Mechanisms of resistance to targeted therapy and chemotherapy in acute lymphoblastic leukemias

• Applicant: Dr. Jesús Duque-Afonso
• Subject Area: Hematology, Oncology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 423352691

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and one of the main causes of cancer death in children and young adults. Although the treatment of ALL has been improved in the last decades, there are still patients developing drug resistance and succumbing to the disease, especially in advanced age and with severe co-morbidities. Therefore, we propose to devise new therapeutic approaches, which are more effective while less toxic. We will establish combination therapies using preclinical in vitro and in vivo experimental models, which will be translated into clinical application in the near future.ALL is a heterogeneous disease and can be sub-classified by karyotype, cell type and immunophenotype. One distinctive immunophenotype is characterized by expression of the pre-B cell receptor (preBCR). Half of the preBCR+ ALL patients harbor the translocation t(1;19), which codes the chimeric fusion protein E2A/PBX1. Dasatinib is a new drug that is FDA approved for treatment of Ph+ CML and ALL. Recent studies have suggested that it might be effective in additional subtypes, including preBCR+ ALL. Previous studies from our group shows that preBCR+ ALL rapidly develop dasatinib resistance and disease relapse. However, genetic inactivation and pharmacological inhibition of preBCR-pathway related genes modulates dasatinib sensitivity and overcomes resistance. In order to identify novel candidate genes/pathways candidate genes, which are involved in proliferation/survival and targeted therapy resistance in preBCR+ ALL cells, we employed functional genomics studies and global transcriptome analysis. Bioinformatics analysis identified several genes/pathways on which preBCR+ ALL cells are dependent, mediate drug resistance and are susceptible of pharmacological inhibition. In this project, we hypothesize that: 1) our previous and novel identified genes in E2A-PBX1+/preBCR+ ALL play a key role in the molecular pathogenesis of a broader panel of lymphoid malignancies.2) pharmacological inhibition of previous and novel identified kinases increases sensitivity to targeted therapy as dasatinib in single and combination treatments.3) novel mechanism of chemotherapy resistance will be identified and characterized using same genetic and pharmacological approaches, establishing more rational combination therapies in ALL.Taken together, we aimed to identify novel therapeutic targets and understand mechanisms of resistance to targeted therapies and chemotherapy in ALL. Our studies will address the novel and important concept of drug resistance driven by alternative signaling pathways and transcriptional plasticity. They will result in an innovative and original way to overcome drug resistance and to identify novel therapeutic targets in lymphoid malignancies and, ultimately, impact the treatment, quality of life and prognosis of patients.

• DFG Programme: Research Grants