Abstract A243: Characterization of NMS-E628, a small molecule inhibitor of anaplastic lymphoma kinase with antitumor efficacy in ALK-dependent lymphoma and non-small cell lung cancer models

Abstract

Abstract The chromosomal translocation t(2;5)(p23;q35) involving the ALK tyrosine kinase gene results in expression of the NPM-ALK fusion protein which represents the driving force for survival and proliferation of a subset of Anaplastic Large Cell Lymphoma. More recently, a distinct chromosomal rearrangement of the ALK gene leading to a new fusion variant EML4-ALK, has been identified as a low frequency event, mutually exclusive with respect to EGFR and K-ras mutation, in Non Small Cell Lung cancer patients. As previously found for NPM-ALK, this new fusion variant has constitutively active ALK kinase and was demonstrated to have strong oncogenic potential. Taken together these findings support the hypothesis that ALK represents an innovative and valuable target for cancer therapy both in ALCL and NSCLC patients whose tumors harbor translocated ALK. Here we further describe the preclinical characterization of NMS-E628, an orally available small-molecule inhibitor of ALK kinase activity. Proliferation profiling on a wide panel of human tumor cell lines demonstrated that the compound selectively blocks proliferation of ALK-dependent cell lines and potently inhibits ALK-dependent signaling. In vivo, NMS-E628 induced complete tumor regression when administered orally for ten consecutive days to SCID mice bearing Karpas-299 or SR-786 xenografts, with ex vivo analyses demonstrating dose-dependent target modulation that was maintained for up to 18 hours after single treatment. NMS-E628 was also highly efficacious in a transgenic mouse leukemia model in which human NPM-ALK expression was targeted to T cells. In this latter model, which faithfully recapitulates pathological features of human ALCL, treatment of NPM-ALK transgenic mice with NMS-E628 for as little as 3 consecutive days induced complete regression of tumor masses observed in the thymus and in lymph nodes. NMS-E628 was also highly efficacious in inhibiting the in vitro and in vivo growth of the NSCLC cell line NCI-H2228, which bears the EML4-ALK rearrangement. Complete regressions were also achieved in this model, and prolonged inhibition of ALK phosphorylation and downstream effector activation were observed at active doses. NMS-E628 has favorable pharmacokinetic and toxicological properties and biodistribution analysis revealed that it is able to cross the blood-brain barrier in different animal species. To confirm that therapeutic doses are reached in the brain, NCI-H2228 cells were injected intracranially in nude mice and NMS-E628 was administered orally with different schedules. Dose-dependent increase in survival, together with inhibition of tumor growth as assessed by MRI, confirmed that NMS-E628 does indeed possess antitumor activity in this setting, an important finding considering that a significant proportion of NSCLC patients develop brain metastases. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A244.