By Ian Bennett
A new study published in Clinical Cancer Research revealed that inhibition of the IRAK-4 protein with a small molecule inhibitor called CA-4948 can downregulate the expression of transcription factors related to cancer, even inside the blood-brain barrier. This discovery could have significant implications for treating certain types of cancer like primary central nervous system lymphoma (PCNSL) and melanoma brain metastases (MBM). Currently, only 2% of all FDA-approved anticancer agents can reach significant activity in the brain, according to a report from The Sidney Kimmel Comprehensive Cancer Center.
Led by collaborators Christina von Roemeling, Ph.D., and Bently Doonan, M.D., the research team included Kelena Klippel; Daniel Schultz, Ph.D.; Lan Hoang-Minh, Ph.D.; Vrunda Trivedi, Ph.D.; Chenglong Li, Ph.D.; Rylynn Russell, Raju S. Kanumuri, Ph.D.; Abhisheak Sharma, M.Pharm., Ph.D.; Han W. Tun, M.D.; and Duane Mitchell, M.D., Ph.D. Together, this team conducted a series of experiments to study the impact of inhibiting the IRAK-4 protein with an oral small molecule drug called CA-4948. IRAK-4, or interleukin-1 receptor-associated kinase 4, is part of a signaling pathway for recognizing pathogens and initiating inflammation. Specifically, the IRAK-4 protein relays signals from proteins called Toll-like receptors and IL-1 receptor-related proteins.
“IRAK-4 has a high clinical importance because it is involved in how many cells respond to inflammation,” Doonan said. “It is a signal that is supposed to stimulate our body to destroy infections but is co-opted and instead used by cancer cells to grow and divide. The drug we used in our experiments is very specific to IRAK-4. The specificity is almost 1,000% higher with this drug, and inhibiting this interaction has broad effects on both the cancer cells and how the immune system interacts with them. We knew that if this molecule were effective, we could have greater control over treatment by targeting this specific protein.”
The team used advanced techniques, methodologies and resources at the University of Florida to analyze the expression of key transcription factors in cancer cells treated with CA-4948. These factors are created as a response to IRAK-4 signaling. The results showed that CA-4948 significantly downregulated the expression of these transcription factors, indicating that the drug could be an effective treatment for certain types of cancer because it can inhibit the function of the IRAK-4 protein.
CA-4948 is being investigated in clinical trials for relapsed and refractory lymphoma, and the team plans to open a first-in-human clinical trial for patients with melanoma brain metastases later this summer. The continuation of this research could have significant implications for the field of oncology and lead to new treatment options for a wide range of cancers.
