New generation of anti-androgen drugs (What portion of the cancer is the real enemy?)

Hi Jerry, those are very good questions, at the core of PC research today. There are theories, that AR becomes over-expressed so even the tiny amount of T can drive the growth (and this theory was the bases for the development of the new-line drugs Zytiga and MDV3100). For example, when we sent samples from my Dad´s biopsy to Dr.Bonkhoff, his AR came as 2+, but apparently there is also 3+ which would indicate that even a small amount of T can stimulate growth, not necessarily a good thing. AR 0 is also not a good thing, as HT would not work in such case.

There are also theories such as you mentioned that over time AR negative portion of PC becomes dominant. As PC progresses, there are more and more mutations that enable these cells to thrive and grow, and they are not just T-driven. Scientists are following various paths in PC research, in order to find a cure (just look at the PCF research awards site). I firmly believe that 20-30 years from now, PC will be considered a chronic, manageable and treatable disease, much like diabetes, as researchers find ways to outsmart cancer cell mechanisms. We also know that no two PCs are alike, just like no two human beings are alike, so individualized treatment will also be the key to success. In this disease, losing hope is no option.

Jerry, I don't have anything to contibute, but this is a great topic and I will follow it closely. I don't think Dr Myers has ever addressed this issue, it would be a great topic for "ask Dr Myers". SpecialLady, I was very much hoping that the time period for managing PCa as a chronic disease would be more like 5 -10 years. BB

BB - I see Myers on Monday.  I will personally ask him.

Riviere - thanks for the link.

SpecialLady - thanks for your response...valuable info....   20-30 years...something to look forward to when I'm 67.

Thank you all...I guess to rephrase one of my questions --- I wonder if the new generation of HT can have an impact on those portion that the traditionalal HT can't.

If you search for articles by Sarah Parsons a researcher on this she has done extensive research into this area, here is one link on it:
http://cancerres.aacrjournals.org/content/69/18/7402.full     She pioneered finding testings of 12,930 genes the one common link to all hrpca to the AR receptor is the PTHrP (parathyroid hormone related protein).

Dr. Laing Cheng on 3 types of pathways:  http://instruct.uwo.ca/biology/410g/Images/jordan.pdf

Also, from stuff I get in my local seminars by our doc whom researches Journal articles have seen presentations showing that there are currently known a fixed set of pathways to effect SRC (sarcoma-cancer cells, in this case PCa), approx. like 5-6 known pathways and so all the drugs we see are similar in categories, that they can only effect PCa via these pathways. At some point AR, can make its own androgen or 'fuel' for increases in PCa cells without testosterone, as weird as that sounds. Some of the estrogenic drugs can do direct apoptosis even to hrpca cells, but apparently isn't likely to get them all or the stem cells survive and thus you cannot kill it all off, presumably. Wish this twilight zone of PCa was simplistic, but it is far from it.

Post Edited (zufus) : 10/3/2012 6:41:32 PM (GMT-6)

SpecialLady,

Great article. Thanks!

There are a few quotes I found particularly relevant to this discussion:

Bonkhoff said...
Cumulatively, these data indicate that CRPCa remains androgen-depending, because of hypersensitive AR’s using androgens at very low levels, de novo synthesis of androgens, and increase of 5a reductase activity. Familiar idioms like androgen-independent, -refractory, and -insensitive PCa do no longer reflect the biology of CRPCa and should be avoided.

Bonkhoff said...
Clinical diagnosis of CRPCa is based predominantly
on serum PSA profiles under ADT. The underlying
disease process, however, predates its clinical detection.
Relevant pathogenetic factors implicated in the
development of CRPCa are detectable in hormone
naive PCa long before the clinical onset of the disease.
In addition, ADT can induce or enhance relevant
pathogenetic pathways in a relative short period
of time, including upregulation of AR, BCL-2, CGA,
EGF-R, andHER2/neu. For example, significant EGF-R
and HER2/neu expression can be induced by neoadjuvant
bicalutamide monotherapy within 4 months
[46].

This last quote is a real eye-opener:

Somebody said...
Current concepts implicate the development of CRPCa as a multifactorial and heterogeneous disease process. It is questionable whether a standard ADT offers an optimal therapeutic strategy for a multifactorial and heterogeneous disease. CRPCa still remains an end-stage disease with poor outcome. Magic bullets with the potential to improve significantly the outcome of end-stage solid tumors, including CRPCa, are currently not available and are unlikely to be developed in the near future. Clinical studies dealing with CRPCa are usually initiated in patients with rising PSA under ADT. The underlying disease process, however, may predate the clinical onset of CR by years.
...
Strategies focusing more on early detection and prevention of CR may be more effective to extent survival of PCa patients than attempts to improve the outcome of patients with established end-stage CRPCa.

