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Dr. Brandon Manley is a urologic oncologist at the Moffitt Cancer Center in Tampa, Florida. He received a 2020 Young Investigator Award for an “Investigation of the Aberrant Epidermal Growth Factor Receptor Splicing Proteome to Determine Drug Repurposing Strategies for ccRCC”, which examines how EGFR, an effective drug target in various cancers, could be useful in kidney cancer.

We spoke with Dr. Manley about his work and what it means for patients.

Splicing lets cells make multiple different proteins from one set of genes. Can you describe how that figures into your research project?

Dr. Manley: Our project takes a deeper dive at some epidermal growth factor receptor (EGFR) splice variants that we’ve recently identified in clear cell kidney cancer. EGFR has been a well-known oncogene for generations and there are a lot of drugs targeting it. EGFR sets off a whole chain of reactions that allows cells to grow and proliferate, which is not good in the cancer setting. Clear cell kidney cancer has not demonstrated to be susceptible to EGFR-targeting drugs, but we haven’t tried for the last 10 years. We didn’t see the classic mutations in EGFR that are present in lung cancer, for example, where EGFR inhibitors are synonymous with treatment. And with immunotherapy coming about, people sort of said, ok let’s move on and focus on that.

The EGFR splice variant we discovered is only seen in kidney cancer, unique to the tumor. Usually, at the molecular level, when you see something like that, it means that the tumor is getting some kind of advantage. Our hope is that by better understanding how this ccRCC EGFR splice variant produces different proteins, we may be able to repurpose some of the EGFR-targeting drugs that exist and target treatment for a subset of patients with kidney cancer.

What’s the balance between new drug discovery and drug repurposing in RCC?

Dr. Manley: You have the opportunity, by studying this pathway, to pick from a library of drugs that have already gone through multiple stages of clinical development and that has a more appealing avenue of impact than developing a drug from scratch, which is really expensive and time-consuming – that would be plan A. Plan B would be the long game of saying, if we can’t find the right drug based on what we’ve studied, can we, just by studying these mechanisms, develop a unique one?

What motivates you?

Dr. Manley: One of the things I love about being a surgeon and treating patients with kidney cancer is I get to have an immediate impact on the majority of those patients. At the same time, I’m only helping one patient at a time. With research, I know that, unfortunately, a lot of times a project may not be successful, especially in complex diseases. But the reward is so huge – you know that with one significant breakthrough, we can help possibly millions of patients worldwide, and maybe for the foreseeable future.

Every surgeon will let you know that, even as good as they may be, you can’t cure every patient that way. So we need to look at the bigger picture and also have options, especially for those with more advanced disease.

Is there anything else you’d like others to know?

Dr. Manley: I’ve been fortunate to be going to KCA meetings since I was in training. It’s certainly gratifying to now have some recognition from that committee, and from not just physicians, but patients and advocates for being willing to support these kinds of efforts, and I’m very appreciative of it.

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