Acute myeloid leukemia (AML) appears as a result of acquired genetic and epigenetic abnormalities in the hematopoietic stem cells. Despite advances in biology and in the development of new therapies, the percentage of patients who relapse is very high. It is therefore necessary to open new therapeutic perspectives aimed at molecular targets.
Reversible phosphorylation is one of the mechanisms that allow the cell to maintain a proper balance between signals that induce and suppress tumors. Hence, the balance between kinases and phosphatases is essential for controlling correct proliferation, apoptosis and differentiation. Many studies have analyzed the abnormal behavior of the kinase proteins in AML but there are few studies on the role of phosphatase proteins, despite the fact that they play a key role in controlling cell signaling. Phosphatase protein 2A (PP2A) is a tumor-suppressing protein that has a central regulating function in the cell, where it controls a large variety of functions and signaling pathways. The inactivation of PP2A appears to be an essential event in different types of cancer, which suggests that it may be a highly common and initial alteration in the process of malignant transformation and, therefore, a target with tremendous potential in therapies aimed at activating it.
Previous results from our group show that inactivation of PP2A is a recurrent event in AML, and that its pharmacological activation affects the activity of AKT and ERK1/2 by blocking proliferation and inducing caspase-dependent apoptosis. Furthermore, 28% of patients with AML have overexpression of the SET oncogene, and endogenous inhibitor of PP2A, and this alteration is associated with poor outcome in this disease. The activators of PP2A, FTY720 and OP499 interrupt the SET-PP2A interaction and have an additive effect with drugs used in AML and with tyrosine kinase inhibitors; however, these molecules have disadvantages in terms of their future administration in clinical practice.
Our hypothesis is that the reactivation of PP2A by inhibiting the action of SET on PP2A may be a therapeutic alternative in AML, especially in the subgroup of patients with overexpression of SET, a marker associated with poor outcome in this disease, and that drugs that activate PP2A could be used in combination with specific tyrosine kinase inhibitors, depending on the molecular profile of the patient, or with conventional chemotherapy.
The general goal of the project is to identify and characterize small molecules that activate PP2A for the treatment of AML. Our results have allowed it to begin the rational development of new small molecules that may activate PP2A specifically in AML.
Discovery and characterization of small molecules that activate the tumor-suppressing protein PP2A for the treatment of acute myeloid leukemia. Spanish Ministry of the Economy and Competitiveness. Carlos III Health Institute (PI14/02073). 2015-2018.
Molecular mechanisms in the development and progression of leukemia and lymphoma. Thematic network for cooperative research on cancer (RTICC), of the Carlos III Health Institute. RETICS 2012 call for proposals (RD12/0036/0063). 2013-2016.
The research team forms part of the Healthcare Research Institute of Navarre (IdiSNA) and of the group "Molecular mechanisms in the development and progression of leukemia and lymphoma" of the Thematic Network for Cooperative Research on Cancer (RTICC).
"Despite advances in acute myeloid leukemia, the percentage of patients who relapse is very high. Studies are therefore needed that open new therapeutic perspectives aimed at molecular targets. Our laboratory is working on the discovery and characterization of small molecules that activate the tumor-suppressing protein PP2A for the treatment of this leukemia" , Dra. María D. Odero, Principal Investigator..