S106: METABOLIC PLASTICITY REVEALS A TARGETABLE VULNERABILITY IN LEUKEMIA (2023)

Background: T-cell acute lymphoblastic leukemia (T-ALL/T-LL) is a class of highly aggressive cancers in children and young adult, marked by an aggressive behavior and poor clinical response, notably for refractory and relapsing (R/R) cases. As in numerous cancers, genetic lesions leading to aberrant PI3K signaling (PI3KSALT) are frequent in T-ALL and convey adverse outcomes from limited therapy response to early relapse and dismal survival rates. Aims: We aimed to explore the metabolic plasticity of PI3K-driven leukemia and unravel targets amenable to novel strategies to leverage the treatment and the outcome of this aggressive disease. Methods: Patients were enrolled in the GRAALL2003-2005 and FRALLE2000 trials. Patient primary samples were analyzed by pan-exome sequencing, arrayCGH, MLPA and RNA-sequencing. Patient-derived xenografts (PDX) were used for in vivo experimentation. PI3K signaling activity, glucose consumption and cell survival were evaluated by flow cytometry. Metabolomics analyses were carried out at our Metabolomics Core. Results: PI3KSALT patients had a poor response to corticoids, a shorter overall survival (5y-OS: 58% vs 74%, p = 0.007) and event-free survival (5y-EFS: 49% vs 65%, p = 0.008), and an increased incidence of relapse (5y-CIR: 39% vs 27%, p = 0.01). PI3KSALT define a subclass of aggressive T-ALL with a poor prognosis, urging innovative therapies for these patients. Primary samples and PDX of PI3KSALT leukemia have an hyperglycolytic profile. PI3KSALT T-ALL cell lines mimic this addiction to glucose. Surprisingly, while cell lines cannot survive glucose limitation, PI3KSALT PDX tolerate this starvation, underpinning their ability to rewire their metabolism to adapt to a nutrient-deprived microenvironment. We showed that PI3KSALT PDX have unique metabolic plasticity upon starvation. These blasts use glutaminolysis to cope with glucose limitation and sustain the TCA cycle, while wild-type PI3KS fail to do so (Fig 1a). Pharmaceutical inhibition of the PI3KS-mTOR pathway and glutamine metabolism presented a marked cytotoxicity ex vivo (Fig 1b). We proposed a therapeutic strategy for PI3KSALT T-ALL based on the targeting of mTOR and glutamine. Erwinase, an L-asparaginase with glutaminase activity, efficiently synergizes with Torisel and demonstrates tumor clearance and prolonged survival in vivo (Fig 1c-d). Critically, we report the case of five patients suffering from R/R PI3KSALT leukemia, with complex clinical history, treated with the association Erwinase/Torisel (ET). All five patients achieved a rapid response. Patients suffering from R/R T-ALL achieved negative minimal residual disease. Patients with R/R T-LL presented a significant decrease in the mediastinal mass (Fig 1e). After complete remission, three patients received consolidation therapy consisting of allogeneic SCT or donor lymphocyte infusion. Two patients remain alive, while two patients rapidly progressed after the discontinuation of ET treatment. Summary/Conclusion: R/R T-ALL/LL have dismal prognosis and outcomes, in part due to chemoresistance acquisition and limited therapeutic options. We propose a promising treatment combining an asparagine and glutamine degrader (Erwinase) with a PI3KS inhibitor (Torisel) that should be considered as a therapeutic option in a bridge-to-transplant approach for R/R T-ALL/LL with PI3KS deregulation. We show that metabolic plasticity conveys a unique and targetable vulnerability in PI3KS-driven leukemia that show promising results in pre-clinical and clinical settings.Keywords: Acute lymphoblastic leukemia, T cell acute lymphoblastic leukemia, Targeted therapy, PI3-K/AKT