“Adaptive Therapy”

to derive supporting evidence. Requests ●Do you have any comments on adaptive therapy? ●This adaptive strategy seems intuitive, yet it’s not widely practiced. What are the barriers or objections to it?

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“Adaptive Therapy” (Brad Power) [#10] — Meeting Notes Brad Power: Today we're going to be talking about the presentation that Bob Gatenby made a week ago on adaptive therapy – using evolutionary and game theory to strategize about how to manage treatments.

For those of you who weren't there, or didn't see the notes of the meeting, there are basically four pillars: drug combinations, low doses, sequencing, and mathematical models. Saed Sayad: We were talking about old fashioned modeling, which is using mathematical equations to measure the change of the concentration of drugs in our system, in our blood.

Based on that model, we can decide that when we reach 50% of the concentration, we can increase the dosage. This is kinetic modeling. This type of model is very limited because we now have huge amounts of data which are mixed data. We should be able to use those data and find the interaction between proteins and genes.

And then instead of the simple mechanical mathematical model, we can use machine learning, data science, and predictive modeling to include many more factors in our equations. Brad Power: In “The Signal and the Noise ”, they talk about weather forecasting, and how the models get more sophisticated and the data gets more sophisticated.

What I hear you're saying is that the standard of modeling today is to have many more variables in the model, instead of just a handful? Saed Sayad: It’s the variety of elements in the model. It means it's not just a simple concentration of a drug; rather, it is about the interaction between different components of the cell, like the DNA, mRNA, and proteins.

Brad Power: Integrating all the different kinds of information you could be bringing together, such as different kinds of -omics, as well as medical history, has been a big theme for Brian. Emma Shtivelman, you put something in the chat last week about bipolar? Emma Shtivelman: I asked about bipolar androgen treatment.

It's sort of taking the evolutionary approach that has been proposed to an extreme.

lar? Emma Shtivelman: I asked about bipolar androgen treatment. It's sort of taking the evolutionary approach that has been proposed to an extreme. Not only do you do short time treatment in this case with androgen deprivation, you then flood the patient and the tumor cells with testosterone, hoping that this will prevent the development of resistance.

The cells that were kind of responding to androgen deprivation will now flourish and the resistant clones will be pushed out of the picture. Dr. Emmanuel Antonarakis is a big proponent of this approach. He reported some successes, particularly in patients who have mutations in the DNA damage repair pathway. It's literally case reports, not big studies, and after bad deprivation.

He reported that patients in several cases responded well to immune checkpoint drugs. The first report was maybe nine years ago or so.

“Adaptive Therapy” (Brad Power) [#10] Brad Power: Pete Kane, do you have any resources or people you've run into that might be able to help us with simulation models? Pete Kane: Possibly. I'll give it some thought and see if I can make some introductions. Certainly there's been a wide cast of characters that we've encountered.

Brad Power: Ally Perlina, we have been having a conversation on drug combinations. We agree on that pillar of Bob Gatenby’s approach. But you challenged the notion of administering the drugs in sequence, rather than as a cocktail combination all at once. That's a very valid question.

I can represent Bob Gatenby's argument: He's saying that if you knock the population down successively, that's a way to get an extinction event. But if you hit the heterogeneous population all at once, up front, when there's a large population, you're going to get some resistant strains that are not going to respond. If you hit it with a combination, you'll get a better response.

Progression free survival and the other metrics will look good, but you won't actually kill it off. There will be some resistant strains that are lurking there in the background, and they will eventually come back. When he talked about Brian's case, he said, “Brian, you have a low tumor burden. There's a low tumor population.

You can go for an extinction, knockout blow if you take three drugs in succession.” If Dr. Gatenby looked at the CureMatch drug combinations, I think he would want to do them in succession, not as a cocktail. I may be misrepresenting him, but I think that's the argument. Ally, you were saying there isn't any evidence to support that. Ally Perlina: I didn't state that.

I was asking because at a quick glance, we couldn't find any papers, but we may not have been thorough enough. I was asking if there's any clinical evidence to validate this theory. Saed Sayad: I read the paper. They said that not only is sequencing the drugs important, but also the order. They were using doxorubicin and other CTL immunotherapy drugs.

ut we may not have been thorough enough. I was asking if there's any clinical evidence to validate this theory. Saed Sayad: I read the paper. They said that not only is sequencing the drugs important, but also the order. They were using doxorubicin and other CTL immunotherapy drugs. They showed that if you change the order, the effect is going to change.

In many cases you can make a cancer cell uncomfortable, instead of killing it. Based on my research, this is a very new field. There are many questions, and few answers. Brad Power: There's a specific example we've talked about. Rick schooled me on the notion of radiation turning a cold tumor hot, and then being responsive to immunotherapy.

That would be a sequence of radiation followed by immunotherapy. Rick Stanton: That's our hope. We looked at our immune deconvolution as assessed by Tempus RNA seq data, and we have very cold tumors. We have some evidence of cytotoxic T- cells in perforin and granzyme A (perforin and granzyme cooperatively induce target-cell death) that contradict that there's no CD8 T-cells.

Nevertheless, it looks like we have pretty much no CD8 T-cells.

“Adaptive Therapy” (Brad Power) [#10] probably not going to work. We need a prerequisite, which in our current thinking is radiation. It might be Pluvicto, which would come in and basically carpet bomb anything that has PSMA (prostate-specific membrane antigen) on it, and that would awaken or heat up the cold tumor. That would be perhaps the first step in what would be a great sequence.

The second step would be immune modulators. I'm very curious about what CureMatch and Ally bring to the table. When I first saw the Tempus report with a super high BRAF expression for Brian, I took it with a grain of salt because I didn't get that section on overexpression in my Tempus report.

Looking at the transcripts per million data that's coming out of Tempus for Brian, it was really apparent that his BRAF is off the charts. Either they made a mistake or that's very reportable. That brings me into the whole concept of BRAF. Nobody is really hitting BRAF for prostate cancer. Why would this make sense? BRAF is a signaling molecule, or protein inside a cell cascade.

It doesn't mean that you have activated or phosphorylated BRAF, it just means you have a ton of BRAF. I make the analogy to a soccer game. At the cell surface an EGFR receptor kicks a soccer ball from the defense, to the midfield, to the strikers, down into the nucleus. Having a bunch of BRAF is like having a thousand midfielders, but it doesn't mean they have the ball.

It doesn't mean that they're being phosphorylated and actively signaling. But Brian’s BRAF was not just a little high. It is like 10 times higher than anyone. It's off the chart. Brian McCloskey: I’m something like number one out of 500 patients. Rick Stanton: Yes.