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Charles Ryan: Hello, I'm joined today by Dr. Michael Korn, who is a specialist in gastrointestinal oncology and the Chief Medical Officer of Caris Life Sciences. Michael, great to see you, long-term colleague, a long-term friend. Great to see you. Great to sit down and talk.

Let's talk about Caris and the various platforms that you are offering. It's a series of genomics platforms for, not only just prostate cancer but all cancers. Tell us about the state of the company right now and your portfolio of offerings.

Michael Korn: Sure. Happy to do that. But first, let me say, it's wonderful to see you in person.

Charles Ryan: It's wonderful to see anybody in person, actually.

Michael Korn: Yes. And it's also wonderful that you are now in this leading position with PCF after we worked together at UCSF for many years, and it's great now that our paths cross again. So I look forward to very productive and exciting work.

Charles Ryan: Thank you for saying that.

Michael Korn: So the reason why I moved from UCSF, being my former main activity, to Caris was really that the company had developed a cutting edge approach to molecular profiling of cancer in general. Always having a particular focus on GU cancers, the approaches that are being used are applicable to the entire cancer spectrum. And as Chadi mentioned before, Dr. Nabhan mentioned, this approach of deep molecular profiling combined with clinical outcomes data has now generated probably the largest data collection of clinically annotated molecular findings in cancer, which now can be mined in all kinds of dimensions.

And so over the years now, Caris has taken this approach to the next level, I would say, and to a very comprehensive level, by analyzing every patient's sample that comes in at the DNA level, by looking at the whole exome. So all expressed genes are being sequenced at full length. And this is combined with an analysis of the whole transcriptome. So the RNA that comes from the tumor cells and the sample that we see.

And these two analyses are done in parallel, and they inform each other. Obviously, the RNA gives us a window into the functional state of cells. And so this has resulted in an enormously powerful data set. There are also technical things that are really important I think, when it comes to, especially GU cancers that many people might not be so aware of. It starts with taking samples.

Obviously, you might have prostate biopsies from the primary tumor, but we know that there are genomic differences between primary tumors and metastases, so it would be great to sample the metastases. But in prostate cancer, because of the tendency to metastasize into the bone, there are just technical difficulties. And in particular, the typical methods that are being used to decalcify bone samples will destroy the DNA and RNA.

Caris has developed a proprietary protocol that avoids that destruction. We can analyze very comprehensively, bone samples, which is extremely important when it comes to prostate cancer. The other part is, and that is also often forgotten, that there is typically always stroma tissue around the tumor cells. So are you really analyzing the tumor or are you somehow getting a lot of normal cell contamination?

Charles Ryan: Right. We've always worried about that.

Michael Korn: And it's a major issue. And you might lose smaller sub-clones at the DNA level, or you actually start measuring the microenvironment and not the tumor cells when it comes to the RNA. So we perform microdissection on every sample, and that really increases our ability to just do successful analyses. So this so-called QNS situation with "quantity not sufficient" is a pretty rare occurrence. And at the same time, we can look into all these details because we are focusing on what we really want to analyze.

Charles Ryan: Well, cancer genomics is now sort of industry into itself. And you are identifying some of the trajectories that the industry is going towards. What do you think, looking five years down the road, we will be doing in terms of genomic sequencing of tumors? Will it still be the tumors? Will it be blood? Will it be a combination of approaches?

You are really at the forefront, looking at all these different tumor types, all of the different research findings, and the different technical aspects. So you really have an opportunity to look down the road and see what you think is practically feasible. What will we be doing in five years?

Michael Korn: I think in five years, first of all, comprehensive molecular profiling will be standard, as you get an x-ray of the chest. It will be, every patient will have to have, on top of the imaging studies, the molecular image of the tumor, right at the outset. Because that will allow the oncologist to really plan forward. Not only decide on the first-line treatment, which might already be in five years from now, might already be molecularly driven, but then it's about how do I set up a strategy for my patient that goes down really into the future and takes into account what I know about this individual patient's cancer. So that is, I think the number one change we will see. Everybody will get a molecular profile.

The second one will be that we will include the molecular findings in our therapeutic decision-making, essentially at every step. We will see that this will be accomplished more and more through blood-based analyses. We have established now, a very comprehensive blood-based analysis, where we essentially took our tissue-based analysis into plasma analysis. That allows you also to easily control for germline mutations and to look for these so-called chip mutations, things like that.

But the reality is that there will be still a number of patients, and that will be very disease-specific, where tissue-based analyses will be the to-go starting point for molecular analysis. So that is at the level of molecular characterization of cancer. But what we also will see, and we see the beginnings already, are additional applications for molecular profiling.

Number one will be that we will use the information we get from the bloodstream, potentially also through re-biopsying, but I think more through just liquid biopsy, we will be able to monitor the effect of treatments at the molecular level.

Charales Ryan: Right.

Michael Korn: And that has two effects. Number one, we can see the predictions, that we will be able to see worsening of the disease much earlier than other findings, maybe even earlier than PSA, I don't know. We will find out. But the second component of this is, we will not only know that the disease is getting worse, but we will also know how the tumor has changed molecularly, at the time it is now resistant to treatment. And we will get the information we need to make the next treatment decision immediately. So that is the treatment monitoring aspect.

Charles Ryan: We've talked about this with respect to the PARP inhibitors and BRCA2 mutations, which the major mode of resistance is they revert, they could develop these reversion mutations, partly discovered by the Cancer Center Director at UCSF, Dr. Ashworth. But this is a pretty early molecular event it seems, in the context of somebody receiving a PARP inhibitor.

So the question is, as the clinician, you're putting this person in these therapies, you see the molecular marker of disease resistance, but the clinical picture is not bad yet for the patient. What do we do? And so that's a big challenge from the perspective of the clinical trial. But as is always the case, the technology will lead the thinking, that will lead to the designing of the clinical trials, that will change the standard of care. So I look forward to hearing more about that.

It's a really exciting time for anybody looking at molecular profiling of tumors and incorporating them into, I think not only therapeutic decision making in obviously prostate and other cancers, but also just as I like to think of it, it gives you a sense of where the patient is in the spectrum of the disease.

And when you see a series of mutations and you understand the biology of the disease, you know whether this patient is at a higher or lower risk biological situation, and there are a lot of models that are helping us to do that. So it's really great to see Caris leading the way on this. Great to see you again, great to talk to you, and I wish you all the best in your future endeavors. And thank you for your partnership with the Prostate Cancer Foundation.

Michael Korn: Wonderful to be here again. Thanks for this exciting conversation. I look forward to the very exciting collaborative work we will do with PCF and with you in particular.

Charles Ryan: Thank you, Michael.

Michael Korn: Thank you.