The androgen-sensitive to androgen-resistant transition: an hypothesis


A media release issued on Tuesday this week by a usually highly respected medical center in the Los Angeles area is misleadingly entitled, “Hormone therapy can make prostate cancer worse, study finds”.

The fact that men treated with androgen deprivation therapy (ADT) can and do progress, quickly or much less quickly, by becoming androgen resistant, and that, in some of those cases, this occurs because of the development of neuroendocrine forms of prostate cancer, is not news, by any manner of means, and the implied suggestion that researchers at Cedars-Sinai Medical Center have just made this discovery is unfortunate at best. (See here for the actual media release.)

What the research team at Cedars-Sinai actually have done is propose a possible mechanism explaining why and how ADT can induce the transformation of androgen-sensitive prostate adenocarcinoma cells into androgen-resistant neuroendocrine cancer cells. And the title of the paper by Mishra et al. (just published in the Journal of Clinical Investigation) that reports their findings and their hypothesis is “Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming”. The paper itself is very clear that transition from androgen-sensitive to androgen-resistant forms of prostate cancer is a common and well-known effect of ADT.

MIshra et al. report detailed findings — based on studies in laboratory mice — about how certain epigenetic effects on prostatic cancer-associated fibroblasts (PCAFs, a specific type of cell found in men with prostate cancer) can lead to secretion of abnormal levels of glutamine, and that there is a clearly higher level of serum glutamine in mice that are resistant to ADT than in those which are responsive to ADT (with an odds ratio [OR] = 7.45). They further postulate that epigenetic regulation of Ras activity in PCAFs is associated with a gene identified as RASAL3, and that expression of this gene and the consequent rise in serum glutamine levels is or at least may be a biomarker for metabolic and neuroendocrine reprogramming in some prostate cancer patients who become resistant to standard forms of ADT. This hypothesis is still to be validated in actual prostate cancer patients (as far as we can tell).

We wish to be very clear that the work reported by Mishra et al. is of considerable interest since it may help us to develop new and better forms of test for the onset of neuroendocrine prostate cancer and for treatment for at least a subset of men who start to become castration-resistant after either orchiectomy or other standard forms of medical castration. However, we also wish to point out that the media release issued by Cedars-Sinai spends four paragraphs implying that no one knew about the transition from androgen-sensitive adenocarcinona to androgen-resistant neuroendocrine carcinoma, which has been well understood for years based on research at centers like the University of California, San Francisco (UCSF), the Johns Hopkins Medical Center in Baltimore, and others.

6 Responses

  1. Sorry — development of neuroendocrine prostate cancer is not the only way for prostate cancer to develop ADT resistance. With patients with progressive prostate cancer you can take a liquid biopsy and analyze for AR receptors. Patients with certain abnormalities in AR almost never respond to ADT and have a short survival if they get ADT instead of other forms for treatment.

    This research is based in men with prostate cancer — so the finding may have external validity. I feel skeptical about studies only based on laboratory findings without any testing in men with prostate cancer. Do the lab findings have external validity. Who knows.

  2. Dear Finn:

    I was very careful to point out that this is an hypothesis that only applies to a subset of men with advanced prostate cancer who progress an ADT, and that it still needs to be validated in studies in man.

  3. Will Estrogen (Transdermal Estradiol) Counter the Transformation to Neuroendocrine Prostate Cancer?

    Thanks for posting on this key topic.

    It is worth mentioning again that Dr. Charles “Snuffy” Myers, MD, an eminent medical oncologist who retired about a year ago after devoting his practice to prostate cancer, but is still active in research, has suggested that this transition, which he and other panelists considered fairly common in late-stage patients on severe androgen deprivation, is blocked and even reversed by use of transdermal estradiol. He used these skin patches extensively in his practice to preserve bone mineral density for men on ADT, and he noted that in his practice they just don’t see this transformation. (PCRI Conference DVD, Disk 4, Meet the Speaker patient Q&A, hour 2, 58:56-59:34.)

    I look forward to reading this complete paper via the link and comments here to try to understand if there is a possible mechanism for reversal of the transformation by estrogen. I’m also thinking this is likely above my pay grade.

  4. While this may be the “good” news, the bad news is that we have no effective treatments for RAS mutations (yet) … at least according to “‘Cracking the nut’ on RAS mutations“, an article in CURE Magazine‘s Summer edition that I happened to read this morning.

    The esteemed Frank McCormick, former President of UCSF Cancer Center, and Director of NCI’s RAS Initiative, whose life research has been dedicated to RAS, does say, “… I’m pretty sure there will be several ways of beating RAS in the next few years. We are not quite there yet but I think we’re cracking the nut.”

  5. I have come to dislike “hypotheses” compiled from studies at the mouse level, when what is published tends to put worry into the minds of patients. Continue studying the “whatever” and only publish when the study is no longer a hypothesis but rather a distinct absolute and counter-measures have been determined.

  6. Dear Chuck:

    That would make it near to impossible for scientists to communicate their ideas to each other around the world.

    If you don’t like reading about hypotheses, that’s fine. Just don’t read about them. I would remind you that few theorems and almost no hypotheses are actually ever “absolute” — not even Einstein’s special theory of relativity!

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