In a preclinical study indo seems to resensitize to Enza by blocking CRXR7 thus indirectly AR-V7. The trial was started in 2018, results should be known in July 2023.
Does anybody know anything from that trial? I just rechallenged with Enza bringing PSA down from 7 to 0.5, if adding cheap indo prevents buildup of AR-V7, then that is pretty important -I could alternate within the BAT concept adding a AR-V7 blocker.
I have just introduced Nubeqa (Darolutamide) into the low side of my BAT cycle. This will be employed in a judicious fashion to enhance and extend its long term effects.
Daro is perfect for BAT due to the short half-life. Please inform if you will add Indomethacin to inhibit Daro resistance. From the publication which has to be studied in detail:
»Indomethacin effectively resensitized C4-2B APALR cells to apalutamide treatment (Fig. 5C), » The same for Daro.
Are you insensitive to daro and you want to use it? I'm not insensitive and BAT should keep it that way. One of the goals of BAT is to keep splice variants and AR upregulation at bay. But if you are already insensitive, perhaps indo or niclo. I have them on hand just in case. I've had them for a couple of years now so probably need to chuck them.
I will take Indomethacin concurrent with Daro in order to suppress AR-V7 development and thereby introducing resistance.
I will have to study this. I wouldn't think I would need to after just the first introduction. After just a couple weeks I'll stop, let it wash out, start the next T cycle.
Similar to ExBAT and STEP-UP. I passed it by Denmeade. No issues.
Still recruiting classic.clinicaltrials.gov/...
I have even thought introducing Nubeqa maybe every other cycle. We'll have to see. I will definitely be used intermittently, maybe extend it's effectiveness.
If STEP-UP is successful, there is no reason that Nubeqa needs to be conserved with BAT.
Until we have more data, or upon progression, an every other cycle schedule is prudent. Personally, I prefer short daro pulses during every cycle rather than longer pulses every other cycle. Theory is to put pressure on the androgen sensitive cells. By using shorter pulses though I might be sacrificing some AR upregulation. But I am not convinced that AR upregulation is a good thing. Yes, it makes SPA more effective. But is it doing that by giving it a problem to solve or is it doing that by making it work in a more therapeutic fashion?
My mind continually goes back to an adaptive approach. Just trying to effect a certain percentage , without causing a complete biological shift.
The only trial of adaptive therapies that is complete is with Zytiga. 32 months average OS.
32 months is nice compared to the trial's SOC OS of 19 months.
If you implement an adaptive approach, let me know the details.
For discussion, How would one consider the introduction of Indomethacin into a BAT style protocol?
I am thinking of using it together with Daro or Enza in the BAT phase having a low T level. It blocks AR-V7, then the combination works even if you are resistant. Antonarakis has stated that that in the BAT syklus it seems that changing from high to low T every 6 to 7 weeks. I don’t see the need for Indo in the high T phase, maybe I am wrong here. Cancer cells hardly changes in 6 weeks, but they are in the process of adepting. (Enza is not optimal in BAT due to the half life of 6 days, takes too long time for wash-out, Daro 20 hours)
I'd talk to Denmeade or Antonarakis before using indo with BAT. This study states that indo degrades the ARs. If this is true and the degradation is substantial, BAT becomes ADT. However, if indo selectively degrades the prostate ARs, you would still have some anabolism via skeletal ARs so, while you wouldn't have the cancer control of BAT, you would have reduced side effects from ADT.
If you become resistant to ARPIs it might be safe to stop BAT, take indo to try to resensitize yourself, then stop it and let the ARs recover (I recall 5+ weeks but I'd ask Denmeade about that number) and restart BAT.
This line of research is important to the very many who have developed resistance to ARSIs. And quite possibly to those on long term ADT+ ARSI treatment who have not yet developed resistance. Niclosamide can be effective in countering AR-V7 resistance. And here we see that Indomethacin may counter AKR1C3 which enables intracellular androgen synthesis.
BTW I agree with the discussion of short term darolutamide in the castrate cycles of modified BAT programs. I now include 2 weeks of daro at the start of my one month ADT cycles on Orgovyx. Again I note that up-regulation of AR activity during ADT periods actually primes for the subsequent High-T (SPA) cycle to be efficacious. Hopefully the short term pulses will minimize chances for resistance to develop. Long term? We shall see. Paul
From their conclusions:
"AKR1C3, a multifunctional enzyme, induces enzalutamide and abiraterone resistance by converting the weak androgens androstenedione and 5α-androstenedione to the more active androgens testosterone and DHT (19, 23). Various inhibitors have been developed to target AKR1C3 activation in xenograft tumor models (43), including indomethacin (44), GTx-560 (45), and ASP9521 (46), however, most untested in the clinical settings so far. Thus, there is a great unmet need to engage AKR1C3 inhibitors for clinical trial initiation. Previously, we have reported that indomethacin, a commonly used NSAID, could efficiently inhibit AKR1C3 activity both in vivo and in vitro (23). Given the promising effect of indomethacin, a phase I/II trial (NCT02935205) aiming at exploring its effect in treating patients with mCRPC in combination with enzalutamide is ongoing. Moreover, we recently found that overexpression of AKR1C3 increases AR-V7 expression (18). This finding was supported clinically by a study where positive AKR1C3 expression from prostate biopsy samples was associated with higher positivity of AR-V7 [7/38 (18.4%) vs. 4/76 (5.3%); P = 0.025; ref. 47]."
I am not resistant. My MO has looked at my mutation status (none) and CTCs (undetectable) and PSA (drops over 95% if I use an ARPI for a week) and determined that I am still HSPC without change in 5 years.
Viewing completed studies and individual results I am hopeful that we will never be resistant. As we know, BAT resensitizes men to ARPIs so while I agree that for the men who solely use ADT/ARPIs these studies are valuable, they aren't actionable (yet) for us.
The Take Home Message on Cujoe's Posting on CRISPR edited T cells--THIS IS HUGE AND IMPORTANT
My new Oncologist needs learning curve help!
