Androgen Receptor Pathway-Independent PCa.

[pjoshea13]

New study below [1].

Back when I began my daily PubMed life, advanced disease was termed "hormone refractory". Most PCa cell studies used one or more of only three cell lines:

- LNCaP - from a lymph node.

- PC-3 - from bone.

- DU-145 - from brain.

From 1990 [2]: "We find that while the LNCaP cell line contains high levels of ... the androgen receptor protein .., the receptor-negative cell lines DU-145 and PC-3 do not express androgen receptor protein".

Years passed & suddenly, it was discovered that real-life hormone refractory PCa usually expressed AR. The cancer was getting androgen from somewhere. & so we now have Zytiga, which interupts steroidogenesis at a very high level.

{The logical approach is to also deprive PCa cells of cholesterol - the starting point for all steroid hormone production.}

How relevant were those old PC-3 & DU-145 studies?

"Hormone refractory" went out the window & the new term was "castrate resistant" [CRPC] - not a great improvement IMO.

Huggins was castrating men before I was born. Earned him a Nobel in 1966. Castration or DES treatment mostly fails within 18 to 24 months, but with late diagnosis & high male mortality rates from other causes, compared to today, Huggins must have seemed like a hero.

{In 1950, The PCa mortality rate in the U.S. was 28.6 per 100,000 lives. By 1990, it had climbed to 38.4 [3]. In the PSA screening era it has gradually fallen (to 18.8 in 2015).}

With the start of the CRPC era, the hunt was on to block all androgen sources. So far, total androgen deprivation has been elusive. What happens when we get there?

Well, it seems that they will have to dust off the the term "hormone refractory".

In a commentary of the new paper [4]:

"In this issue of Cancer Cell, Bluemn et al. report that ∼20% of metastatic castration-resistant prostate cancers express neither AR nor neuroendocrine genes and show AR pathway-independent growth, driven instead by a FGFR/MAPK/ID1 signaling cascade."

From the new paper:

"Through the molecular assessment of mPCs {metastatic prostate cancer} over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype." {"NE" is "neuroendocrine"}

...

FGR is fibroblast growth factor. Evidentally, there is now a need for a FGR inhibitor. From a 2013 paper [5]:

"FGF/FGFR pathway deregulations are increasingly recognized across different human cancers. Understanding the mechanisms at the basis of these alterations and their multiple roles in cancer promotion and drug resistance is a fundamental step for further implementation of targeted therapies and research strategies."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/290...

[2] cancerres.aacrjournals.org/...

[3] statista.com/statistics/184...

[4] ncbi.nlm.nih.gov/pubmed/290...

[5] cancerdiscovery.aacrjournal...

[Neal-Snyder]

Hi Patrick,

Thanks for this very illuminating post.

To your knowledge, is there any FGR inhibitor-PCa research in progress?

Neal

[pjoshea13 in reply to Neal-Snyder]

Neal,

PD 173074 from Pfizer is one.

-Patrick

[Neal-Snyder in reply to pjoshea13]

Thank you, Patrick.

Neal

[Hidden]

Wow.

The claim the PC-3 and DU-145 are AR-null, and only LNCaP is AR positive is quite a shock. It would seem to mean that late state bone mets (super-scans) would not be associated with stratospheric PSAs. I wonder if that is true.

But the general thrust, that neither AR strategies nor NE strategies (PRRT) can be expected to obliterate the disease, is a challenge. Mountains beyond mountains.

[pjoshea13 in reply to Hidden]

Martin,

Cell lines are used because of their known characteristics. One should not assume the one's bone mets match with PC-3 cells.

When my solitary spine met at L5 was zapped, my PSA fell by over 60%.

Clearly, PC-3 is a CRPC cell - but is it typical?

-Patrick

[Hidden in reply to pjoshea13]

yea

[Frank_M]

Ursolic acid has significant inhibitory effects on fibroblasts.

~ Frank

[BigRich]

This disease is so complex. Thank you for your efforts in helping us to understand it.

Rich

[Sisira]

FGR inhibitor could be a great breakthrough and a very useful bullet.

Thanks a lot Patrick for your post.

Sisira