"Our goal is to develop new treatments for patients with hematological tumors by understanding the pathogenesis of the disease."
DR. FELIPE PRÓSPER SENIOR RESEARCHER. MYELOID PATHOLOGY RESEARCH GROUP
Myeloid diseases are disorders of the blood or hematopoietic stem cells (HPCs) of the myeloid lineage. Alteration in cell maturation or abnormal proliferation of these cells leads to infections, anemia, bleeding and cancers such as leukemias. These diseases commonly affect people between 65 and 70 years of age, and their prevalence is expected to increase in the coming decades.
Research progress in recent years in understanding the molecular basis of many hematologic cancers has translated into clinical benefit for the patient. However, among these myeloid neoplasms, myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) are two very aggressive diseases that lack effective treatment.
For this reason, our Myeloid Pathology Group at Cima focuses on the study of the mechanisms of transformation of these two major diseases. Our research includes the identification of genetic and epigenetic changes (cellular reactions that change the functions of genes, without being part of the DNA), the development of new drugs that can be molecular targets in patients, and resistance to therapy determined by the tumor microenvironment.
We work in close collaboration with other researchers in the Hematology-Oncology Program at Cima and clinicians at the Clínica Universidad de Navarra with a primary focus on translational research and clinical trials exploring innovative treatments for these diseases.
Our program is linked to the Centro de Investigación Biomédica en la Red de Cáncer (CIBERONC) of the Instituto de Salud Carlos III (ISCIII), as well as to numerous academic and research centers nationally and internationally.
Objectives of the Myeloid Pathology
We seek to develop innovative strategies to improve the treatment of these aggressive hematological malignancies
To delve into the processes of oncogenesis of myeloid malignancies to decipher initial lesions and molecular alterations that lead to their progression.
Develop a combined functional strategy using multi-omics technologies, genetically modified animals and multiparametric flow cytometry.
To analyze the levels of organization and cellular relationships that occur in the bone marrow niche in homeostasis and after neoplastic transformation.
FROM THE LABORATORY TO THE CLINIC
Innovation in epigenetic drugs
In recent years it has been shown that cancer is a disease caused by both genetic and epigenetic alterations. Epigenetics refers to inherited cellular reactions that change the functions of genes, without being part of the DNA.
With this knowledge our group has developed new compounds capable of inhibiting the action of several key enzymes in DNA methylation, one of the main epigenetic mechanisms.
Lines of research
PI: Xabier Agirre
Our general objective is to study and gain in-depth knowledge of both the altered epigenome and the aberrant regulation of the enzymes that regulate epigenetic mechanisms (DNA methylation and histone modifications) in the tumor cells of different hematological malignancies. This objective pursues the aim of better understanding the disease and detecting new targets, in this case epigenetic, for the development of new therapeutic strategies for the treatment and improvement of the quality of life of these patients.
- Detection of epigenetic mechanisms that present alterations and epigenetic enzymes deregulated in AML.
- Detection and functional studies in essential and deleterious genes in hematological diseases.
- Synthesize and validate new small molecules directed against epigenetic targets for the treatment of tumors.
- Study the role of dual small molecules against HDACs and DNMTS involved in the treatment and differentiation of AML.
PI: Lola Odero
Despite advances in the biology of acute myeloid leukemia (AML), the percentage of patients who relapse is very high. Therefore, it is necessary to open new therapeutic perspectives directed to molecular targets. Reversible phosphorylation is the main mechanism controlling intracellular events.
In this sense, the balance between kinases and phosphatases is essential for the control of correct proliferation, apoptosis and differentiation. There are many studies analyzing the aberrant behavior of protein kinases in AML. However, the role of protein phosphatases has been less studied, despite the fact that they play a key role in the control of cell signaling.
Our results indicate that the combination of kinase inhibitors and phosphatase activating drugs may be an effective therapeutic option for AML. Our goal is to continue to investigate into the process of AML oncogenesis and use this knowledge to innovate and improve therapeutic strategies in this aggressive disease.
- To identify and functionally characterize new small molecules that reactivate phosphatases indirectly, through blocking their endogenous inhibitors.
- To study the effect of a combination therapy in AML with PP2A activating drugs and other drugs whose targets are in the molecular pathways controlled by PP2A, and with new drugs that are being developed in clinical trials in AML.
- Characterize at the genetic and genomic level samples from AML patients and develop zebrafish xenografts derived from these samples, using this model to study the efficacy of drug combinations according to the molecular alterations detected in each patient.
PI: Teresa Ezponda
Studies in myelodysplastic syndromes (MDS)
have focused on the characterization of the mutational profiles associated with this disease. However, few studies investigate the fundamental molecular basis at the origin of this pathology. Our group aims to further study the mechanisms that contribute to the development of MDS. Specifically, we focus on the study of the transcriptome of patients with MDS, both coding and non-coding, with the aim of identifying molecular pathways involved in the development of this disease. In addition, we aim to characterize the regulatory mechanisms at the transcriptional level in order to identify potential therapeutic targets for the treatment of this pathology.
- Characterization of the miRNome of hematopoietic stem cells and progenitor cells in patients with MDS and healthy subjects.
Identification of miRNA involved in molecular pathways in hematopoietic stem cells and progenitor cells in MDS patients.
- Identification of the transcriptional profile of hematopoietic progenitors during aging and progression to MDS, as well as the regulatory mechanisms of these transcriptomes.
- Identification and validation of potential therapeutic targets responsible for the phenotypic and functional alteration of hematopoietic progenitors in MDS.
PI: Borja Saez
The tissue and organ organization characteristic of metazoans is closely dependent on homo- and heterotypic interactions between different cell types. However, our knowledge of tissue organization remains limited. Stem cell systems and their niches are highly controlled microenvironments that offer a unique opportunity to advance such knowledge. Reductionist approaches have proven highly useful for dissecting the complexity of stem cell niches in a unidirectional fashion. However, these approaches fail to recognize the complex three-dimensional structure of tissue.
In the laboratory, we are interested in understanding the different levels of organization and cellular relationships that occur in the bone marrow (BM) niche in homeostasis and after neoplastic transformation. To this end, we employ a systems biology strategy combined with the use of genetically modified animals, multi-parametric flow cytometry and multi-omics technologies.
Another major interest of our laboratory is the development of hematopoietic stem cell mobilization regimens, as well as the development of non-genotoxic conditioning agents that allow the use of hematopoietic progenitor transplantation in monogenic diseases and congenital and acquired immunodeficiencies.
- Define the cellular and molecular complexity of the MO niche.
- To delineate the homo- and heterotypic cellular interactions that define the functioning of the BM niche.
- Describe the cellular and molecular changes that occur in the OM following neoplastic transformation.
- Validate new therapeutic dependencies in leukemias resulting from their relationship with the cells of the OM microenvironment.
Meet the research team
Scientific activity of the
Myeloid Pathology Research Group
Latest scientific publications
- Endogenous retroelement activation by epigenetic therapy reverses the Warburg effect and elicits mitochondrial-mediated cancer cell death May 1, 2021 | Magazine: Cancer Discovery
- The Role of lncRNAs in the Pathobiology and Clinical Behavior of Multiple Myeloma Apr 20, 2021 | Magazine: Cancers (Basel)
- Characterization of complete lncRNAs transcriptome reveals the functional and clinical impact of lncRNAs in multiple myeloma [SP] Feb 17, 2021 | Magazine: Leukemia
- Measurable residual disease in elderly acute myeloid leukemia: results from the PETHEMA-FLUGAZA phase 3 clinical trial Feb 9, 2021 | Magazine: Blood Advances