Leukemic Mutations Create 'Therapeutic Window' for Spliceosome Modulators

Leukemic Mutations Create 'Therapeutic Window' for Spliceosome Modulators
Leukemic Mutations Create 'Therapeutic Window' for Spliceosome Modulators

ORLANDO, FLGenetic and pharmacologic evidence point to splicing factor mutant leukemias as being “preferentially sensitive to splicing modulation in vivo compared with spliceosomal wildtype counterpart cells.”

“This proof-of-concept study has very broad clinical implications,”, said Stanley Chun-Wei Lee, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, at the plenary session of the 57th American Society of Hematology (ASH) Annual Meeting.

Dr. Lee and his team created murine leukemia models and found that spliceosomal-mutant leukemias displayed greater sensitivity to pharmacologic modulation of splicing than their wildtype counterparts.

They next generated patient-derived xenografts from patients with acute myeloid leukemia (AML) splicing wildtype (2 patients) or splicing mutant (3 patients). Ten mice were engrafted per patient and treated with vehicle or E7107 for 10 days once human bone marrow chimerism was greater than 50%.

In each patient-derived xenograft model, “targeted genomic analysis of human leukemic cells confirmed faithful engraftment of the major leukemic clones as found in patients pre-engraftment and that spliceosomal mutations were present in the major leukemic clone engrafted in mice,” Dr. Lee reported.

The splicing mutant AMLs were found to be more sensitive to treatment with E7107, prolonging survival in Srsf2-mutant AML.

The SRSF2 mutant cells were found to be “preferentially sensitive to further perturbations of RNA splicing relative to SRSF2 wildtype cells,” with the SRSF2 mutant cells dependent on the wildtype allele for survival. E7107 resulted in global splicing changes, which was found to be “modestly enhanced in Srsf2 mutant leukemic cells,” Dr. Lee said.

He explained these SRSF2 mutations create “vulnerabilities” to further splicing modulation, thereby “creating a potential ‘therapeutic window' that can be exploited clinically,” especially in the myeloid malignancies. Several spliceosome modulating agents are currently under investigation.

Reference

1. Lee S C-W, Dvinge H, Kim E, et al. Therapeutic Targeting of Spliceosomal Mutant Myeloid Leukemias through Modulation of Splicing Catalysis. Oral presentation at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 6, 2015; Orlando, FL.

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