THE "NEW" PROSTATE CANCER INFOLINK

We have commented before on the potential of epigenetics in the development of innovative therapies for the management of prostate cancer.

A review on this topic, originally published in Nature Reviews Urology, has now been reproduced on line on Medscape. In this review, Perry et al. provide a good introduction to the pros and cons of the application of epigenetics to drug development as it relates to new treatments for prostate cancer — but this is still a technically “dense” topic, and difficult even for those with training in the biological sciences.

Fundamentally, epigenetics is the study of inheritable changes in the ways that specific genes are “expressed” and the way such expression is affected by the environment as opposed to the underlying sequence of a person’s DNA.

During the development and progression of prostate cancer, the genetic materials of individual tumor cells can undergo a series of “abnormal” epigenetic modifications over time; examples of such modifications can include:

• Methylation of DNA — in which methyl functional groups (CH₃ groups) get added to specific molecules with the patient’s DNA
• Histone deacetylation — in which acetyl functional groups get removed the histones that help to form chromosome structure)
• Nucleosome remodeling

Hyper-methylation of DNA is particularly common during the transformation of prostate cells into prostate cancer cells.

Let’s not worry too much about the detail. What this means is that we end up with “epigenetic changes” in the cells’ chromosomes. These changes promote cellular instability and can lead to the shut-down of tumor-suppressor genes and the reactivation of oncogenic retroviruses.

Because epigenetic changes are known to be common in prostate cancer, this area of research is, at least in theory, an exciting area of potential for the development of new opportunities  for prostate cancer drug development through the restoration of a “normal” epigenome. At least in theory, this can be done by inhibiting the behaviors of enzymes that stimulate and/or facilitate epigenetic change.

Reactivation of tumor-suppressor genes by demethylating agents and histone deacetylase inhibitors are the two most widely recognized  strategies that may lead to additional new treatment options for patients with advanced disease. However, the great trick is going to be finding and refining targetable drugs that can act uniquely on enzymes that prevent or reverse epigenetic change in prostate and prostate cancer cells, respectively, while not affecting the behavior of other cells. The very earliest of these types of drugs have already been approved for prescription in the USA and elsewhere. The drug vorinostat (Zolinza/Merck) is a very specific example.

Vorinostat has been approved for the treatment of for a type of cancer known as cutaneous lymphoma. It has also been tested in prostate cancer, and clinical trials are ongoing. However, early data suggested that — at the dose used in one trial — vorinostat had limited potential in patients with metastatic castration-resistant disease.

The “New” Prostate Cancer InfoLink believes it will be a while before the true potential of epigenetics can be well enough understood to optimize drug development for prostate cancer. The great unanswerable question is whether that “while” will be a short “while” or a long “while.”

Filed under: Drugs in development, Management, Treatment | Tagged: drug development, epigenetics, epigenome, review, vorinostat |