O1-1-3 - Treatment with Hedgehog Inhibitor, Pf-913, Attenuates Leukemia-Initiation Potential in Aml Cells

Abstract

Background: Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in a variety of cancers, and required for maintenance of the leukemic stem cell (LSC) populations in several experimental systems. Cumulative evidence suggests that dormant self-renewing LSC contribute to acute myeloid leukemia (AML) propagation and relapse by evading conventional chemotherapies that target cycling cells. PF-913 is a novel oral small molecule inhibitor that selectively binds and targets Smoothened (SMO), a membrane protein regulating the Hh pathway. Treatment with PF-913 has shown promising results regarding safety, tolerability, and early signs of efficacy in AML patients. However, the detailed mechanisms and biomarkers remain to be elucidated in AML therapy.Results: In primary AML cells, the Hh signaling pathway was activated more in CD34+ cells than CD34- cells. Ex vivo-treatment with PF-913 in AML cells induced minimal cell death as well as decrease of the quiescent cell population. In vivo-treatment with PF-913 attenuated leukemia-initiation potential in AML cells through the serial transplantation system, while limiting reduction of tumor burden in the primary leukemia system. Also in the colony-assay system using primary AML cells, treatment with PF-913 reduced serially colony formation. Comprehensive Gene Set Enrichment Analysis (GSEA) revealed that PF-913 treatment modulated embryo stem (ES) cell-like signature in primary AML cells. Moreover, combined treatment with PF-913 abrogated resistance to Ara-C in AML cell lines co-cultured with HS-5 stromal cells and sensitized AML cells to Ara-C in the cutaneous tumor system.Conclusions: Our findings imply that PF-913 treatment can attenuate the leukemia-initiation potential in AML cells, and can also improve AML therapy through sensitizing dormant LSC to chemotherapy and overcoming the resistance in the bone marrow microenvironment.