UCLA researchers have identified a class of small molecule phosphodiesterase inhibitors that suppress let-7 target genes and inhibit cell growth in acute myeloid leukemia cancer cell lines.
Acute myeloid leukemia (AML) is the most common leukemia in adults and comprises about 20% of the leukemia cases in children. According to the American Cancer Society, more than 20,000 patients were diagnosed with AML and 10,500 died of AML in 2016. Current standard of care is dominated by generic chemotherapeutic agents and approaches that focus on single targets which are thought to be uniquely expressed in leukemic stem cells (LSCs). However, given the heterogeneity and clonal evolution of LSCs, this may often cause AML relapse and resistance. Therefore, there is an urgent need for developing novel targeted therapies in the current AML treatment landscape which abolish critical driver mechanisms of LSCs.
The let-7 micro RNA (miRNA) family exerts its tumor suppressor and anti-proliferative activities through repression of several oncogenes and by regulating key factors involved in cell cycle and metabolism as well as differentiation and apoptotic pathways. Downregulation of let-7 is a common phenomenon in several cancers including AML, and restoration of normal let-7 expression has been found to prevent cancer growth and inhibit cancer stem cell formation. As a result, let-7 represents a potential therapeutic target in AML therapy.
Researchers at UCLA have identified small molecule phosphodiesterase inhibitors that suppress let-7 targets and oncogenes such as cMYC and HMGA2. The lead compound is found to upregulate the endogenous expression of tumor suppressor let-7 miRNAs, efficiently suppresses let-7 target genes (HMGA2, cMYC, and LIN28B) involved in AML pathogenesis, shows strong growth inhibitory effects and abolishes colony forming capacity of LSCs in a variety of cytogenetically different AML cell lines.
·Novel targeted therapeutic approach for AML