Introduction: Canine lymphoma (CNL) is similar to the human disease and accounts for ~6% of all cancers in dogs. The majority of CNL are of B-cell origin (B-CNL), although a significant proportion are T-cell lymphoma (T-CNL; ~28%). Standard of care chemotherapy is effective against B-CNL but lacks meaningful activity in T-CNL. Our preclinical studies have demonstrated exceptional activity of a nanoparticle of romidepsin (nanoHDACi) against T-CNL, which offers a unique approach for managing this disease.
Results: Targeted drug screens were performed in T-CNL and human PTCL cell lines in vitro. Among the drugs tested, romidepsin exhibited the most significant cytotoxicity with low nanomolar IC50 in T-CNL lines (UL1, Ema, and CNK-89), consistent with the pattern seen in human PTCL cells. NanoHDACi exhibited cytotoxicity similar to or better than the raw drug (romidepsin) in all T-CNL lines tested in vitro. At the molecular level, nanoHDACi induced histone acetylation and apoptotic or non-apoptotic cell death. To better understand the cross-species similarities/differences, RNAseq studies are being conducted in nanoHDACi treated canine and human T-cell lymphoma lines. Using a T-CNL xenograft mouse model successfully established by engrafting luciferase expressing UL1 cells, we are exploring nanoHDACi activity in T-CNL in vivo.
Conclusion: T-CNL cells are uniquely sensitive to nanoHDACi, which functions by inducing histone acetylation and apoptotic or non-apoptotic cell death. In ongoing RNAseq studies in vitro and drug testing in vivo, we will further characterize nanoHDACi activity in T-CNL. Future studies will explore the merits of this therapy in companion animals with spontaneous T-cell lymphoma.