Nellie

Post Edited (Riviere) : 10/4/2012 6:31:38 AM (GMT-6)

Still, the most effective "Hormone Treatment" is the first one, orchiectomy..It's also the least expensive..

When I first read Jerry's post, I thought that the paper on PSA-low stem cells answered the question. I think I'm returning to that view. The paper I cited states that these stem cells either have no androgen receptor or a very weak presence. The "no receptor" variant would then be the "smoking gun," which does not use androgen and does not respond to any kind of ADT. In fact, the authors concluded that to be successful, treatments had to be modified to include ADT and a new approach for these deadly stem cells.

Here's a link to a different summary of the paper that you might find interesting: "Scientists Identify Therapy-Resistant Subset of Tumor-Propagating Prostate Cancer Cells," www.genengnews.com/gen-news-highlights/scientists-identify-therapy-resistant-subset-of-tumor-propagating-prostate-cancer-cells/81246733/?kwrd=MD%20Anderson%20Cancer%20Center

Article said...
Initial studies on the two lentiviral-vector expressing isogenic cell types indicated that in addition to their lack of androgen receptor protein expression, the PSA-lo cells demonstrated very different gene expression patterns compared with PSA+ cells. Up to 10% of the 561 genes significantly overexpressed in the PSA-lo cells were involved in antistress responses, including hypoxia response and DNA-damage sensing and repair. These cells also underexpressed many proapoptotic genes. In fact, when both the PSA-lo and PSA+ cell types were subjected to chemical stresses including etoposide, pa***axel, or hydrogen peroxide, the PSA-lo cells expanded, while numbers of PSA+ cells decreased.

Interestingly, the PSA-lo LNCaP cells also underexpressed dozens of cell cycle and mitosis-related genes, indicating that they were a quiescent cell population, compared with the rapidly dividing PSA+ cells. This suggestion was supported by cell cycle analysis. Importantly, the PSA-lo LNCaP cell population preferentially expressed a number of stem cell and developmental genes, possessed a higher capacity to establish holoclones and anchorage-independent prostaspheres, and generated larger spheres and a greater number of secondary spheres than PSA+ cells.

Another summary said that the PSA-low stem cells could begin to regenerate a tumor with a clump of only ten stem cells. So you have a quiescent stem cell (can remain dormant?) that can regenerate itself, and only needs a few divisions to start creating big tumors. Sounds to me like the bugaboo of PCa that remains dormant for years and suddenly comes back with a vengeance.

I wish I had access to the paper itself, and not just a news summary, as I wonder if it might answer the question. Obviously I'm not qualified to do much more than ask questions, so I hope Profession Bonkoff finally gets to address this issue.

If you note the other article in my first post, it discusses stem cell presence in various cancer cell lines. The authors found that CRPC had a very high percentage of stem cells compared to other PCa cell lines.

So I agree with SpecialLady that there is yet no clear answer. And even if the first article has it right, there is no current treatment to eliminate PSA-low stem cells.

Nellie

Post Edited (Riviere) : 10/5/2012 6:54:33 AM (GMT-6)

Jerry, similar situation with my Dad, he had all cores positive, high Gleason, 2 bone metastasis but PSA of only 7.5. Some say, this is aggressive, but so far he has done well on HT. In one of his presentations, I recall Dr.Myers saying something that caught my attention, he said that not all patients with a low PSA and bone involvement have an aggressive disease, if I can dig out that video, I´ll link it. You seem to be doing great, as well.

I do not think you should assume that all those cells that do NOT produce PSA are automatically stem cells without any receptors. From what Dr.Bonkhoff wrote, stem cells seem to present only a miniscule portion of the tumor mass.

SpecialLady,

I would be very interested in seeing that video.  I actually see Myers next week.

Thanks,

Jerry

Nellie, I agree, I am no expert either, but appreciate these discussions and learn (& get confused) a whole lot.

Jerry, here is the video, at minute 42:50 there is a question from an audience member, and an answer where Dr. Myers says cancer with bone mets under 10 could be aggressive, but not always:

link.brightcove.com/services/player/bcpid1311218266001?bckey=AQ~~,AAABMTO41yk~,0BDF4jnPRYk18rLHqrcfnGVhJxC-Y8Rm&bctid=1344770020001

Have a great visit with Dr.Myers, I really believe you have the best doctor in the world for advanced PC!

Thanks Special Lady and Riviere.

This is my 3rd visit with Dr. Myers. He views the disease as a golf game. I view it as a game of chess and he is an important piece.

Myers has a profound understanding of PCa. In so many ways he resembles Captain Ahab in his knowledge of, and pursuit of the great white whale. In many ways his treatment plans raise eyebrows among other members of your medical team. Still, when you walk out of that appointment you leave with new weapons and a fresh horse.