Therapeutics: Homeobox A9 (HOXA9); poly(ADP-ribose) polymerase (PARP); myeloid-lymphoid or mixed-lineage leukemia (MLL; HRX)

Cell culture and mouse studies suggest inhibiting HOXA9 and PARP could help treat MLL-rearranged AML. In primary AML cells from patients and mouse hematopoietic cells transformed with human leukemia-associated oncogenic fusions, MLL fusions were associated with high HOXA9 levels and resistance to the PARP inhibitors Lynparza olaparib and veliparib. In mouse leukemic stem cells expressing human MLL oncogenic fusions, HOXA9 knockout increased sensitivity to Lynparza compared with normal HOXA9 expression. In a mouse model of MLL-rearranged AML, a tool compound that indirectly inhibits HOXA9 plus Lynparza increased survival compared with either agent alone. In a xenograft mouse model of MLL-rearranged AML, the inhibitor combination decreased leukemic cell growth and increased survival. Next steps include clinical testing of the combination therapy.

AstraZeneca plc has Lynparza approved to treat ovarian cancer and in Phase I to Phase III testing to treat other solid tumor types...