Epigenetic influence on cell plasticity in HSPC by EZH2 inhibition

• Applicant: Dr. Christopher David Hirtsiefer
• Subject Area: Reproductive Medicine, Urology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552317552

Hormonal therapies are vital in metastasized hormone-sensitive and castration-resistant prostate cancer (PCa). Androgen deprivation (ADT) leads to castration resistance by intratumoral androgen production and increased androgen receptor (AR) expression. Therapy is escalated to AR inhibitors (ARPi), whose prolonged use induces resistance, aggressive variants, and neuroendocrine trans-differentiation (tNEPC) of PCa. Genomic inactivation of RB1/TP53 correlates with tNEPC. Epigenetic and molecular pathways under ARPi remain poorly understood, though methylation and upregulation of EZH2 are linked to therapy resistance and lineage plasticity. EZH2-inhibition (EZH2i) was recently shown to reverse ARPI-induced plasticity to a luminal state in vitro. PCa cell growth slowed when enzalutamide (ENZ) was combined with EZH2i. To foster epigenetic understanding and improve pathological complete remission (pCR) in the neoadjuvant setting of castrate-naïve, high-risk PCa, the Vancouver Prostate Center (VPC) designed an adaptive multi-stage, multi-arm trial, named Genomic Umbrella Neoadjuvant Study (GUNS, NCT04812366). With GUNS incorporating VPC’s experience, we will extend analysis to deep pathological processing with multiomic sequencing and correlation of pCR with plasticity pathways (Aim 1). Biopsy- and prostatectomy-tissue will be used to define plasticity pathways in genomically-segmented PCa and to nominate new therapeutic strategies. Patients will receive 8 weeks of LHRH-Antagonist (LHRHa) + apalutamide (APA) and will be assigned to one of 4 sub-protocols (SP) for another 16 weeks after genomic sequencing before undergoing prostatectomy: SP-1 (no target): LHRHa/APA +/- 2nd ARPi abiraterone SP-2 (aggressive genotype): LHRHa/ABI +/-Chemo 6 cycles docetaxel SP-3 (DNA repair deficiency): LHRHa/ABI +/- PARP-Inhibitor (PARPi) niraparib SP-4 (mismatch repair deficiencies): LHRHa/APA +/- PDL-1 inhibitor atezolizumab. We anticipate that a) induction of plasticity will correlate with altered TP53/RB1 and low pCR, b) preexisting genomic alterations to be determinants of pCR with ARPi inducing plasticity pathways to a greater extent in SP-2 c) SP3/4 also show emergence of plasticity. A series of patient derived PCa-xenografts (PDX), matched with GUNS subgroups will be established for testing EZH2i tazemostat. We will analyze efficacy of influencing plasticity epigenetically and exploit results for subgroup selection (Aim 2). We will evaluate ENZ +/-EZH2i, and ENZ + PARPi +/- EZH2i in PDX models available in VPCs experienced and well-equipped PDX lab. PDXs will reflect the 3 predominant subgroups SP1 (LuCaP23, 49, 78), SP2 (LuCaP96; LTL331, 648) and SP3 (LuCaP70, 136, 208.1). We expect a) EZH2 and plasticity pathways to be activated to a greater extent in SP2 b) Tazemetostat to block adaptive responses to ARPi and to delay time to plasticity emergence and recurrence in AR- tNEPC (LTL331). The success of tazemostat in PDX could trigger its human application.

• DFG Programme: WBP Fellowship
• International Connection: Canada
• Host: Professor Dr. Martin Gleave