From the Desk of Evan Yu: “Polycomb Complex Enhancer of Zeste 2 (EZH2), A Regulator of Lineage Reprogramming and A New Drug Target.”

Prostate cancer is a disease that universally responds to androgen deprivation therapy (ADT), as it is driven by androgens and their interaction with androgen receptors (AR). However, over time, prostate cancer will become resistant to ADT, delineating the castration-resistant disease state. The field has adapted to address this problem with even more potent hormonal therapies to cope with adrenal and intracrine androgen production. Hence, agents like abiraterone acetate, enzalutamide and apalutamide have regulatory approval in various prostate cancer disease states. However, when the disease eventually becomes resistant to these agents, multiple other mechanisms are at play that drives resistance.

One of the mechanisms of resistance to novel hormonal therapies include a transformation away from the luminal phenotype, that is AR-signaling dependent and prostate-specific antigen (PSA)-producing and -expressing. This invokes lineage plasticity, resulting in prostate cancer cell acquisition of neuroendocrine and stem-like developmental programs and features.1 It is extremely rare to observe de novo neuroendocrine or small cell prostate cancer, and it occurs more commonly through treatment resistance. Initially felt to also be a rare occurrence, in the modern era, we are recognizing that 15-20% of metastatic castration-resistant prostate cancers evoke downregulation of AR expression and signaling and adopt alternative lineage pathways as an adaptive treatment mechanism.2, 3

Much of this plasticity of lineage occurs through alteration in epigenetic programs that include changes in DNA methylation and upregulation of the polycomb complex gene enhancer of zeste 2 (EZH2).4, 5 EZH2 is the catalytic subunit of the polycomb repressor complex 2 (PRC2). This activated complex repressed genes associated with apoptosis and differentiation and silences the luminal program while reprogramming lineage.6, 7 Activating point mutations, amplification and resultant overexpression of EZH2 have been observed in many different malignancies, such as melanoma, small cell lung cancer, esophageal cancer, and prostate cancer. Overexpression of EZH2 in metastatic castration-resistant prostate cancer, along with a decreased expression of target genes, has a correlation with disease stage and prognosis.8 Preclinical testing of EZH2 inhibitors have shown activity in AR-dependent prostate cancer cell models and synergistic inhibition of cell growth when combined with AR-targeted agents.5, 9

As a result, there are many novel agents in early phase 1/2 trials with EZH2 inhibitors. The ProSTAR study presented data, at the American Association of Cancer Research 2019 meeting, on CPI-1205, a small molecule inhibitor of EZH2.10 Metastatic castration-resistant prostate cancer patients, who were previously treated with either abiraterone acetate or enzalutamide, were treated in multiple dosing cohorts, resulting in some patients with PSA, RECIST 1.1 and/or circulating tumor cell reductions. It was determined that the recommended phase 2 dose would be CPI-1205 800 mg po TID in combination with either standard doses of abiraterone acetate or enzalutamide. As a result, a couple of clinical trials (not yet available on clinicaltrials.gov) are planned to evaluate CPI-1205 in a phase 2, single-arm combination with abiraterone acetate and prednisone and in a randomized trial in combination with enzalutamide. Below, are other ongoing trials that are actively accruing patients, including those with prostate cancer, to receive agents that either directly inhibits EZH2 or that affect other proteins that physically interact with EZH2.

As this field moves forward, the opinion of this investigator is that a greater focus should be made to identify a more enriched population of patients who have already demonstrated reprogramming of their original prostate cancer luminal lineage. Rather than targeting patients who have just progressed on either abiraterone acetate or enzalutamide, we need to study even more heavily pre-treated patients. We should perform metastatic and liquid tumor biopsies to evaluate for RB1 loss in cooperation with either p53 or pTEN alteration. Additionally, we should develop targeted studies for those patients who are identified histopathologically to already harbor neuroendocrine prostate cancer. It has also recently been shown that inhibition of EZH2 catalytic function promotes T-cell infiltration into tumors via induction of T Helper Type 1 (TH1)-type chemokine expression and antigen presentation pathways in tumors.11 This leads to the synergism of EZH2 inhibition with immune checkpoint inhibitors and potentiated antitumor activity. As a result, the basis to study the combination of EZH2 inhibitors with immune checkpoint inhibitors has already been generated and soon requires action. I look forward to this and other intelligent trial combinations in the near, immediate future.

Highlighted trials for prostate cancer patients with EZH2 inhibitors

Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine; Member, Clinical Research Division, Fred Hutchinson Cancer Research Center; Clinical Research Director; Genitourinary Oncology, Seattle Cancer Care Alliance; Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium.

References:
  1. Beltran H, Hruszkewycz A, Scher HI, et al. The role of lineage plasticity in prostate cancer therapy resistance. Clin Cancer Res 2019; Epub July 30, 2019.
  2. Buemn EG, Coleman IM, Lucas JM et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell 2017; 32:474-89.
  3. Aggarwal R, Huang J, Alumkal JJ, et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: A multi-institutional prospective study. J Clin Oncol 2018; 36:2492-503.
  4. Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med 2016; 22:298-305.
  5. Ku SY, Rosario S, Wang Y, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 2017; 355:78-83.
  6. Beguelin W, Teater M, Gearhart MD, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 2013; 23:677-92.
  7. Bradley WD, Arora S, Busby J, et al. EZH2 inhibitor efficacy in non-Hodgkin’s lymphoma does not require suppression of H3K27 monomethylation. Chem Biol 2014; 21:1463-75.
  8. Yu J, Rhodes DR, Tomlins SA, et al. A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer Res 2007; 67:10657-63.
  9. Xiao L, Tien JC, Vo J, et al. Epigenetic reprogramming with antisense oligonucleotides enhances the effectiveness of androgen receptor inhibition in castration-resistant prostate cancer. Cancer Res 2018; 78:5731-40.
  10. Taplin ME, Hussain A, Shah S, et al. ProSTAR: A phase 1b/2 study of CPI-1205, a small molecular inhibitor of EZH2, combined with enzalutamide or abiraterone/prednisone in patients with metastatic castration-resistant prostate cancer. AACR 2019; Abstract CT094.
  11. Zingg D, Arenas-Ramirez N, Sahin D, et al. The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep 2017; 20:854-67.
Further Related Content: 
EAU 2011 - Prostate cancer-associated up-regulation of AMACR, EZH2, and PSMA correlates with diminished expression of specific microRNAs - Session Highlights
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