The pharmaceutical industry once deemed transcription factors that drive cancer "very difficult targets to make drugs for." UVA Health researcher John Bushweller, PhD, is undeterred.
Aberrant behaviors of certain transcription factors play an important role in several cancers, including leukemia, prostate cancer, lung cancer, and Ewing sarcoma.
"Transcription factors have traditionally been viewed as 'undruggable' due to the need to target the more challenging protein-protein or protein-nucleic acid interactions through which these proteins act," Bushweller shares. "There are still relatively few examples of such agents for cancer treatment. We are exploring several unique approaches to target this important class of proteins for drug development."
Watch Bushweller talk about his research and read his answers to our questions below.
What are you working on right now?
We have two current projects we are very excited about.
We developed an inhibitor of the CBFβ-SMMHC transcription factor fusion protein that is the primary driver in the inv(16) subtype of acute myeloid leukemia (AML) and established on-target activity, efficacy in a mouse model, and efficacy against patient samples.
However, our first generation inhibitor could not be given orally. Recently, we developed analogs with excellent oral bioavailability, which significantly enhances the likelihood of deployment to the clinic. This targeted approach to treatment should be both more effective as well as less toxic than the current classical cytotoxic chemotherapy used to treat inv(16) AML.
We have also developed an inhibitor of the transcription factor ERG, which is a driver in prostate cancer, leukemia, and Ewing sarcoma. We are exploring its utility in all of these cancer settings. Again here, this targeted approach should be both more effective and less toxic.
What are the most intriguing potential clinical applications of your work?
The CBFβ-SMMHC inhibitor will provide a targeted approach to the treatment of inv(16) AML, which is a stark contrast to the classical cytotoxic chemotherapy used to treat these patients currently. The current treatment kills all rapidly growing cells indiscriminately and, as a result, has significant toxicity associated with it.
The targeted approach directly inhibits the primary driver of the disease and we have shown it has little to no effect on cells that do not have CBFβ-SMMHC. It has limited, if any, toxicity. Furthermore, we have data that shows that CBFβ-SMMHC is the primary driver of relapse, so we believe inhibiting it will improve outcomes.
Similarly, the ERG inhibitor presents a targeted approach to treat multiple cancers, including prostate cancer, leukemia, and Ewing sarcoma. In the cases of prostate cancer and Ewing sarcoma, we have established on-target activity of the inhibitor and are working to advance these inhibitors further.
The inhibitor will directly target a primary driver of the disease, which should improve outcomes. As a targeted therapy, it should have limited toxicity and improve patient quality of life.
What discovery, paper, or presentation impacted the way you think?
The development of proteolysis targeting chimeras (PROTACs) opened our eyes to a whole range of cellular activities we can modulate with small molecules.
PROTACs have two components linked together via a linker, with one binding to the protein being targeted and the second binding to a protein that will mark the target protein for destruction in the cell, resulting in a reduction of the level of the target protein in the cell.
Two of these, targeting the androgen receptor (AR) and the estrogen receptor (ER), have entered clinical trials, and many are in development.
This work opened up the idea of proximity mediated pharmacology, where bringing a target protein close to another protein that can modify it somehow can completely alter its activity. This is being used to manipulate cells in a myriad of ways and has the potential to be transformative in how we approach pharmacology.
What made you choose UVA Health as the place to do your research?
I've been at UVA Health for 26 years! When I first came here, I was seeking a vibrant research community where our research could thrive. I certainly found that. We have outstanding researchers who we collaborate with regularly. We also have a thriving NCI designated cancer center, which makes this the perfect environment to do the work we're doing.
What do you wish more people knew about your area of research?
We strongly believe that targeting transcription factor drivers in cancer is a paradigm that can have substantial benefits for patients. When targeting a transcription factor, you are altering the expression of many genes, which makes it possible to alter the identity and behavior of those cells.
Transcription factors are more challenging targets for drug development because of the need to target protein-protein or protein-DNA interactions, but even pharmaceutical companies have now recognized the potential of this approach and are moving aggressively into this area.
How did you become interested in your area of research?
I have always been fascinated by science and interested in cancer. In elementary school, I told my parents my career aspiration was to cure cancer. While I am certainly a bit more realistic in my expectations as an adult, I still have the drive to try to develop new and more effective approaches to treating cancer.
My interest in leukemia in particular stems from watching the daughter of a neighbor suffer and ultimately succumb to leukemia, as well as from a long-standing collaboration with my friend and scientific collaborator Nancy Speck. Nancy introduced a young, very green assistant professor to the realm of leukemia research, and we have worked extensively in that area ever since. I am so thankful to Nancy for pointing me in that direction.
