR, IHC and Western blot. Despite recent progress in the field, men with AVPC still face a terminal prognosis, and no current therapy provides durable response. The results of this research will help pave the way for early-phase clinical trials testing the efficacy of EZH2 inhibitors in combination with enzalutamide and/or PI3K/AKT/mTOR inhibitors. Citation Format: Katherine L. Morel, Christopher J. Sweeney, Leigh Ellis. Targeting EZH2 and PI3K/mTOR for a novel combination therapeutic strategy in aggressive variant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B29.