New video for those interested/concerned about AR-V7 & Zytiga/Xtandi resistance.
I don't know what form AR-V7 test results takes. One can have a few AR-V7 cells at diagnosis, but that shouldn't stop one from using either drug. & at the point of drug failure, AR-V7 may get the blame, but will the test give the degree of preponderance - 60%, 70&, 80%, etc. Other types of resistant cells may also be present.
onclive.com/insights/prosta...
-Patrick
Very interesting presentation regarding AR-V7 mutations. I think this could lead to advances in treatment since it is one of the more common routes of resistance in CRPC.
Maybe I'm not understanding something, but one thing that I thought was contradictory in the video is at the beginning, Dr. Armstrong states: "In my mind, the most useful clinical application would be following progression on frontline abiraterone or enzalutamide where the prevalence of the test becomes more common."
But then later he says "the biomarker indicated that in the frontline setting, AR-V7 was exceedingly rare—making drug development in that frontline setting pretty difficult when the test is so rare."
I have done some reading about AR-V7 and it's almost exclusively found in CRPC so it makes sense that you are not going to get a positive test result in a frontline setting.
I can see that it could be useful though when you become castrate resistant. The presence of AR-V7 would direct you away from second-line AR-based treatments toward Taxane chemotherapy to which AR-V7 has shown no resistance.
Makes sense to me. Early detection of ar-v7 in the chartted and stampede patients for more effective treatment. Will definately view the vidio at my next setting. Thanks. Rocco
"The presence of AR-V7 would direct you away..."
Yes, would direct you toward treatments aimed at the cancer specific part of prostate cancer, rather than the prostate specific part of prostate cancer.
==Maybe I'm not understanding something, but one thing that I thought was contradictory in the video is at the beginning, Dr. Armstrong states: "In my mind, the most useful clinical application would be following progression on frontline abiraterone or enzalutamide where the prevalence of the test becomes more common."==
Antonarakis talks about a multi center trial recruiting men starting on enzalutamide. I assume that he expects almost all of these men to have zero AR-V7 at the start, and a subgroup to gradually progress in the incidence of AR-V7. So the point would be to see which test picks up AR-V7 best, and see that the AR-V7 levels predict the failure of enzalutamide. The failure of half the people is at the 4 month mark I thought.
If the test is validated, it might or might not be given prior to enzalutamide, for the purpose of directing to a taxane treatment those that the drug would not work for. Mostly because enzalutamide is much more expensive than the test. If 5% of the patients have AR-V7 and enzalutamide is more than 20 times the cost of the test, then it is cost effective to always do it. Otherwise it could be left to clinical judgment, based on the health of the patient, and the aggressiveness of the disease.
My understanding.
Although if enzalutamide has failed, and the AR-V7 test is negative, what then? I suppose continue with enza or even switch to abi? ??
The AR-v7 is an "Androgen Receptor" that does not receive androgen. The ligand binding domain is missing, so there is no place for AR to "receive" "androgen". The naming of the macromolecule as AR is like calling a car a Gasoline Receptor (GR), and the Tesla would then be the v7 variant of the Gasoline Receptor (GR-v7).
Many drugs try to interfere with the binding of testosterone (or DHT) to the AR. One would think that if one could create a drug that would clip off the Ligand Binding Domain (LBD) altogether, that would be ideal. But it's not. So I think that the LBD itself prevents the movement of the AR into the nucleus, and the attachment of testosterone at that point, prevents the inhibition, by transforming the shape of the AR macromolecule.
Nice to see the report of a multi-site trial of multiple tests for v7.
I could not find the trial that antonarakis referred to in his chat, on the trials website. ??
Some trials get selected with ARV7, and others with AR-V7.
Apparently testosterone is not essential to the action of the AR when it enters the nucleus, since the ARV7 does not have testosterone, but still causes something bad to happen in the nucleus. I wish I knew all the things that the AR was in control of; ie all the proteins that it was crucial to the expression of. I assume PSA, but dont even know that. And cell division, almost certainly. And...? Seminal fluid? Maybe not.
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