In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. e13520-e13520
Abstract:
e13520 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 population in several experimental systems. PF-04449913 (PF) is a novel oral small molecule inhibitor that targets Smoothened (SMO) in the Hh pathway. Treatment with PF has shown promising results regarding safety, tolerability, and early signs of efficacy in a phase 1 study of hematologic malignancies including acute myeloid leukemia (AML) (Jamieson C, et al. ASH, 2011). Methods: We used AML cell lines and primary AML cells in order to elucidate mechanisms and biomarkers in PF treatment. We also used a co-culturing system with HS-5 stromal cells, and an immunodeficient NOD/SCID/IL2rγ null (NOG) mouse model serially xenotransplanted with primary AML cells to evaluate effects of PF on AML propagation. Results: In vivo-treatment with PF attenuated leukemia-initiation potential in acute myeloid leukemia cells through the serial transplantation system, while limiting reduction of tumor burden in the primary leukemia system. Ex vivo-treatment with PF inhibited proliferation and minimally induced cell death in leukemia cell lines and primary AML cells increased expression of the myeloid differentiation marker, CD11b. In addition, PF treatment down-regulated mRNAs encoding downstream effector GLIs in the canonical Hh pathway using RQ-PCR assays and decreased nuclear expression of GLI-2 using immunofluorescence assays. Moreover, combined treatment with PF abrogated resistance to Ara-C in MOLM-14 cells co-cultured with HS-5 stromal cells. We are also investigating biomarkers in these models including CD markers (such as CD44) as well as the toxicity for normal cord blood cells with PF treatment. Conclusions: These results imply that PF treatment can attenuate leukemia-initiation potential in acute myeloid leukemia cells and improve AML therapy through overcoming the resistance to chemotherapy in the bone marrow microenvironment.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2013.31.15_suppl.e13520
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2013
detail.hit.zdb_id:
2005181-5
