Targeting SIRPα in cancer

Despite decades of clinical trials, the prognosis of patients with acute myeloid leukemia (AML) remains poor and many of them experience recurrent disease. One factor contributing to the high relapse rate of AML patients is the intrinsic resis-tance of leukemia stem cells (LSC) to standard chemotherapy. Hence, research is currently focused on the development of novel anti-leukemic agents that bet-ter target these disease-sustaining cells. However, it has recently been shown that leukemias are composed of genetically and functionally diverse subclones,1,2 predict-ing that LSC-directed therapeutics may not eradicate the disease when distinct LSC subclones are not equally dependent on the drugged pathway. The recognition of both intratumoral and inter-patient heterogeneity in leukemia has also led to a greater use of primary patient samples, as opposed to cell lines, for drug develop-ment, as the latter cannot capture the het-erogeneity of therapeutic responses that is frequently seen in the clinic. The efficacy of candidate anticancer agents against LSCs can be tested by treating immuno-deficient mice bearing human leukemic grafts in xenotransplantation assays, with the hope that observed drug responses will predict responses in patients. These aspects of anticancer drug devel-opment converged in our recent stud