Dr. Ed Reznik is a computational oncologist at Memorial Sloan Kettering Cancer Center (MSKCC) and a recipient of a 2019 Young Investigator Award to examine tumor metabolism as it relates to the tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC).
Dr. Reznik, under the mentorship of Dr. Ari Hakimi, a surgeon at MSKCC, proposed that a better understanding of the TME and its varied components, which include blood vessels, stroma, and immune cells, might help indicate which types of immunotherapies are more likely to be effective in patients with ccRCC as well as identify potential new therapeutic targets.
We spoke with Dr. Reznik and Dr. Hakimi about the research and it’s impact.
Ed Reznik: I was generally interested in cancer metabolism and, as it turns out, RCC is really a wonderful place to study cancer metabolism because many of the familial types of RCC are genetically defined by mutations to metabolic enzymes.
From Ari’s findings, it became clear that the kinds of cells that infiltrate the tumor can dictate the potential for a patient to respond to immunotherapy and they characterize what happens after a patient sees immunotherapy. So, the therapy itself shapes the composition of the tumor and we think that could influence the prognosis of the patient going forward.
ER: The reason the microenvironment is important is that it’s the interactions between cells that dictate whether or not you respond to therapy. It could be, for example, that immune cells and tumor cells may be competing for the same nutrients. If they are and that nutrient is limiting, one of those cells may lose out and that may dictate whether the tumor as a whole responds. We kind of view the microenvironment as this set of interacting actors that can each play a role in ultimately dictating whether a therapy works or not.
Ari Hakimi: Our goals obviously are to come up with better treatments but In the short term we can learn more about what features in a patient’s tumor might be associated with particular drug responses and also try to customize the treatment strategy on these features.
ER: I’m a new entrant to the field of metabolism of immune cells… but I’m not a wet lab biologist I’m a computational biologist. We have a database of metabolic data and we can start to address the same kinds of questions that the wet lab biologists are doing from the other end of the spectrum. Rather than in a focused experiment isolating immune cells, manipulating them, and seeing what happens, we can look at primary data from tumor specimens and, using correlative analyses and machine learning analyses, we can try to pinpoint what the association is between metabolism and the microenvironment.
ER: One of the valuable principles I’ve gleaned hanging around wet lab biologists is we need to have, when we do computational experiments, positive and negative controls.
Going forward, the way to analyze this data is to have some specific hypotheses in mind and go directly after testing them and challenging them. Our hypothesis is that there’s a particular metabolite called kynurenine which seems to be strongly associated with the abundance of immune cells across many different cancer types. We are designing our computational approach to specifically test it. The beauty of that is by one way or another it will be borne out to be true or false. But by building out all of the methodologies to do that, we’ll also be able to explore other possibilities. So even if kynurenine turns out not to be the silver bullet, the same method we built to test that will probably uncover what is the key metabolic determinant of the microenvironment, if there is one.
AH: This is an unprecedented opportunity to both look at metabolic changes that occur in immunotherapy but also compare it to the untreated baseline. Obviously, we hope that will give us fundamental insight into metabolic changes that occur after common therapies but also a look at what could be the next target.
ER: I would add that there are a lot of emerging metabolic therapies on the market, not just for RCC but for lots of other cancer types. A lot of these drugs target enzymes that are universally expressed across all lineages. And it’s provocative to think that if the benefits of immunotherapy can be augmented by introducing a combination with a metabolic target, that we may already have drugs in the pipeline which are safe in humans which could be paired with immunotherapy relatively quickly in order to increase the benefit to patients.
ER: Things changed recently, I went to a conference organized by patient advocates. For computational biologists, we never interact with or see patients and for many years I’ve never personally met a kidney cancer patient. So, it was very moving to hear the experiences of patients, family members, and their friends of what going through kidney cancer is like and the struggle they experience.
Before, my motivation was largely intellectual. I have a passion for metabolism. Scientifically, it’s a really cool topic. More recently, I’ve realized the impact this could have for patients, even though it’s a relatively basic project. It’s still striving towards the goal of improving the life of even a single person. That motivates me to pursue it.
AK: I have my dream job in that I get to operate and see patients but also get to work closely in the science world. Because what I study is the microenvironment and you need human tissue to do that – it can’t be recapitulated in a mouse, certainly not in a dish – it’s very motivating for me to make some hopefully fundamental discoveries. I’m thankful every day that patients are willing to help us by giving us blood or access to their tissue or being in trials that allow us to do this. It’s very gratifying to see this kind of working relationship between patients, physicians, and scientists.