gdc-0449 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Topics: Anilides; Animals; Fusion Proteins, bcr-abl; Humans; Hydrogen-Ion Concentration; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines

The Hedgehog signaling pathway is a key regulator of cell growth and differentiation during development. Whereas the Hedgehog pathway is inactive in most normal adult tissues, Hedgehog pathway reactivation has been implicated in the pathogenesis of several neoplasms including BCR-ABL1-positive leukemia. The clear link between the Hedgehog pathway and BCR-ABL1-positive leukemia led to an effort to identify small molecules to block the pathway.. We investigated the combined effects of vismodegib and ponatinib, a pan-ABL1 kinase inhibitor, in nonobese diabetic/severe-combined immunodeficiency (NOD/SCID) repopulating T315I BCR-ABL1-positive cells in vitro and in vivo.. We observed that combination with vismodegib and ponatinib helps to eliminate therapy-resistant NOD/SCID repopulating T315I BCR-ABL1-positive cells. The percentage of CD19-positive leukemia cells in peripheral blood was significantly lower in vismodegib + ponatinib-treated mice than that of the vehicle or ponatinib alone (P < 0.001). Spleen weights were also lower in vismodegib + ponatinib-treated mice than in ponatinib alone (P < 0.05). Overall tumor burden, as assessed by BCR-ABL mRNA from bone marrow cells, was significantly lower in vismodegib + ponatinib-treated mice than in ponatinib alone (P < 0.005). We also found that vismodegib significantly reduced BCR-ABL1-positive leukemia cell self-renewal in vitro as well as during serial transplantation in vivo.. The combination with a Smo inhibitor and ABL1 tyrosine kinase inhibitors may help eliminate therapy-resistant T315I BCR-ABL1-positive leukemia cells. Our preclinical results indicate that vismodegib has potential as an important option for controlling minimal residual cells in BCR-ABL1-positive leukemia.

Topics: Anilides; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Cell Proliferation; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Hedgehog Proteins; Humans; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, SCID; Pyridazines; Pyridines; Signal Transduction

Disease relapse remains a major cause of death in patients with BCR-ABL-positive leukemia despite advances in treatment with kinase inhibitors. Significant efforts are underway to target pathways that maintain leukemia stem cells. Targeting these pathways holds promise for definitive leukemia eradication or improvement of the effectiveness of currently available therapies.

Topics: Anilides; Animals; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Pyridazines; Pyridines

Hedgehog (Hh)-glioma-associated oncogene homolog (Gli) signaling is implicated in a large number of human cancers such as leukemia. In this study, we investigated the effects of the potent Hh antagonist GDC-0449 on the BCR-ABL-positive cell line OM9;22 and primary samples when leukemia cells were protected by a feeder cell line (S9 cells). The numbers of OM9;22 cells significantly increased with S9 cells. Treatment of OM9;22 cells with GDC-0449 caused cell growth inhibition and induced apoptosis. Moreover, GDC-0449 inhibited the colony growth of Philadelphia chromosome (Ph)-positive primary samples. We next investigated the effects of a combination of GDC-0449 and dasatinib on these cell lines. The growth inhibition typically promoted by dasatinib was significantly reduced in the presence of S9 cells. Treatment of Ph-positive leukemia cells with GDC-0449 and dasatinib in the presence of S9 caused significantly more cytotoxicity than that caused by each drug alone. Inhibition of Gli1 or Gli2 by siRNA transfection reduced the growth of the Ph-positive cell line K562 and increased cytotoxicity of dasatinib. Moreover, colony formations of Gli1 or Gli2 knockdown cells were also reduced. Data from this study suggest that administration of the Hh inhibitor GDC-0449 inhibits BCR-ABL-positive cell growth and enhances the cytotoxic effects of dasatinib in the presence of feeder cells.

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Dasatinib; Feeder Cells; Hedgehog Proteins; Humans; Intracellular Space; Kruppel-Like Transcription Factors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Nuclear Proteins; Pyridines; Pyrimidines; RNA, Small Interfering; Signal Transduction; Thiazoles; Transcription Factors; Transfection; Zinc Finger Protein GLI1; Zinc Finger Protein Gli2