Ricerc@Sapienza

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.