“Lynchpin molecule for the spread of cancer found”


This type of heading in media stories and press releases tends to drive your Sitemaster to distraction because there is almost invariably a major “may” or a “possibly” in the actual story when you get into the details. However, in this particular case there may be some justification for the headline.

The media release from Thomas Jefferson University (just two blocks down the street from your Sitemaster) that has been posted by ScienceDaily refers to multi-center research led by Dr. Karen Knudsen of the Kimmel Cancer Center (see Goodwin et al. in the journal Cancer Cell). Dr. Knudsen has specialized in research into the causes of metastatic and castration-resistant prostate cancer over the years, so this piece of research deserves our attention.

What Goodwin et al. are now reporting is that there are reasons to believe that a molecule known as DNA-PKcs — an enzyme called a DNA repair kinase — may be fundamental to the ability of cancer cells to keep repairing themselves when they should actually be either self-destructing or dying off after treatment with differing types of therapy. Basically DNA-PKcs can

rejoin broken or mutated DNA strands in a cancer cell, acting as a glue to the many broken pieces of DNA and keeping alive a cell that should normally self-destruct. In fact, previous studies had shown that DNA-PKcs was linked to treatment resistance in prostate cancer, in part because it would repair the usually lethal damage to tumors caused by radiation therapy and other treatments.

If this hypothesis is correct, then the ability to block the activities of DNA-PKcs could be critical to halting the progression of cancers as they metastasize, and, in the case of prostate cancer, as it becomes hormone-resistant and stops responding to androgen deprivation therapy (ADT).

Again, quoting the story on ScienceDaily:

Dr. Knudsen and colleagues also showed that in mice carrying human models of prostate cancer, they could block the development of metastases by using agents that suppress DNA-PKcs production or function. And in mice with aggressive human tumors, an inhibitor of DNA-PKcs reduced overall tumor burden in metastatic sites.

In a final analysis that demonstrated the importance of DNA-PKcs in human disease, the researchers analyzed 232 samples from prostate cancer patients for the amount of DNA-PKcs those cells contained and compared those levels to the patients’ medical records. They saw that a spike in the kinase levels was a strong predictor of developing metastases and poor outcomes in prostate cancer. They also showed that DNA-PKcs was much more active in human samples of castrate-resistant prostate cancer, an aggressive and treatment-resistant form of the disease.

At this stage, we clearly think that we need to “watch this space” and see if further research can help to lead to molecules that are clinically effective and safe in man. Apparently there is at least one agent in Phase 1 testing (see NCT01353625) — a DNA-PKcs inhibitor from Celgene known as CC-115.  A new trial of CC-115 will also be starting in the near future — in patients with progressive prostate cancer on standard of care therapies. This will presumably be a Phase II trial and is going to be available at multiple centers connected through the Prostate Cancer Clinical Trials Consortium. No specific data about this trial is available yet, however.

2 Responses

  1. What is the outlook of DNA-PKcs as a screening tool for risk of progression? Is it a relatively available (cost effective) lab test?

  2. Mike:

    I am not aware that anyone has actually investigated its use as a tool to monitor progression as yet, although that may be a potential use in patients with late stage disease.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

w

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: