Abstract
Anaplastic large cell lymphoma (ALCL) constitutes approximately 10–30 percent of childhood lymphomas and 3 percent of non-Hodgkin lymphomas in adults. Approximately 50–60 percent of ALCL patients express the ALK tyrosine kinase fused to a variety of partner proteins as a result of chromosomal translocation. The activated ALK fusion kinase drives proliferative and survival signaling in lymphoma cells that carry these translocations, and the native ALK protein is overexpressed in a variety of other hematologic and non-hematologic malignancies. Given the known functional role of NPM-ALK in the pathogenesis of some lymphomas, we developed the small molecule ALK antagonist TAE684 that targets the kinase catalytic domain. In Ba/F3 murine hematopoietic cells and human ALCL cells that require NPM-ALK for growth, TAE684 was selectively cytotoxic and rapidly triggered apoptotic cell death. We have extended these findings to animal models of hematopoietic neoplasia driven by the expression of NPM-ALK. In a murine NPM-ALK-Ba/F3 allograft model, oral administration of TAE684 prolonged the survival to 83 days, compared to 51 days for the control placebo-treated group (p=0.0028). Moreover, we used a murine retroviral bone marrow transplant model of NPM-ALK-driven hematopoietic neoplasia to assess the efficacy of TAE684 treatment. The median survival in the placebo-treated group was 18 days (range 11–18 days), whereas all but one mouse treated with TAE684 oral gavage survived to the study endpoint (range 23–25 days). The prolongation in survival was highly significant (p<0.0001) and was associated with a reduction in peripheral blood leukocytosis, decreased splenomegaly, and resolution of tissue infiltration with atypical granulocytic, B-lymphoid, and histiocytic/macrophage cells. Thus, in two rapidly progressive models of hematopoietic neoplasia, oral administration of the TAE684 compound was able to produce marked control of disease in most recipient mice. The prolonged survival of mice treated with TAE684 can be attributed to the ablation of aggressive hematopoietic malignancy that is driven by expression of the NPM-ALK fusion kinase. We anticipate that TAE684 will be effective in the management of lymphomas that express ALK fusion kinases and in non-hematologic malignancies associated with aberrant expression of the native ALK protein.
Acute toxicity analysis of Disarib, an inhibitor of BCL2
