UCLA researchers in the Department of Pathology and Laboratory Medicine have developed small molecules which inhibits the protein IGF2BP3, a highly expressed oncofetal protein in certain cancers, especially in B-acute lymphoblastic leukemia.
BACKGROUND: Cancer remains the second leading cause of death in the U.S. Advancements in targeted therapies in which cancer cells are specifically targeted, in contrast to chemotherapy which kills any rapidly dividing cell, have improved patient prognosis in various cancers. However, the largest challenge in therapeutic development is identifying a suitable target that is highly expressed and critical in cancer cells and has minimal expression in non-cancerous cells. Dr. Dinesh Rao’s research group has discovered that an RNA-binding protein, IGF2BP3, is highly overexpressed in mixed lineage leukemia–rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL). This cancer is associated with poor prognosis and high risk of relapse. IGF2BP3 is required for survival of all B-ALL cell lines and is therefore an excellent target for cancer treatments. In vivo experiments with a genetic knockout of IGF2BP3 showed that it was not required for normal development, but was indeed required for the development of MLL-rearranged leukemia. These findings, along with the definition of the RNA binding profile of IGF2BP3, form a firm foundation for targeting this protein with a wide therapeutic window.
INNOVATION: Scientists at Dr. Dinesh Rao’s laboratory have performed a high-throughput screening of 190,000 compounds and have identified a promising compound that inhibits RNA binding of the IGF2BP3. This compound shows cell growth inhibitory activity in multiple leukemia cell lines tested, with an IC50 of approximately 2 µM. The compound causes the cancer cells to enter partial cell cycle arrest at G0/G1 resulting in apoptosis of the cancer cells. Additional synthesis of analogs based upon the initially identified compound has led to the discovery of additional compounds with high anti-cancer activity in IGF2BP3-high leukemia cells. Based on database searches, IGF2BP3 is overexpressed in up to 15% of all human cancers which makes the IGF2BP3 inhibitors potential candidates to treat other types of cancer as well. This led the researchers to validate the anti-tumor function of these compounds in various cancer models, including Non-Hodgkin's lymphoma, pancreatic cancer and glioblastoma and mouse model of leukemia.
POTENTIAL APPLICATIONS:
- Developing drugs that block the IGF2BP3 protein to stop cancer cell growth can be a new pan-cancer target therapy including leukemia, Non-Hodgkin’s lymphoma, pancreatic cancer, and glioblastoma
- Novel and highly specific biomarker for various cancers
ADVANTAGES:
- Reduced side effects as this therapy specifically targets cancer cells with no expression in healthy tissues
- IGF2BP3 is a key target in multiple types of cancer
- Small molecules allow for ease of delivery and manufacturing costs
DEVELOPMENT-TO-DATE: Small molecules have been developed and shown cancer effectiveness in mouse studies for leukemia and other cancer models including Non-Hodgkin’s lymphoma, pancreatic cancer, and glioblastoma. Paper in review for first small molecule.
Related Papers (from the inventors only):
Tran TM, Philipp J, Bassi JS, Nibber N, Draper JM, Lin TL, Palanichamy JK, Jaiswal AK, Silva O, Paing M, King J, Katzman S, Sanford JR, Rao DS. Leukemia. 2022 Jan;36(1):68-79. doi: 10.1038/s41375-021-01346-7.
Palanichamy, J. K., Tran, T. M., Howard, J. M., Contreras, J. R., Fernando, T. R., Sterne-Weiler, T., Katzman, S., Toloue, M., Yan, W., Basso, G., Pigazzi, M., Sanford, J. R., & Rao, D. S. (2016). RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation. The Journal of clinical investigation, 126(4), 1495–1511.
Lin TL, Jaiswal AK, Ritter AJ, Reppas J, Tran TM, Neeb ZT, Katzman S, Thaxton ML, Cohen A, Sanford JR, Rao DS. Targeting IGF2BP3 enhances antileukemic effects of menin-MLL inhibition in MLL-AF4 leukemia. Blood Adv. 2024 Jan 23;8(2):261-275.
Tran, T. M., & Rao, D. S. (2022). RNA binding proteins in MLL-rearranged leukemia. Experimental hematology & oncology, 11(1), 80.
Keywords: cancer, leukemia, cancer inhibition, blood cancer