Acute myeloid leukemia is a very aggressive disease in which cells proliferate abnormally, invading the bone marrow and interfering with the production of normal blood cells. It is the subject most common acute leukemia in adults and the one with the worst prognosis. Knowing what genetic alterations these patients have is core topic for the development of more effective treatments.

Researchers from the Cima and the School of Sciences of the University of Navarra have identified a new molecular mechanism involved in the development of this disease. Thanks to this finding, the team proposes a new drug combination that could be useful to treat 30% of patients with this aggressive leukemia. The results have been published in Blood Cancer Journal reference letter journal in the field of hematology oncology.

"PP2A is a protein that regulates essential functions in the cell and prevents tumors from developing. This ''anti-cancer'' molecule is inactivated in patients with acute myeloid leukemia because of another ''pro-cancer'' protein, an oncogene called SET. SET sample is known to be abnormally elevated in 30% of patients and promotes tumor development. Likewise, PP2A activating drugs decrease proliferation and promote the death of leukemic cells," explains Dr. Elena Arriazu, researcher in the Hemato-oncology Program at Cima, a member of CIBERONC and first author of work.

Lower doses and higher efficacy

In this academic publication, the researchers have identified a new process by which SET prevents the protective action of PP2A. "Thanks to this, we propose a two-drug combination that could offer a more effective treatment for these very aggressive tumors. One of the drugs prevents the process that activates the SET oncogene. The other drug reactivates PP2A and helps it to function properly. Our work shows that when the two drugs are administered together their effect is more potent," says Dr. Carmen Vicente, a researcher on this team at the University of Navarra thanks to a financial aid grant from the association Española Contra el Cáncer (AECC).

Complementary to this study, the researcher team at Cima has developed a new drug that activates the PP2A tumor suppressor protein. "It is a small molecule with the same efficacy, but safer for the patient, as it has no toxic cardiological effects, which could help it reach the clinic," says Dr. Vicente, first author of the scientific article , published in the journal Cancer Letters.

The team has confirmed its results in patient samples from the Navarra Hospital Complex (CHN), thanks to partnership with Dr. María Carmen Mateos, a specialist in the Hematology Department of the CHN. In addition, a very innovative animal model has been used in research, the "zebra fish", transparent fish that allow the evolution of the tumor to be followed.

" Tumor tracking in zebrafish: Tumor cells (marked in red) reduce their growth and colonization when using different drugs. This effect is much greater when both drugs are combined. PHOTO: Cima University of Navarra

The programs of study, carried out at the framework of the high school of research Sanitaria de Navarra (IdiSNA), open the doors to a new therapy directed towards these tumors.

Dr. María Dolores Odero, professor of Genetics of the University of Navarra, director of the laboratory of Acute Leukemias of Cima and member of CIBERONC, has directed these studies, which have counted with the partnership of Dr. María Luisa Cayuela, of high school Murciano de research Biosanitaria, and Dr. Ángel Nebreda, of high school de research Biomédica (IRB Barcelona).

• Bibliographic references:
  Blood Cancer Journal: https://www.nature.com/articles/s41408-019-0270-0#citeas
  Cancer Letters: https://www.sciencedirect.com/science/article/pii/S0304383519304987