“Because BD4 is especially important for PBRM1 activity, we wanted to understand how cancer-associated mutations in PBRM1-BD4 impact the ability of the protein to engage in its cellular functions as a tumor suppressor,” said Karina Bursch, BS, graduate student in the Brian Smith Laboratory and in the Medical Scientist Training Program (MSTP). “Excitingly, we observed that the stability of isolated PBRM1-BD4 protein in a test tube correlated strongly with the stability of the entire PBRM1 protein in cancer cells. This means that less time- and resource-intensive computational and biophysical studies of PBRM1 bromodomains are a good proxy to understand the cellular roles of full-length PBRM1 protein in cells, providing key information for patient diagnosis and treatment.”
“We discovered that cancer-associated PBRM1-BD4 mutations had a wide variety of impacts on PBRM1 stability and function. We are optimistic that the insights gained from this study will contribute to the development of future precision medicine strategies that target PBRM1 and its bromodomain interactions for cancer treatment.” —Karina Bursch, BS
The study team measured the stability and target binding ability of mutated PBRM1-BD4 proteins in test tubes, then tested how these mutations affect the behavior of cancer cells in the lab. Their results showed that mutations in PBRM1-BD4:
- Make the protein less stable
- Affect how well PBRM1 binds to specific targets in cells
- Impact the protein’s ability to suppress cancer cell growth
Because PBRM1 is frequently mutated in clear cell renal carcinoma (ccRCC), the most common type of kidney cancer, Bursch said the team is currently studying PBRM1 bromodomain mutations in patients with ccRCC to determine how kidney cancer cells may respond to cancer therapies. Additionally, in collaboration with MCW’s Program in Chemical Biology (PCB), researchers have developed a selective, cell-active PBRM1 inhibitor. They welcome collaborations from other scientists at MCW who would like to test this PBRM1 inhibitor or work with the PCB to develop novel drugs that bind important proteins in other diseases.
After she completes her MD-PhD training through the MSTP, Bursch hopes to maintain an active physician-scientist career as an oncologist and a principal investigator at an academic medical center, leading a research laboratory dedicated to exploring the biochemical foundations of cancer.
“I am grateful to my PhD mentor Dr. Brian Smith for providing his expert input as scientific projects evolve, and for allowing me to take full responsibility for developing hypotheses, conducting experiments, and preparing manuscripts. I am confident that the strong training that I am receiving in biochemistry, molecular and cellular biology, and computational biochemistry will allow me to understand and probe the nuances of cancer in greater detail,” she said. “I am also grateful for the support that I have received from the MCW Cancer Center. My graduate fellowship for my project, “PBRM1 missense mutations in ccRCC vascular signaling,” was especially instrumental for my subsequent successful NCI F30 fellowship application.”
Read the full study in the Journal of Biological Chemistry