Integrating evolutionary dynamics into treatment of MCRPC

Quite interesting! Here the full article

sci-hub.tw/10.1038/s41467-0...

[AlanMeyer]

I only skimmed the article and I don't know enough to follow the math, but I thought the idea was really interesting. For those who haven't read it, the theory they were working on was treating someone with a drug, for example lupron or abiraterone, which killed off many of the testosterone (T) sensitive tumor cells - then stopping the drug before killing all of them off and letting the T sensitive cells recover. Being naturally stronger than the T-insensitive cells, they would soon dominate the cancer population. Then the lupron or abiraterone would be restarted - and back and forth to control the cancer.

My first thought was that this was tried already and intermittent ADT was not better than, and maybe not as good as, continuous ADT. But they knew that already and showed that, according to their mathematical analysis, the schedule for ADT vs T was not correctly worked out. Then they tried their theory on 11 men and got time to disease progression more than double that of men on continuous ADT and, in addition, used fewer total drugs and at lower total cost and fewer drug side effects.

As the scientists always say, more study is needed, but this sure is an appealing idea.

Alan

[rococo in reply to AlanMeyer]

Their must be an ideal timing of cycles for each or all to get the best result. Right now their all over the place. Rocco

[cbgjr in reply to rococo]

Each enrolled patient began on abiraterone (1000 mg by

mouth daily; and prednisone) until achieving a > 50% decline in their baseline

levels of PSA pre-abiraterone. Upon achieving this decline, abiraterone therapy was

suspended.

Patients were monitored every 4 weeks with a lab (CBC, COMP, LDH, and PSA) and clinic visit. Every 12 weeks, each patient received a bone scan, and a computed tomography (CT) of the abdomen and pelvis. Abiraterone plus prednisone were reinitiated when a patient’s PSA increased to or above the pre-abiraterone PSA baseline. Abiraterone therapy was stopped again after the patient’s PSA declined to > 50% of his baseline PSA.

etc.

[pjoshea13 in reply to AlanMeyer]

Hi Alan,

For many, the off-phase of IADT is not a return to normal T. Dr. Steve Freedland says that it is mostly a continuation of ADT. It takes more than 6 months to reach the new high, which is usually lower than the old T high. Added to that is the likelihood of the old high being close to the hypogonadal cut-off of 350 ng/dL.

T restoration might stress cells that are adapting well to low T and select for cells that are more like pre-ADT cells. Would be interesting to see if men could get more cycles with that approach.

-Patrick

[Hidden in reply to AlanMeyer]

They did also another study:

Gatenby and his colleagues investigated whether it would be possible to find the perfect balance of chemo that would kill off enough tumor cells but not be potent enough to encourage the resistant cells to come forward. They took cells from two different types of breast cancers and grew them in mice, which were then treated to standard chemo, or a modified chemo. In one scenario, the mice were given lower-dose chemo and then skipped sessions if their tumors shrunk, while in the other group, the animals were given continuous but gradually lower doses of chemo.

The group that got the continuous but gradually lower dose of chemo showed the best response in terms of slowing tumor growth. In up to 80% of the animals, their tumors continued to shrink to the point where they eventually didn’t need any additional chemotherapy at all. In contrast, tumors in the animals that received the standard high dose aggressive chemotherapy and those that skipped doses didn’t see their tumors shrink at all.

[cbgjr]

Thanks for posting! Theirs is a very interesting premise! Really thinking outside the SOC box!

It's a shame that some really good ideas never get past the point of proof-of-concept small studies. Which pharmaceutical is going to spend the stockholders' $ funding trials designed to find out if patients can better survive with lower dosages. Eh?

CG

[AlanMeyer in reply to cbgjr]

A lot of the funding for research comes, not from pharma companies, but from the U.S. or other governments. For example, the U.S. Congress has appropriated $100 million dollars in 2019 for prostate cancer research to be managed by the Department of Defense Prostate Cancer Research Program. That program spent $1.72 billion since 1997. And that's just one of the major government projects funding PCa and other research. In Fiscal Year 2017, the last date I could find, the National Cancer Institute funded 876 prostate cancer research projects with sums ranging from a few thousand dollars to multiple millions for a total of $233 million dollars.

I'll make a separate posting about this so more people will see it.

Alan

[cbgjr in reply to AlanMeyer]

thank you

[PhilipSZacarias]

I quite agree. I presented this to my medical oncologist and he was not impressed, which surprised me. This is the protocol I will very likely follow when I start abiraterone, assuming of course that I respond to it. Cheers, Phil

[Hidden in reply to PhilipSZacarias]

I am trying to get more info on adaptive therapy. It is really a very interesting approach that could be used also on a multi drug concept. If I find specific news I will post it here.

[PhilipSZacarias]

Likewise...thanks. Phil