Promising drug-like compounds found to have strong action against blood cancers

For researchers, projects can sometimes feel like babies, and there’s nothing more satisfying than watching your baby grow. For William Tansey, professor of cell and developmental biology, that baby began 10 years ago when he and Stephen Fesik, the Orrin H. Ingram II Professor of Cancer Research and professor of biochemistry, discovered that a protein called WDR5 is a “complicit” of MYC, a transcription factor and oncogene that is often mutated in cancers. In fact, dysregulation of MYC is estimated to be responsible for about a third of all cancer deaths each year.

This research baby is growing fast. Tansey, Fesik and other researchers around the world have produced hundreds of papers on WDR5 in the last five years alone. Among the findings: WDR5 recruits MYC to chromatin to control the expression of genes that cancer cells use to make the proteins they need to thrive. This makes WDR5 a prime candidate for targeting drugs against MYC-related cancers.

Previous research by Tansey and Fesik led to the discovery of WDR5 inhibitors called WIN site inhibitors, or WINis. WINis have only been shown to be active against a handful of rare cancer types. But for their most recent paper, Tansey recruited Vito Quaranta, professor emeritus of pharmacology, to help them analyze a panel of 300 cancer cell lines derived from 20 different cancer types to determine their sensitivity to WINis.

Their latest work, published in the Proceedings of the National Academy of Sciencesshows that blood cancers are particularly sensitive to the effects of WINi and that combining WINi with venetoclax improves the drug’s efficacy in suppressing leukemia progression in an animal model; venetoclax is a drug approved by the Food and Drug Administration to treat acute myeloid leukemia.

The synergy between WINi and venetoclax means that clinicians may be able to reduce the dose of venetoclax needed for treatment, thereby reducing its side effects while potentially improving outcomes for leukemia patients.

Quaranta wasn’t the only other collaborator involved in the project. “Collaborating with Qi Liu helped us understand the mechanism of action of combining our inhibitors with venetoclax. Collaborating with Michael Savona allowed us to show that our inhibitors were effective when combined with venetoclax,” Tansey said. Liu is a professor of biostatistics and Savona is a professor of medicine.

“This is a very local story,” Tansey said. “I’m grateful that we have such a variety of world-renowned experts here that we can work with to do such robust research.” Tansey also worked with April Weissmiller of Middle Tennessee State University, William Moore of the National Cancer Institute and Gordon Stott of the Frederick National Laboratory for Cancer Research on this paper.

For now, the potential of this baby of research is multiplying. “Before this work, we thought that future drugs would have limited clinical utility,” Tansey said, referring to earlier results indicating that WINi were active against only a handful of rare cancer types.

“Our finding that leukemia and lymphoma cells have broad sensitivity to WINi, both in vitro and in vivo, represents a significant expansion of the number of cancer cases that could benefit from WINi in the clinic.”

Blood-borne cancers (leukemia, lymphoma, and myeloma) account for about 10% of all cancers diagnosed in the United States each year and are responsible for about 3% of annual cancer deaths.

The study authors noted that some solid cancer cell lines, particularly those derived from ovarian and breast cancers, were also sensitive to WINi in cellular studies, a finding that represents a still unexplored area of ​​research.

In the United States, both types of cancer represent a significant burden of disease: breast cancer is the second most common type of cancer in women, and ovarian cancer is the second most common type of gynecologic cancer in women. In addition, breast cancer and ovarian cancer are closely related, and a diagnosis of breast cancer increases the risk of developing ovarian cancer and vice versa.

Targeting blood, breast and ovarian cancers means WINi has huge potential. But before it can help patients, Tansey said, “these studies will help us understand how WINi can be applied in the clinic and how to best leverage it to improve hematologic malignancies.”

In the meantime, he added, “the National Cancer Institute is working with us to turn these inhibitors into drugs.”