Project members: María Villa Morales (PI), Laura Vela Martín, Isabel Sastre Merlín (UAM); Pilar Llamas Sillero, José Luis López-Lorenzo, Javier Cornago Navascúes, Rocío Salgado Sánchez (IIS-FJD); Concepción Aláez Usón, Sara Nistal Gil (HLA-Moncloa).
Collaborators: Pablo Menéndez (Josep Carreras Leukaemia Research Institute); Françoise Pflumio (Inserm/CEA/Université Paris); Pablo Fernández Navarro (ISCIII), Pablo Mínguez (IIS-FJD).
Project Summary
T-cell lymphoblastic neoplasms (T-ALL/LBL) are a type of aggressive hematological cancer derived from immature T-cells, mostly affecting children and adolescent boys. Treatment with multiple high-dose chemotherapy has proven to be highly effective, but not infallible, due to acute and long-term toxicity and poor prognosis in case of relapse. With the ultimate goal of implementing personalized and precision medicine, our team is analyzing molecular-genetic alterations in T-ALL/LBL patients; in a T-ALL patient at IIS-FJD who did not overcome the disease with conventional treatment and who, unfortunately, died in 2020, we have found the novel, oncogenic and targetable SEPTIN6::ABL2 fusion [1]. According to the molecular nature of the fusion protein and to the results using cellular models, we suggest that the patient would have benefited from targeted treatment with tyrosine kinase inhibitors (TKIs). However, since such inhibitors may not completely eradicate the corresponding tumor cells, there is a growing need to identify additional pharmacological inhibitors that efficiently block oncogenic signaling triggered by ABL2 alterations, which can be used as second-line treatments or as co-adjuvants together with TKIs to improve the efficiency rates of current therapies.
With this project, we aim to identify therapeutic targets within the oncogenic signaling pathways induced in T-cell lymphoblastic neoplasms by ABL2 alterations like SEPTIN6::ABL2 fusion. This information would allow to propose tailored therapeutic strategies.
1. Lahera, A., et al., Comprehensive characterization of a novel, oncogenic and targetable SEPTIN6::ABL2 fusion in T-ALL. Br J Haematol, 2023. 202(3): p. 693-698.
