Identifying unique therapeutic targets for chromophobe kidney cancer

In this interview, David A. Braun, MD, PhD, shares in-depth insights into the study, “Investigation of ferroptosis and mTOR signaling in chromophobe renal cell carcinoma (ChRCC),” which was presented at the 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium in San Francisco, California. Braun is an assistant professor of medicine at Yale Cancer Center in New Haven, Connecticut.

This transcript was AI generated and edited by human editors for clarity.

David A. Braun, MD, PhD

Could you describe the background/rationale for this study?

A lot of this stems from what we see in the clinic, which is when a patient with clear cell kidney cancer comes in, we're fairly informed about what to do. We have lots of trial data to guide us. There are still individualized decisions, but [there are] lots of pieces of data [to guide those choices]. When a patient with chromophobe kidney cancer comes in, I think it's a very different story. There's a lack of data, and most of our approaches are extrapolations from things like clear cell, even though we know the biology of chromophobe kidney cancer is dramatically different.

The background for this study is, can we use some of our more advanced technologies, like single cell sequencing approaches, to understand the biology of chromophobe kidney cancer and related oncolytic neoplasms—benign oncocytomas, and then intermediate, low-grade oncolytic tumors. That's the motivation for this. [Can we use] those approaches to understand what is the cell of origin, where do these tumors come from, and then why or why not might they be sensitive to immune therapies or other types of therapies that we use for kidney cancer?

What were the key findings?

There are a couple of key points. The first is, what is the cell of origin for chromophobe kidney cancer? It's different from clear cell or even papillary [disease]. Clear cell and papillary come from the proximal tubule, early in the renal tubule. [Chromophobe] comes from the distal tubule, particularly the α-intercalated cells. So, we now know the cell of origin. We're empowered with that information to compare how the tumor cells are different from their cell of origin.

What we see is a fairly dramatic down regulation of antigen-presenting machinery, so it's actively hiding from the immune system. That might explain why we don't see phenomenal immune responses in general for chromophobe. It upregulates regulators of ferroptosis and also of mTOR signaling. What we think or hope, at least, is this might give some hint as to what might be therapeutic vulnerabilities that are unique to chromophobe kidney cancer.

We began to investigate that within this project. So, we worked with the IMDC group, which is a large real-world data set of kidney cancer outcomes. What we saw was those patients who were treated with mTOR inhibitors, if they had chromophobe kidney cancer, they actually did remarkably better, on average, than those with clear cell who were treated with mTOR inhibitors. Again, [this finding was] stemming from the biology. What we hope overall is that this is a biological study that might inform therapeutic development for this disease.

What should urologists be aware of when diagnosing chromophobe kidney cancer?

I think a key aspect is having a really well-trained and good GU pathologist. I've been so fortunate throughout my career at Dana Farber and Yale to have just world-class GU pathologists. That's one of the key first steps to effectively treating and understanding these diseases. If you don't know what you're fighting, it's hard to know what the optimal approach or optimal therapy is. There are markers, ones that we've looked at within our single cell sequencing data and ones that are also more widely used, like c-kit and others. But the key is don't go it alone. This is a multidisciplinary effort, and our approach to chromophobe is one that includes not just medical oncologists, but close collaboration with pathologists and urologists. Often, there are areas that are resectable with radiation oncologists and others. I think that's a key to approaching this disease.

How might these data affect the current treatment landscape?

I think this study does a couple of things. [Our prior hope] was that we could largely extrapolate our treatments from clear cell kidney cancer and hope that they applied to chromophobe. That's what we did with immune checkpoint inhibitors. This study is indicating we need to think differently. These chromophobe kidney cancers, unfortunately, have very few immune cells; that's different from clear cell kidney cancer. Among those immune cells, even fewer of them are CD8+ T cells, which we think of as the main effectors. The ones that are there, they actually don't express a lot of PD-1. So, if we're giving a drug that targets the PD-1 pathway, and there's no target present, there's not a high hope that that's going to be effective.

Then finally, one of the things we looked at in the study is, what is the specificity of those T cells that are there? Are they capable of recognizing and attacking the tumor cells, or are they just bystanders that are there, non-specifically and recognizing things like the flu virus or other things? It seems, by and large, that they're the latter. They are bystanders. Although it's discouraging in some ways that our current therapies are less likely to be effective, my hope is it provides a roadmap for how we can [drive] therapeutic development in this disease. What we need to do is get more T cells there, and we need to get the right phenotype and the right specificity. And there are approaches to do that. There are T cell engagers and many other strategies. I think those are the ones we're going to have to employ to improve immune therapies for this disease.

What next steps are planned based on this study?

This was the first step. It was a wonderful collaboration with Elizabeth Henske [,MD]’s group at the Brigham [and Women’s Hospital], which has been studying chromophobe kidney cancer for many years, Sachet Shukla [, PhD], at MD Anderson, and Toni Choueiri [, MD, FASCO], at Dana Farber. It’s going to require a collaborative effort to study these rare tumors. The hope is that now that we're beginning to dissect away what the biology is and that's going to inform therapeutic development. We can use data sets like this to say, what are the targets that are there? How might we be able to bring in more T cells? How can we work as a collaborative group to start trials that would be specific for this disease? That's my hope of where this is going to go.