Target discovery and biology of acute myeloid leukemia

Research Activity

Leukemias account for approximately one third of all pediatric malignancies and remain a leading cause of morbidity and mortality in children and adolescents. Acute myeloid leukemia (AML) in children is one of the most genetically heterogeneous diseases among pediatric cancers. With the current therapeutic approaches, the event-free survival rate ranges between 55 and 70%, with one out of three children experiencing a refractory or relapsed disease. Market authorization of targeted and immune therapies emerged as salvage treatment for other diseases, whereas in AML, they are unfrequently used, with intensive chemotherapy and stem cell transplantation still representing the main treatment options. The actual dearth of new agent approval for pediatric AML underlines that performing AML underlined mechanisms and robust preclinical studies are mandatory for pediatric drug advance. Our research aims at the identification of new genetic aberrations and mutations with prognostic value to be used as biomarkers to improve diagnosis and risk stratification of patients and their treatment response by employing tailored adapted therapies. We apply NGS at diagnosis of leukemia to find relevant prognostic mutations and design new quantitative molecular assays for monitoring minimal molecular disease, increasing the ability to stratify patients at diagnosis, during treatment and at follow up. For most aggressive AML where cytogenetic aberrancies or mutations are present, we set up functional studies deepening into the mechanism of leukemogenesis. We deep into the intimate connection between the dysregulation of gene expression and malignant transformation and highlight the importance of investigating key players in the regulation of gene expression to shed light on transforming events to define new targeted therapeutic approaches. We employed RNA and DNA sequencing and proteome status of AML and to be studied in vitro we recapitulated an innovative in vitro three-dimensional (3D) model, and in vivo models’ patient-derived xenografts (PDXs). We established >30 AML PDXs through sequential engraftment of primary AML cells in NSG mice, representing most of the14 high-risk genetic subtypes. AML-PDXs robustly resembling the original AML in terms of immunophenotype, genomic, and transcriptomic profiles offer a comprehensive view of the disease complexity, useful for tailor therapies.

The whole-exome sequencing characterization evidenced a high intra-tumoral heterogeneity of the disease giving the opportunity to trace disease evolution and thus select and test new drugs. The use of PDX models to perform unconventional trials such as umbrella, basket and platform trials will accelerate the use of preclinical studies toward personalized medicine approaches, in compliance with clinical needs. The 3D model is created for mimicking bone extracellular matrix and is composed of 70 wt% hydroxyapatite/30 wt% collagen type I where different cell types of the stroma of the bone marrow are cultured with leukemia cells or healthy hematopoietic stem cells. The 3D system allows proliferating long-term co-cultures up to 21 days and maintains the cell features. Our research delved into the intricate interactions between primary mesenchymal stromal cells (MSCs) and acute myeloid leukemia cells in the bone marrow niche and produced evidence that this contact is generating several changes inducing leukemia microenvironment (TME) and inflammation.

These models are helping in the understanding of cancer transformation mechanisms for the developing of promising alternatives or complementary therapeutics including target and immune therapies to current chemotherapy, particularly for the AML that undergoes to relapse. A patent for a drug selective for one aggressive AML subtype has been generated and we are developing a sub-area for developing novel drugs and testing to be successfully advanced in clinical trials. More recently, we are dissecting the leukemia stem cell metabolism and mitochondrial characterization and targeting. We are actively participating to the Children’s Liver Tumor European Research Network creating PDX for an innovative anticancer drug for the treatment of patients with high-risk hepatoblastoma facing disease recurrence or chemotherapeutic treatment-failure.

Our research aims to introduce a novel translational dimension to the field of conventional approaches towards novel applications based on scientific and biological evidence with the final aim to improve blood diseases cure.