Acute myeloid leukemia (AML) is a very aggressive disease in which cells proliferate abnormally, invading the bone marrow and thereby interfering with the production of normal blood cells. It is the most common acute leukemia in adults and the one with the worst prognosis. In recent years new drugs have been C ; however, obtaining a prolonged response to treatment remains a challenge.

Researchers at Cima University of Navarra have proposed a new approach for the development of more effective therapeutic strategies in this disease. "PP2A is a protein that regulates essential functions in the cell, such as cell survival and proliferation. It is also known to promote cancer cell death. In previous programs of study we demonstrated that this protein is inactivated in 70% of AML patients and developed novel drugs to activate it. On this occasion, we confirmed that re-activating PP2A is also important in the response to treatment of this leukemia," explain Dr. María Dolores Odero and Dr. Carmen Vicente, researchers in the Hemato-Oncology Program at Cima, part of the Cancer Center Clínica Universidad de Navarra, and directors of work. The results have been published in Blood, a scientific journal of the American Society of Hematology.

The study demonstrates that the combination of PP2A-activating drugs with those used in the clinic to treat this disease (venetoclax and azacitidine) has a synergistic effect, and significantly increases the response to treatment in preclinical models of this disease. "These results have been confirmed in cell lines, in primary patient samples and by xenograft (transplantation of patient tumor tissue in model animal)," says Irene Peris, researcher at training of Cima and first author of this work, which has been part of her doctoral thesis .

New safer drugs

In addition, using gene editing tools, the researchers identified the mechanisms by which PP2A reactivation enhances venetoclax-induced cell death (termed apoptosis). These results open the door to development of future clinical programs of study with new, safer and more efficient drug combinations for AML patients.

The work, carried out at partnership with the University Hospital of Navarra and at framework of the Cancer Center (CIBERONC) and high school of research Sanitaria de Navarra (IdiSNA), has received funding from high school de Salud Carlos III, the association Española contra el Cáncer and the "la Caixa" Foundation.

reference letter bibliographic

→ Blood. 2023 Mar 2;141(9):1047-1059. doi: 10.1182/blood.2022016466. PMID: 36455198.

→ Peris et al. Activation of the PP2A-B56α heterocomplex synergizes with venetoclax therapies in AML through BCL2 and MCL1 modulation.