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Scientists at VCU Massey Comprehensive Cancer Center have uncovered a powerful new drug combination that could overcome resistance in T-cell lymphoma (TCL), an aggressive and often treatment-resistant form of blood cancer.

The study, recently published in the British Journal of Haematology, shows that combining an approved class of drugs known as histone deacetylase inhibitors (HDACIs) with the investigational compound GGTI-2418 dramatically enhances cancer cell death and reverses drug resistance through suppression of the AKT survival pathway.

The research is the result of a close collaboration between the laboratory of Said Sebti, Ph.D., associate director of basic research at Massey and a professor in the Department of Pharmacology and Toxicology at the VCU School of Medicine, and the laboratory of Steven Grant, M.D., co-leader of the Developmental Therapeutics research program at Massey and a professor in the Department of Hematology, Oncology and Palliative Care at the VCU School of Medicine.

Although HDAC inhibitors such as belinostat and romidepsin are approved for treating T-cell lymphomas, some patients relapse, in part, because their tumor cells may activate AKT, a key molecule that promotes survival and cancer therapy resistance. The VCU team found that adding GGTI-2418, which disrupts prenylation of tumor cell proteins, to HDAC inhibitors shuts down this escape mechanism, a finding validated by genetic approaches. In preclinical models, the combination therapy effectively reduced tumor growth compared to either treatment alone.

“The synergism between these two drug classes is striking and consistent,” Grant said. “By combining complementary targeted agents, we can block the mechanisms that drive resistance and potentially achieve more durable clinical responses.” 

“Our findings show that resistance to HDAC inhibitors can be overcome by simultaneously targeting the AKT pathway with GGTI-2418,” said Sebti, who also co-invented GGTI-2418. “This discovery not only deepens our understanding of how T-cell lymphomas evade treatment, but also provides a clear and rational path toward more effective therapies for patients.”

The preliminary evidence of activity of GGTI-2418 in T-cell lymphomas, along with the approval of HDACIs in these disorders, makes this a particularly attractive combination strategy. Specifically, the data reported through the latest study provides a theoretical foundation for proposing a phase I clinical trial combining these two drugs in patients with a sub-type of relapsed/refractory T-cell lymphomas, and efforts are currently in development.

“This discovery exemplifies Massey’s mission—translating innovative science from the lab to the clinic to bring new hope to patients,” said Robert A. Winn, M.D., director and Lipman Chair in Oncology at Massey. “The work of Drs. Sebti and Grant highlights how our collaborative research environment accelerates progress against even the most challenging cancers.”

 GGTI-2418 by itself has also shown encouraging activity against T-cell lymphomas and has advanced to a global phase 2 clinical trial for cutaneous T-cell lymphoma.Massey is the first activated site for patient accrual in the United States in this international study.

VCU collaborators on the latest published research include Xiaoyan Hu, Ph.D., Lin Li, Aslamuzzaman Kazi, Ph.D., Jewel Nkwocha and Hitesh Vasiyani, Ph.D.