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

How to answer this VERY common question is a pretty daunting task. Last week I was at the PCF 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 Knudson 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 (Zytiga™) and enzalutamide (Xtandi™)

OK, if you have followed this far, 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 in Wikipedia. (please, please click on that link and read the paragraph on its complexity to get a feel for the research described below)

Honestly, Glode, get to the point….(and I sincerely hope you took a look at some of the links I put in above to make the structures and details more available)

OK, so to make it more relevant to Pca, 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 Androgen Receptor 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 got 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” and thanks to the science community for working so hard on unraveling what we need to know about how cancer operates!

10 Comments

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10 responses to “Deep in the weeds. “Doc, is there anything new?”

  1. drjacobschor

    Conferences like this make me long for the good old days when chemicals and their pathways had actual names rather than acronyms.Thanks for the PARP 1 explanation. I try to explain to people that this Parp business is in part why curcumin enhances these new drug. See: http://www.ncbi.nlm.nih.gov/pubmed/23825154
    Though something about the very sound of the term PARP 1 causes many people’s eyes to glaze over.

  2. Dan

    Dr Glode ,Thank you for your research. It is great to know that new things are still being explored in our disease.
    Dan

  3. Bob Lederer

    Mike, There remains such a great need to bring the research down to a readable level for those of us not in the field or passed by in the new science. This helps me explain to family and friends where I am heading next in treatment when my ADT fails as it appears to be doing.
    Bob

  4. It ain’t so simple any more…

  5. Eric Richard

    Dr. Glode, I’m new on your blog. I came out of the Snowmastadon dig last February – one of those dinosaurs who presented with metastatic prostate cancer (and in spite of yearly PSAs to boot). I’ve now apparently run through Lupron’s defenses with an again rising PSA after 6 months. I think I’m pretty close to the tiger class. A handful of bone lesions; a Gleason of 8/9; and a PSA that doubled in 6 weeks from 12/13 to 2/14 [I DON’T KNOW IF I’M HI OR LOW VOLUME, BUT I AM PRETTY FAT :)]. Apparently the sequencing of my next-step protocol is key and from what I’ve read so far Docetaxel and Enzalutamide are on my personal A list. But I cannot find any conversation – medical or otherwise – of whether or what sequencing of these new drugs is likely to be the most efficacious. Can you direct me where to look in any way?

    • Hi Eric,
      I have a “policy” of not answering personal questions, but I think the generic answer may be of help here. There really IS no preferred sequence of using docetaxel or the newer “HEAT” (Highly Effective Antiandrogen Therapy) drugs. Practically everyone who is anyone (except me of course, because I don’t think I have anything to add that hasn’t already been said 5 times) has written an article on the question you raise. Here is an example: http://www.sciencedirect.com/science/article/pii/S0302283813007379 I hope that helps a bit and wish you well with you and your physician’s decision! Sorry for your problems…

      • Eric Richard

        Thanks very much Dr. Glode. I’m new to blogging, medical opinion research and CRPC. You’ve offered a place to start delving into on point opinion – all I asked for or expected. I understand and accept your policy. I’d do the same.

  6. Don Welker

    Just bought some stock in CELG and Jazz…. Happy Thanksgiving. Take care and God bless, Don

  7. David Stevens

    Dr. Glode – wondered if you might have a comment on this article from Weill Cornell Medical College: http://weill.cornell.edu/news/news/2014/12/molecular-link-discovered-between-prostate-and-breast-cancer-chakravarty-sboner-rubin.html

    A troubling quote later in this article seems to indicate that those of us with very high Gleason scores may very well NOT benefit from ADT: “The data revealed that estrogen receptor-regulated NEAT1 is the most significantly over-expressed long non-coding RNA in prostate cancer. It is found in both early stage prostate cancer, and in the most aggressive, androgen-resistant cancer, Dr. Chakravarty says, adding that it may be that androgen-deprivation therapy pushes cancer to switch to the estrogen receptor and NEAT1 activation to continue growing.”

    Am I reading this right, that ADT can actually make things worse for some? I am getting close to starting ADT and, with a Gleason 9, I am a little nervous. Thanks.

  8. Pingback: 3 Articles and a forth | prost8blog

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