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Dr. Sheldon Holder received a 2022 KCA Trailblazer Award for his research on the “Exploration of the causes and effects of increased PIM1 kinase activity in renal cell carcinoma”. Dr. Holder is a physician-scientist at The Legorreta Cancer Center at Brown University. We spoke with Dr. Holder about his work and the impact it can have on people with kidney cancer.

What was the inspiration for this research project? Why do you think it’s necessary right now?

I have been interested in targeting PIM1 kinase in various tumor types for many years. More specifically, a few years ago we published a paper showing PIM1 protein levels are elevated in kidney cancer compared to normal kidney tissue. We also showed that in pre-clinical models, adding a PIM1 kinase inhibitor to standard VEGF-R targeted therapy improved the depth and duration of response and overcame VEGF-R targeted therapy resistance. Thus it was clear to me that PIM1 is a therapeutic target in kidney cancer. However, the reason PIM1 protein levels are high in tumor tissue remains unknown. Additionally, the downstream targets of PIM1 kinase activity that contribute to kidney cancer remain poorly understood. This research project seeks to fill both of these knowledge gaps.

Our project is necessary right now because new targets are needed for kidney cancer therapy. Numerous medications are currently available to treat kidney cancer, but there is significant overlap in the targets of these medications. Moreover, medications that have different targets that we used to give sequentially, we are now using in combination. As a result, when patients develop resistance to the combination therapy I believe we will need new therapeutic targets in order to continue to successfully treat these patients. When we consider that cases of kidney cancer have been rising over the past decade, it is even more pertinent that we identify new targets for therapy now.

What kinds of opportunities for drug repurposing exist for RCC?

We believe that as we uncover the pathways causing increased PIM1 protein levels, we will find targets for which there are already clinically available therapies. For example, our early data show that an IL-6/JAK/STAT pathway is likely driving increased PIM1 kinase protein levels. Interestingly, IL-6 blocking agents and JAK inhibitors are already in use in the clinic to treat other medical conditions. We believe that these agents may be effective in treating kidney cancer where this pathway is active. Because these agents are already in use clinically, we are very interested in repurposing these agents to treat kidney cancer.

How should researchers balance repurposing with new drug discovery?

There is a good place for both initiatives. Repurposing allows a more rapid time to implementation of the science, because the therapy is already known to be safe. The shorter time to clinical application benefits patients sooner. Simultaneously, the nuances of how the target is involved in one disease may be sufficiently different in a second disease to allow room for development of a more efficacious medication. • What motivates you? I would say there are two main motivators: 1) the science – I have a continued desire to understand the mechanisms that cause and promote cancer development and growth. 2) Patients – One of the most difficult conversations to have with a patient is to tell them that modern medicine has no more medications to offer them for their cancer. Seeing patients in clinic who need a new therapy, with no therapy to offer them, drives me to continue to look for new and better ways to treat cancer.

Anything else you’d like others to know about you or your work?

I am honored to be one of the recipients of the Kidney Cancer Trailblazer award. The Holder lab is focused on identifying, interrogating, and implementing new science into patient care. Thank you to the Kidney Cancer Association for funding this project.

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