UF researchers discover breakthrough anticancer drug
Researchers from the University of Florida College of Pharmacy have discovered a safer and more effective anticancer drug to target leukemia, lymphoma, and breast and lung cancers. The journal Nature Medicine published the findings this month.
Known as DT2216, the drug acts on a protein called B-cell lymphoma-extra large, or BCL-XL, which fuels the growth of malignant cells and strengthens their resistance to therapy. An inhibitor of the protein already exists, but it causes a drop in blood platelets, raising the risk of bleeding. Because of these concerns, the U.S. Food and Drug Administration has not approved that drug and scientists have been seeking alternatives.
UF researchers developed the new BCL-XL-targeting anticancer drug using a technology that relies on PROTACs, small molecules that, instead of just suppressing cancer-promoting proteins, help cells break them down. The result was more potent against a variety of human tumor cells bolstered by BCL-XL, yet were less toxic to platelets.
“We were fascinated by our findings because this was a first-of-its-kind study presenting a novel strategy to reduce the toxicity of an antitumor drug using PROTAC technology,” said Daohong Zhou, M.D., a professor of pharmacodynamics in the UF College of Pharmacy and the Henry E. Innes Professorship of Cancer Research at the UF Health Cancer Center. Zhou also serves as the Cancer Center’s associate director for translation and drug development.
The researchers demonstrated in mathematical and mouse models that DT2216 suppressed the growth of several tumors — including T-cell acute lymphoblastic leukemia and drug-resistant breast and small cell lung cancers — on its own and in combination with other drugs, without significantly lowering blood platelet count. Additional testing is required before moving to clinical trials in people.
“These findings support the potential of DT2216 to be developed as a first-in-class BCL-XL-targeting antitumor agent,” said Guangrong Zheng, Ph.D., an associate professor of medicinal chemistry in the UF College of Pharmacy, who jointly directed the research alongside Zhou.
The study was supported by a multidisciplinary research team from the University of Florida, the University of Texas M.D. Anderson Cancer Center, Columbia University, the Children’s Hospital Los Angeles and the University of Texas at San Antonio. The team brought together their diverse research expertise in cellular and molecular biology, drug discovery and development, medicinal chemistry, hematology and bioinformatics.
Along with Zhou and Zheng, the other researchers include Sajid Khan, Ph.D.; Xuan Zhang, Ph.D.; Dongwen Lyu, Ph.D.; Qi Zhang, Ph.D.; Yonghan He, M.D., Ph.D.; Peiyi Zhang, Xingui Liu, Ph.D.; Dinesh Thummuri, Ph.D.; Yaxia Yuan, Ph.D.; Janet S. Wiegand, Jing Pei, Weizhou Zhang, Ph.D.; Abhisheak Sharma, Ph.D.; Christopher R. McCurdy, Ph.D.; Vinitha M. Kuruvilla, M.Sc.; Natalia Baran, M.D., Ph.D.; Adolfo A. Ferrando, M.D., Ph.D.; Yong-mi Kim, M.D., Ph.D., M.P.H.; Anna Rogojina, Peter J. Houghton, Ph.D.; Guangcun Huang, M.D., Ph.D.; Robert Hromas, M.D.; and Marina Konopleva, M.D., Ph.D.