Constitutive oncogenic signaling by the BCR-ABL fusion kinase initiates and drives Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myelogenous leukemia (CML). Despite their good performance in CML, the BCR-ABL kinase inhibitors (BCR-ABL-KIs) imatinib, dasatinib and nilotinib provide poor leukemia reduction and relapse control in patients with non-mutated BCR-ABL in Ph+ ALL. Researchers at St. Jude Children’s Research Hospital have identified Interleukin 7 (IL7) as the dominant host-factor that blocks response to BCR-ABL-KIs both in vitro and in vivo. By screening a library (including FDA approved drugs) to identify potential combination drugs that could overcome this IL7 imparted BCR-ABL-KI-resistant phenotype they discovered that among the validated hits, the well-tolerated anti-malarial drug dihydroartemisinin (DHA) displayed potent activity in vitro and some activity in vivo as a monotherapy against BCR-ABL-KI–resistant Ph+ ALL. Co-treatment with DHA and dasatinib in vivo strongly reduces primary leukemia burden and improves long-term survival in a murine model that faithfully captures the BCR-ABL-KI-resistant phenotype of human Ph+ ALL. This treatment protocol durably cures 90% of treated animals. This finding strongly suggests that the combination of dasatinib and DHA should be explored in the clinic against Ph+ ALL.
BCR, ABL, KR, Lymphoblastic Leukemia (ALL), malaria, drug resistance, chronic myelogenous leukemia (CML), imatinib, dasatinib, nilotinib, relapse, Interleukin 7 (IL7), anti-malarial, dihydroartemisinin (DHA), cancer and cancer drugs, cell-based assays, kinases, phenotypic drug discovery
Granted Patents or Published Applications
WO Pub. 2013/177420
Related Scientific References
Singh H, “A screening-based approach to circumvent tumor microenvironment-driven intrinsic resistance to BCR-ABL+ inhibitors in Ph+ acute lymphoblastic leukemia.” J Biomol Screen. Jan, 2014; Epub Aug, 2013.
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