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Deep in the weeds: “Doc, is there anything new?”

Deep in the weeds: “Doc, is there anything new?”

L. Michael Glode, MD, FACP, FASCO

Oct 31, 2014
How to answer this very common question is a pretty daunting task. Last week, I was at the Prostate Cancer Foundation annual scientific retreat. This is the ultimate place to hear about new science in prostate cancer and the incredible progress being made. That said, distilling even one of the many lectures given by leaders in the field is challenging. If I were writing for the National Enquirer, I would have enough notes to write at least a year’s worth of “CANCER BREAKTHROUGH PROMISES PROSTATE CANCER CURE” articles.

So, let me just wander into the weeds a bit from only two such lectures. Karen Knudsen is one of the best prostate cancer researchers on the planet at this point. She works effectively with clinicians and basic scientists alike on a variety of projects that ultimately yield insights into what controls prostate cancer cell biology. Her lecture this year was on DNA repair targets. (Disclaimer: It is very much beyond my area of expertise to try and cover DNA repair at a sophisticated level, but there is an excellent article dealing with this in the New England Journal this week). So here we go, weed hunters.

The DNA in each cell is not the long strand of double helix you are used to seeing. Rather, it is intimately wound up with proteins that give it structures looking like a thread wound around a protein ball, then these are further formed into bundles that aggregate and ultimately form the chromosome pictures you find in biology textbooks. The nuclear proteins that are part of this process, in turn, are not only structural, but also contribute to how the androgen receptor (AR) binds to specific locations on the DNA and leads to cell growth, turning on the gene that makes PSA and so forth. As you know, AR biology insights led to abiraterone and enzalutamide.

Get ready for more complexity. The nuclear proteins can all be modified in their functions (helping to initiate the replication of DNA, peeling off the RNA that will go to the cytoplasm to code for proteins, changing the structure of the chromosomes, etc.) by enzymes that change the proteins themselves (their shape, charge, function). There are several such modifications, but common ones consist of adding CH3 (methyl) molecules to specific spots on the proteins, or COCH3 (acetyl) molecules. These changes can have dramatic effects on which genes are expressed in which tissues, and there is an easy-to-read overview called the histone code on Wikipedia. (Click on that link and read the paragraph on its complexity to get a feel for the research described below.)

Honestly, Glodé, get to the point…

OK, so to make it more relevant to prostate cancer, an important modifier that has explicit functions in cancer is a protein called PARP1. This is an enzyme that modifies the nuclear proteins by a process called ADP ribosylation and adds simple molecules called ADP-ribose to various proteins (including itself) for modifying function. It turns out that PARP1 binds at sites similar to the place where the AR binds in the DNA and also changes other other proteins called DNAPKs that help to repair DNA. The DNAPKs are dramatically over-expressed in castrate-resistant prostate cancer, and if you inhibit them, you can suppress metastases from forming. Inhibitors of PARP1 and inhibitors of DNAPKs are under intense study as possible therapeutics for prostate (and other) cancers. One such example is cc-115 that is being studied by Celgene, but there are others.

So, if you read this far, you have successfully navigated exactly 35 minutes of notes from Karen and another colleague from Celgene, Kristen Hege. And remember, the program went on for a day and a half with me furiously writing notes. It was like drinking from a fire hose, but the net result is this answer to the question, “Anything new?”: "OMG, YES!” Thanks to the scientific community for working so hard on unraveling what we need to know about how cancer operates!

This post originally was published on prost8blog, a blog to help patients and their families understand various aspects of prostate cancer, and is reprinted with permission of Dr. Glodé.


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