Acute Myeloid Leukemia (AML) is the most frequent malignant myeloid disease in the adult population. Over the last few decades, the treatment of AML has not improved significantly, with the prognosis of patients remaining severe. CPX-351 is a promising novel agent, a combination of daunorubicin and cytarabine, encapsulated in multilamellar liposomes at a fixed ratio (7:2:1) of distearoylphosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol. CPX-351 showed positive results on AML patients, improving overall response rate and survival. However, the activity of each component of CPX-351 has been found impaired by the rewired metabolism in resistant leukemic cells. The rewiring of cell metabolism is in fact currently considered one of the main mechanisms of resistance for cancer cells. Higher glycolysis, fatty acid oxidation and glutaminolysis have all been showed as possible candidates, as cellular processes able to help cells to overcome the toxic effects of chemotherapy. In this project, we plan to investigate the metabolic impact of CPX-351 on AML. We will assess the impact of CPX-351 on metabolism of leukemic models (cell lines and primary samples) using cutting edge technology, and how metabolic processes influence cell response to this agent. This analysis may reveal additional metabolic targets to be exploited by the combination of CPX-351 with specific metabolic inhibitors, in order to improve the efficacy of the first and to overcome the insurgence of metabolism-related resistance mechanisms.
Despite the remarkable advances in cancer treatment achieved with the development of a wide and still growing spectrum of low molecular weight kinase inhibitors, novel therapies have displayed some limitations. The main cause of their limited effectiveness is represented by the intrinsic and acquired mechanisms of resistance exhibited by cancer cells against such drugs (von Manstein et al., 2013). Cancer cells can in fact activate compensatory pathways that allow them to grow and survive independently from the initial target (Masui et al., 2013; McCubrey et al., 2016; Grant, 2008). Hence, the need for exploring other strategies in order to avoid the insurgence of these resistance mechanisms. In this perspective, particular attention has been paid to the study of metabolic rewiring as a resistance factor (Desbats et al., Front Oncol 2020) and the effects induced by the combined use of specific inhibitors. However, combination approaches aimed at disrupting these mechanisms require taking into account the mechanistic knowledge of molecular components that drive therapeutic sensitivity and resistance to successful translate the pre-clinical data in effective and innovative therapeutic approaches to AML. This project aims at characterizing the metabolic impact of a promising drug, CPX-351, in AML setting, in order to rationally design new combination strategies able to improve its efficacy and prevent the insurgence of resistance. The translational impact of these new findings can be substantial, as CPX-351 is currently being studied in various clinical trials, and the combination with already available metabolic agents can readily improve the effectiveness of therapy.