Acute myeloid leukemia (AML) is a common and aggressive hematologic malignancy affecting both children and adults which continues to have high mortality rates as well as high morbidity from toxic therapies. New treatments are needed to improve cure rates and decrease morbidity. A niche-based high throughput screen done in a murine system identified candidate small molecules potentially toxic to leukemic stem cells (LSCs) while sparing normal hematopoietic stem cells (HSCs) and bone marrow stroma (Hartwell KA, Miller, PG et al., in preparation). One such compound, SB-216641, demonstrated dose-dependent activity against leukemia in both a cell autonomous and non-autonomous manner, by modifying niche–based support. SB-216641 is a selective serotonin receptor antagonist specific for the 5-HT1B receptor, highlighting a pathway not previously investigated in the context of AML or leukemia stem cell biology.
5-HT1B receptor antagonists have not previously been known to be active against AML or leukemic stem cells. Some hematopoietic cells including platelets express serotonin receptors and T-cells specifically have been found to express the 5-HT1b receptor. Selective 5-HT1B receptor antagonists have found to have apoptotic effects in vitro against cell lines of other cancers and may be involved in MAP kinase and P13K/Akt signaling pathways. SB-216641 is a highly promising compound which warrants further investigation. Its high toxicity to LSCs and sparing of normal HSCs make it appealing for possible clinical use in the future.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.