Project Funding Details

Nowadays, relapse represents the major obstacle in pediatric T-acute lymphoblastic leukemia (T-ALL) patients' treatment, since for relapse patients the prognosis remains dismal due either to the drug resistance or to the high toxicity for chemotherapy intensification. Thus, it is necessary to identify novel therapeutic targets and new biomarkers of refractory/relapse disease to recognize patients that at relapse could benefit from innovative therapeutic approaches, preventing a poor outcome. It is well known that deregulated protein signaling pathways can promote drug resistance development and maintenance. So far, to the best of our knowledge, no studies on the proteomic profile on T-ALL pediatric patients at relapse have been published. To this purpose, relapsed T-ALL pediatric patients' full proteomic characterization could unravel new leukemia vulnerabilities, useful for a patient's tailored therapy. Our hypothesis is that at relapse the protein signaling pathways active in T-ALL patients that are either refractory to therapy or that further relapse (poor prognosis), are different from the ones that achieve a complete remission (good prognosis). Thus, the proteomic profiling of these patient subgroups can reveal protein alterations responsible for chemotherapy resistance and poor outcome, from which take advantage for the identification of novel biomarkers and therapeutic targets. By performing the full proteomic profile of poor and good prognosis relapsed T-ALL pediatric patients we aim to uncover new biomarkers and novel therapeutic targets useful to identify patients that at relapse could benefit of a more patients' tailored therapy to prevent therapy resistance occurrence and excessive toxicities. First, by Mass Spectrometry (MS) based proteomic/phosphoproteomic profiling on poor and good prognosis relapsed T-ALL patients we will identify the deregulated proteins characterizing poor prognosis relapsing patients, putatively responsible for drug resistance and patient's poor outcome. Next, the most significant abundant/active proteins characterizing poor prognosis subgroup will be prioritized by Reverse Phase Protein Array (RPPA) in an enlarged cohort of diagnosis/relapsed T-ALL patients. By the drug high throughput screening (HTS), a Kinase Inhibitors (KI) compounds library will be tested on T-ALL cell line models resembling the poor prognosis T-ALL patients proteomic profile, to identify those KIs potentially usable to treat relapsed T-ALL patients. MS/RPPA and HST data will be integrated to unveil the most significant kinases associated with poor therapy response and the most promising KIs that, in combination with standard chemotherapeutics, can represent new therapeutic approaches to treat T-ALL pediatric patients at the relapse. Finally, a preclinical study will be conducted to evaluate the efficacy of identified KI(s) in combination with standard chemotherapy in relapsed T-ALL PDX models. From the accomplishment of this project, we expect to unearth deregulated proteins in poor prognosis relapsed pediatric T-ALL patients, that can represent both new biomarkers and therapeutic targets to identify and treat more specifically poor prognosis relapsed T-ALL patients. Results from this project will provide a rationale for alternative diagnostic and therapeutic approaches that can be easily introduced into current clinical protocols to promote the achievement of a complete remission of T-ALL relapsed patients, thus reducing the gap between a preclinical setting to the bedside.