Johns Hopkins University
Project Term: October 1, 2021 - September 30, 2024
Mutations in the spliceosome gene SF3B1 are common in myeloid malignancies, but they are currently untargetable. Our previous work has shown that SF3B1 mutations reprogram energy metabolism and create vulnerability to restriction of the nonessential amino acid serine. Here we propose a preclinical project studying PEGylated cystathioinine beta synthase (pCBS), a recombinant enzyme that catabolizes serine, as a treatment for SF3B1-mutant myeloid malignancies.
Certain forms of leukemia are caused by a mutation in a gene called SF3B1. This mutation is quite frequent, occurring for example in greater than 30% of patients with myelodysplastic syndromes (MDS). SF3B1 mutations mess up a process called RNA splicing, but we still don’t understand very well how this causes cancer. We also don’t yet have drugs that can specifically target cancers with SF3B1 mutations, but we need them. In our recent laboratory work, we found that SF3B1 mutations also mess up metabolism, the process by which cells get and use nutrients to grow and survive. We found that cells with SF3B1 mutation must get a nutrient called serine from their environment, in contrast to all other cells in the body, which can make serine for themselves. Because of this different need, reducing serine in the blood can slow the growth of cancer cells with SF3B1 mutation, while sparing healthy cells that make their own serine. We have now identified a drug called pCBS that can reduce serine levels in the blood. This drug has been given safely to laboratory animals, and it is now being given to patients with a metabolic disease called homocystinuria in a clinical trial. Our proposal to the Translational Research Program is to study pCBS as a treatment for leukemia with SF3B1 mutations. There will be two parts to this study. First, we will determine how well pCBS stops the growth of different leukemias grown in culture dishes and in laboratory mice. Second, we will determine how SF3B1 mutation makes cells so responsive to this treatment. Success in these studies will not only reveal important information about what SF3B1 mutations do in leukemia, but it will also tell us that pCBS should next be tested in patients with SF3B1-mutated leukemia.