The authors of a study of an epigenetic protein inhibitor concluded that ZEN-3694 shows encouraging disease stabilisation, robust target modulation and is well tolerated.

In a company first, Zenith Epigenetics is presenting preliminary Phase II results from its investigation of the epigenetic protein inhibitor, ZEN-3694, at the American Association for Cancer Research Annual Meeting which concluded on 3 April in Atlanta, Georgia, US.

Epigenetics and cancer

ZEN-3694 is a bromodomain and extra-terminal inhibitor (BETi) proposed to down-regulate the expression of genes that drive resistance to androgen receptor antagonists.

The drug is being investigated in combination with Xtandi to treat progressive metastatic castration-resistant prostate cancer (mCRPC) patients with prior resistance to Janssen’s Zytiga (abiraterone acetate) and/or Astellas/Pfizer’s Xtandi (enzalutamide). The study authors concluded that ZEN-3694 shows encouraging disease stabilisation, robust target modulation and is well tolerated.

Prostate cancer and mCRPC

The deadliest form of prostate cancer is mCRPC. While patients live longer with currently available treatments this form of the disease remains incurable. Without an available cure, improved therapeutic approaches like those within the field of epigenetics continue to be explored.

As part of this new and exciting therapeutic approach, proteins involved in generating heritable changes to the genome other than nucleotide changes represent a rich pool of untapped cancer drug targets, including candidates that are the target of two pipeline prostate cancer drugs.

GlaxoSmithKline’s molibresib is another BETi shown to suppress oncogene expression. It is being investigated in CRPC patients as a monotherapy in a Phase I/II trial and in combination with androgen deprivation therapy in a Phase I trial. The other drug is Pfizer’s PF-06821497, an inhibitor of the enhancer of zeste homolog 2 (EZH2).

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The EZH2 protein plays a role in silencing the expression of genes that control cell proliferation and is often overexpressed in cancer cells. Pfizer is investigating PF-06821497 in a Phase I trial as a monotherapy and in combination with the standard of care to treat CRPC patients.

Current knowledge about epigenetics is also being exploited in other interesting ways. For example, Oxford BioDynamics, a biotechnology company based in the UK, has developed a blood-based assay, EpiSwitch, to detect chromosome conformation signatures (CCSs) using a chromosome conformation capture technique commonly used in that field.

Chromosome conformation regulates gene expression, which drives how cells behave in predictable ways. The relationship between chromosome conformation and gene expression yields unique CCSs, especially in prostate cancer cells, and EpiSwitch is designed to detect those signatures.

Epigenetic biomarkers

The company recently partnered with Imperial College London to test samples from the PROSTAGRAM (Prostate Cancer Screening Trial Using Imaging) trial. The goals of that collaboration are to continue to validate EpiSwitch and to discover, detect and monitor new epigenetic biomarkers.

The practice of applying discoveries from the field of epigenetics to improve prostate cancer treatment is still in its infancy. With the drug and diagnostic assay trials still in the early stages, it will take a few years before the utility of these approaches and their impact on the prostate cancer treatment paradigm is revealed.

However, positive outcomes will give first-movers the advantage in the marketplace and, most importantly, provide patients with more treatment options for the most lethal form of prostate cancer.

Forthcoming report
GlobalData (2019). Prostate Cancer – Global Drug Forecast and Market Analysis to 2028, To Be Published