Q: The clinical trial is based on research and discovery from your own research laboratory. Can you tell me more about that?
Behura: Everything we know about CK2 in these diseases, we learned at Penn State. No other groups are working on CK2 in neuroblastoma and Ewing sarcoma, and the pharmaceutical industry may not have this target on their list as a top priority.
The first five-to-eight years of our work was in a completely different cancer. I started working in my mentor Sinisa Dovat’s lab to understand how CK2 affects a protein called Ikaros in high-risk leukemia. Ikaros is a transcription factor, which helps turn genes on and off, and it tries to suppress the formation of tumors. However, when CK2 is present in high amounts, it impairs the function of Ikaros and aids in the development of leukemia.
What’s interesting is that this kinase is actionable, meaning that we can target CK2 and inhibit its function, which in turn affects the stability and activity of Ikaros. This is important because directly targeting a transcription factor protein is difficult. Their structure and function are complicated, and we can’t easily find a drug that can restore or inhibit their function.
There is a new small molecule compound that inhibits CK2. Dr. Dovat’s group showed that this kinase inhibitor restored the function of Ikaros in high-risk leukemia patients. Then, in 2022 my lab began pre-clinical studies to test CK2 inhibitors in pediatric solid tumors.
Q: What’s the function of CK2 in the development of cancer?
Behura: Every cell needs CK2 to function. Without CK2, the cells die. But its levels are found to be elevated in many different cancers, including breast, prostrate and pancreatic cancers, as well as cholangiocarcinoma, a rare cancer that develops in the bile ducts.
In neuroblastoma, there’s a very important protein called Myc, which promotes cancer cell growth and proliferation, among other things. It drives much of the aggressive nature of high-risk neuroblastoma. Cancer cells need to maintain a certain level of this protein to survive.
We found that CK2 is part of a group of three or four kinases that forms a protective shield around Myc and stabilizes it. By inhibiting CK2, we weaken the shield and destabilize Myc. Myc then degrades quickly and the cancer cells die. That’s the mechanism we are working to understand better in our laboratory.
Q: Once you’ve made a promising discovery in the laboratory, what does it take to move it to a clinical trial?
Behura: Once we understood and verified the mechanism of CK2, we tested efficacy of the new CK2 inhibitor using patient-derived mouse xenograft models. These models use tumor tissue from patients to study, in mice, whether the drug shrinks the tumor and lets the mice survive longer.
The drug, a small molecule inhibitor, became available in 2022 and we began studying its effect on neuroblastoma and Ewing sarcoma in mouse models. These results were critical in obtaining permission from the Food and Drug Administration to test this drug in children with solid tumors.
It’s a critical part of the pre-clinical research. Many compounds don’t move forward past testing in the lab because researchers don’t have the animal models, access to patient tumor samples and resources. We were able to move quickly because we had access to patient samples, we had the animal facility, and we had funding to support this work, especially from Four Diamonds.
There are challenges in pediatric cancer drug development. There is often less pharmaceutical company interest in testing drugs to treat rare diseases such as pediatric cancer. However, we are grateful the drug company agreed to supply the drug for our clinical trials.
Q: What role do partnerships play in your research?
Behura: We couldn’t do this work without our partners. Four Diamonds provided critical funding for our research infrastructure, including, laboratory space, personnel, access to cutting edge equipment and technology and our animal facility, to name a few.
Another collaborator, the Beat Childhood Cancer Consortium (BCC), has a large biorepository of the tumor samples that we needed for pre-clinical research and patient-derived xenograft models. Those samples include some from our own patients that are treated here at Penn State. Partnering with BCC consortium was important to ensure timely accrual of research study subjects needed to make meaningful conclusions as BCC has a network of over 50 hospitals across North America.
As a medical doctor with no Ph.D. or prior research experience, receiving mentorship and support from established physician-scientists at Four Diamond Laboratories was absolutely the key to my career.
Q: You’ve been studying CK2 for 13 years. What keeps you going?
Behura: This work is very rewarding. The environment, mentors and collaborators that I worked with during my early years also inspired me to continue to work on projects that have clinical application in near future.
Our initial work established the importance of targeting this kinase and later having the patient samples and animal models helped us to quickly translate the results from our studies to show effectiveness. It’s this connection between bench-to-bedside, to take what we see in our lab and seeing the opportunity to make a difference in a child’s life, is very motivating and inspiring.