If PC is driven by androgren resistant cells then why do we use HT?

It's been 9 months since my husband's G9 diagnosis and I'm still struggling to get a grasp on the science and the logic and the emotional aspect of HT.

From everything I've read, HT only works on PC cells that are sensitive to testosterone. However it is the PC cells that are insensitive to testosterone that are driving the growth of the cancer. If this is the case, why use HT at all if we are not attacking the testosterone resistant cells?

Is it because the hormone sensitive cells can (will) eventually mutate into insensitive cells and HT just keeps their numbers down? So is it all a matter of volume control, especially for high risk guys like my husband?

I've also read that some believe that HT is just teaching the PC to become smarter, faster. Any truth to this?

Hi, it is because at the beginning PC consists mostly of cells that have testosteron receptors on their surfaces, and removing the testosteron or the fuel will dry these cells up. The result can be observed through decreased prostate volume, clearing of bone mets, lowering of pain if present.

HT can keep the cancer at bay for a long time, for years. Eventually, the androgen insensitive kind take over. In a large number of cases, the cancer finds a way to circumvent the pressure applied to it by a certain type of medication. It does that through mutations, and in this way it survives. In this way, the medication, including HT, help, but also drive the cancer cell evolution.

Most oncologist agree that a combo is better than single-medication cancer therapies, precisely for the reason of making it harder for the cancer cell to evolve to its resistent form. Hope this helps.

Tall Allen, Yes but are there in fact studies or trials that survival/mortality benefits exist after the castrate resistant cells are dominant and presumedly the the HT sensitive cells , if continually replicating are in a continuous state of dying from the HT? This question seems to me, to be at the very heart of the peanuts question. I do not know the answer. Patrick Walsh seems to indicate, and this I believe is also an hypothesis of an expert in the field. It must be only hypothesis or it would not be, controversial seems too strong a word, so i will say it is still a dialectical argument twix experts of good will. If it were not, obviously a great problem has been solved. Any thoughts on this?

Tall Allen,

Your last point about "fuzzy area" is exactly where I am at. Personally in no hurry to start ADT, as I figure it will be for the rest of my life, however long that may be. Next PSA and meeting with oncology at Sloan in early January. It is always interesting. Best wishes to all.

Newspaper Lover
Age 72
11/09 DaVinci surgery upstate NY; nerve bundle taken; clean margins, clean seminal vessels, no incontinence, alas no erections.
06/11 PSA re-emerged.
Gleason 8
Time to recurrence 18 months
Three month doubling time (summer 2011).
PSA rose from .07 on 06/11 to .17 on 11/11.
09/11 hernia surgery to repair hernia resulting from the DaVinci.
10/11 Moved management of my case to Memorial Sloan-Kettering in New York City.
12/11—06/12 SRT plus HT (Lupron, Casodex).
07/12 – 06/14 Five six-month tests returned PSA "undetectable" and testosterone in “normal range”
12/14 PSA .06
01/15 PSA .08.
07/15 PSA .11
07/15 CAT and Bone scans find no evidence of metastases disease..
Currently receiving no treatment. Next PSA January ’16.

Peanuts,
It's not at all hard to find. Here is what the NCCN Guidelines state: " Androgen receptor activation and autocrine/paracrine androgen synthesis are potential mechanisms of recurrence of prostate cancer during ADT (castration-recurrent prostate cancer [CRPC]). Thus, castrate levels of testosterone should be maintained while additional therapies are applied."

www.ncbi.nlm.nih.gov/pmc/articles/PMC1602218/
clincancerres.aacrjournals.org/content/10/2/440.long

You are holding an overly simplistic notion about what castrate resistance means on the cellular level. It does not mean that the AR is no longer activated by androgens - they very much are. In fact, exquisitely so. So much, in fact, that even the smallest amounts of androgens (testosterone and atypical ones) can activate them. There are about a half dozen "strategies" used by the AR, some of which include making its own androgens, receptor amplification, translocation, sensitivity to new ligands, self-stimulation, etc.. But they are still very much activated by extracellular androgens, which should therefore be minimized.

Gemlin - you have to be very careful about trotting out outdated studies like that. They have often been superseded, as all those have. Nothing there is relevant in the modern era.

- Allen

peanut307,

From the start it is important to understand that not all prostate cells are androgen dependent. In a normal human prostate most prostate cells depend on androgen to survive and to maintain the gland operational(new cells are born while others die). When deprived of androgens, androgen dependent cells undergo a programed death. This does not mean all cells die at once. The main cell death process mechanisms are apoptosis, necrosis, autophagy and necroptosis. Androgen deprivation also causes a reduction of blood flow to the gland that is reported as the cause of massive cell death. See the following for a detailed information:
Arnold JT, Isaacs JT. Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault. Endocr Relat Cancer. 2002 Mar;9(1):61-73. Review. PubMed PMID: 11914183; PubMed Central PMCID: PMC4124629.

How androgens affect prostate tissues? The main reason androgen suppression is not curative is because the gland is made up of cells that do not need androgen to survive. This compartment of prostate cells is in the minority in quantity, but not in importance. These androgen-independent cells of the prostate are the basal, pluripotent stems cells (mother of all cells) that make up and maintain the functioning of the gland.

How does prostate cancer, which for the most part is so androgen-dependent, get to the point where it does not need androgen to progress? How to explain the fact that if there are individuals that are androgen-independent or androgen resistant at diagnosis(those that do not respond or respond poorly to ADT)? This must be a consequence of a natural adaptation process driven by a lack of androgen or by genetic changes (mutations) that cause the cancer cells to be unstable and to be able to proliferate and grow without their normal androgenic stimulus.

If for example, the ratio of androgen-dependent cell compartment to the androgen-independent cell compartment of the prostate gland is 80:20, there is a natural progression to androgen-independence by which this ratio is tilted to the independent side. Dr. Bruchovsky contends that when the compartment of stem cells reaches a certain ratio to the number of tumor cells, resistance develops as an initial step to androgen-independence. In other words, the natural progression of prostate cancer to an endpoint seems to be androgen-independence, if given sufficient time before diagnosis in such patients.

Recently in patients considered androgen independent while on ADT ( rising PSA while testosterone is at castrate level) new chemical entities that work by different mechanisms have demostrated that the so called androgen independence is not total and those newer chemicals can alter the process by which the cells proliferate. Abiraterone and Enzalutamise have demostrated a survival benefit in those patients.

The answer to peanut307's question is that it is preferable to mantain androgen deprivation even when the patient is classified androgen independent because prostate cancer cells can among other mechanisms to produce their own androgen to grow and proliferate and the less androgens present at that point the better it is.
RalphV

Peanut: thomas Dolby is the songwriter...he also gave us Dolby Audio--a clearer version of audiotaping.