Myelodysplastic syndromes (MDS) are a group of hematological disorders characterized by ineffective hematopoiesis affecting one or more myeloid cell lineages: red blood cells, platelets or some white blood cells. In over 30% of the cases, patients with MDS develop secondary Acute Myeloid Leukemia (sAML), a much more aggressive type of cancer with particularly poor outcomes.
The best treatment options for many patients with high-risk MDS -those more frequently evolving to sAML-, unelegible for a bone marrow stem cells transplant, are the nucleoside analogs azacytidine (AZA) and decitabine. However, the response to these treatments is partial, with less than 50% of patients showing positive response and only 10% complete response. In light of these numbers, better options are urgently needed to improve drug response.
In a recent publication in Nature Communications, members of a team led by Dr. Marcus Buschbeck at the Josep Carreras Leukaemia Research Institute, show that the activity of AZA could be greatly enhanced when combined with the inhibition of the histone acetyltransferase and transcriptional coactivator CBP and its closely related p300 protein. This finding is relevant since natural loss of p300 in a tumor is commonly associated with disease progression. Besides, data show this enhancement is exclusive for AZA but not for its counterpart decitabine, probably due to the RNA-dependent effects of AZA.
Another major and surprising finding of the study was that CBP/p300 inhibition drastically reduces protein synthesis. This could explain the AZA-dependent sensitivity, since AZA but not decitabine incorporates into RNA and also reduces protein synthesis. Therefore, both drugs converge on limiting protein synthesis to a point that is not tolerable for cancer cells.
Taken together, the findings reported point at the development of a next generation of CBP/p300 inhibitors, with improved characteristics, to be used in combinatorial treatments with AZA as a new therapeutic option for patients diagnosed with high-risk MDS lacking alternative treatment options.
Diesch, J., Le Pannérer, MM., Winkler, R. et al. “Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis” Nat Commun 12, 6060 (2021). https://doi.org/10.1038/s41467-021-26258-z