The present invention relates to methods, compositions, and diagnostic tests for treating and diagnosing proliferative disorders, such as cancel-, that result in dysregulation of malic enzyme 2. In particular, the methods and compositions include monotherapy with malate, or a derivative thereof, as well as combination therapy, such as malate, or a derivative thereof, combined with another therapeutic agent, such as a malic enzyme 2 inhibitor, an antineoplastic agent, a glycolysis inhibitor, an antiangiogenic agent, an immunomodulatory agent, an antibody, or a cytokine.