A surprise : The virtual assembly is... - Advanced Prostate...

Advanced Prostate Cancer

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A surprise

MateoBeach profile image
10 Replies

The virtual assembly is ongoing today and tomorrow. Open to all this year on virtual platform. This one presentation on two (competing /exclusive) driver pathways (ERG and SPOP) surprised me: Does this open the possibility for genetic testing to determine if the cancer will respond to androgen deprivation? Vs. showing if it would rather beresponsive to high-level androgen treatment? (!)

This is their published article but the same as the talk:

biorxiv.org/content/10.1101...

Abstract: "Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually-exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG up-regulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation."

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MateoBeach
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LearnAll profile image
LearnAll

Mateobeach, The subtypes...ERG positive and SPOP mutant hypothesis fits with the clinical observation that there are men who remain androgen sensitive for long time whereas other men move fast towards androgen resistance. The first type can go for long time with regular , milder ADT such as Lupron by itself....whereas the second type require more an d more stronger ADT to achieve the same goal of tumor control.

I assume that high T/DHT can jolt the one variety but can cause flare up in ERG positive . What's your view about this? Can the subtypes be identified by biomarkers and pattern of response until genetic tests are discovered ? How can we apply this knowledge in our own cases in practical way ?

MateoBeach profile image
MateoBeach in reply toLearnAll

Good considerations All. There is lots of science being done on the genetics and on bio markers that I could not even follow. Very active and promising area of research. Numerous small molecule drug candidates being tested. But until something passes through clinical trials it is unknowable. PC is such a crafty and evil coyote. Many of the most promising candidates are foiled or reverse altogether in humans. So we ultimately must choose our strategy from what is available and guided by the best available clinical evidence. Which will always be imperfect and incomplete. We are each trials-of-one.

MateoBeach profile image
MateoBeach in reply toMateoBeach

I would add that it makes sense to me to change up strategies sometimes even before a regimen fails ( adaptive or evolutionary approach). Then monitor very closely to identify adverse responses in PSA or on scans to correct course promptly with that information. Of course it is hard to get off a good horse when it is running well. Pony express?

GP24 profile image
GP24

"... a blueprint toward their therapeutic exploitation." Currently there is no drug to target this mutation pattern.

MateoBeach profile image
MateoBeach in reply toGP24

The idea is no new drug required. Just ADT vs Supraphysiologic T or similar. Based upon a genetic test to determine which of the two pathways is active. That is how it appears to me. Of course such a test is not currently available.

GP24 profile image
GP24 in reply toMateoBeach

The Foundation One CDx Test will check for ERG and SPOP:

assets.ctfassets.net/w98cd4...

Here are three articles discussing the influence of SPOP:

clincancerres.aacrjournals....

ncbi.nlm.nih.gov/pmc/articl...

cell.com/cancer-cell/pdfExt...

MateoBeach profile image
MateoBeach in reply toGP24

Thank you. I stand corrected and will read those today.

LearnAll profile image
LearnAll in reply toGP24

Thanks GP24. The last article (cell.com/cancer) is specifically very informative and well written, I had a quick read. I will take a few days to digest so much great information from it.

Do youknow if Color.Com also checks for ERG and SPOP.?

GP24 profile image
GP24 in reply toLearnAll

I had a Color test two years ago. I had the kit sent to a Canadian friend and he sent it on to me. The return postage included covered the entire world so I could just drop into the next mailbox to return it.

ERG and SPOP are not tested. They wrote:

Genes

APC, ATM, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4*, CDKN2A(p14ARF), CDKN2A(p16INK4a),

CHEK2, EPCAM*, GREM1*, MITF*, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2*, POLD1*, POLE*, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53

* These genes are only analyzed at specific locations (see Limitations).

In my case they wrote: "No mutations were identified"

This is a germline test. A somatic test using fresh tumor tissue may have different results.

LearnAll profile image
LearnAll in reply toMateoBeach

There can be possibly simple models to know who has how much androgen sensitive cells to begin with. Because if someone has almost all of his PCa cells highly androgen sensitive..he might end up getting a very vey low Nadir PSA just with Lupron. Thus it will take much longer for those sensitive cells to get fully converted to Androgen Resistant or neuroendocrine ones. Identifying different subsets of PCas and attacking them with right meds/treatments is the future..(precision medicine)

The conversion of cells is merely a function of time...or also of..intensity of ADT used or both ? Meaning stronger ADT.. more likely hood of fast resistance .

Can flooding the cancer cells off and on with testosterone.. dis incentivise them to change to androgen resistant ? The very premise of Intermittent ADT.

But, I will say that we still need to stay alive and keep our bodies as healthy as possible so we are able to handle these upcoming treatments .

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