Christensen, J. G. et al. Cytoreductive antitumor activity of PF2341066, a novel inhibitor of anaplastic lymphoma kinase and cMet, in experimental models of anaplastic large-cell lymphoma. Mol. Cancer Ther. 6, 3314-3322
A t(2;5) chromosomal translocation resulting in expression of an oncogenic kinase fusion protein known as nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) has been implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL). PF-2341066 was recently identified as a p.o. bioavailable, small-molecule inhibitor of the catalytic activity of c-Met kinase and the NPM-ALK fusion protein. PF-2341066 also potently inhibited NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells (mean IC50 value, 24 nmol/L). In biochemical and cellular screens, PF-2341066 was shown to be selective for c-Met and ALK at pharmacologically relevant concentrations across a panel of > 120 diverse kinases. PF-2341066 potently inhibited cell proliferation, which was associated with G(1)-S-phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells IC50 values, similar to 30 nmol/L) but not ALK-negative lymphoma cells. The induction of apoptosis was confirmed using terminal deoxyribonucleotide transferase-mediated nick-end labeling and Annexin V staining IC50 values, 25-50 nmol/L). P.o. administration of PF-2341066 to severe combined immunodeficient-Beige mice bearing Karpas299 ALCL tumor xenografts resulted in dose-dependent antitumor efficacy with complete regression of all tumors at the 100 mg/kg/d dose within 15 days of initial compound administration. A strong correlation was observed between antitumor response and inhibition of NPM-ALK phosphorylation and induction of apoptosis in tumor tissue. In addition, inhibition of key NPM-ALK signaling mediators, including phospholipase C-gamma, signal transducers and activators of transcription 3, extracellular signal-regulated kinases, and Akt by PF-2341066 were observed at concentrations or dose levels, which correlated with inhibition of NPM-ALK phosphorylation and function. Collectively, these data illustrate the potential clinical utility of inhibitors of NPM-ALK in treatment of patients with ALK-positive ALCL.
"While only 3–5% of NSCLC tumors are ALK-rearrangement-positive   , this translates into a considerable number of patients affected worldwide. Crizotinib (XALKORI; Pfizer Inc., New York, NY, USA) is an inhibitor of ALK, MET, and ROS1   . Crizotinib gained approval in the US for the treatment of adults with ALK-positive advanced NSCLC within 4 years of the discovery of the importance of ALK rearrangement and has subsequently been approved "
[Show abstract][Hide abstract] ABSTRACT: Within 4 years of the discovery of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC), the ALK inhibitor crizotinib gained US and European approval for the treatment of advanced ALK-positive NSCLC. This was due to the striking response data observed with crizotinib in phase I and II trials in patients with ALK-positive NSCLC, as well as the favorable tolerability and safety profile observed. Recently published phase III data established crizotinib as the new standard of care in the second-line setting for this NSCLC molecular subset. A consequence of such rapid approval, however, is the limited clinical experience and relative paucity of information concerning optimal therapy management. In this review, we discuss the development of crizotinib and the clinical relevance of its safety profile, examining crizotinib-associated adverse events in detail and making specific management recommendations. Crizotinib-associated adverse events were mostly mild to moderate in severity in clinical studies, and appropriate monitoring and supportive therapies are considered effective in avoiding the need for dose interruption or reduction in most cases. Therapy management of patients following disease progression on crizotinib is also discussed. Based on available clinical data, it is evident that patients may have prolonged benefit from crizotinib after Response Evaluation Criteria in Solid Tumors-defined disease progression, and crizotinib should be continued for as long as the patient derives benefit.
Lung Cancer 12/2014; 87(2). DOI:10.1016/j.lungcan.2014.12.010 · 3.96 Impact Factor
"ocal approach to RTK - specific inhibitors . Treatment targeted against EGFR ( erlotinib ) , PDGFR ( imatinib ) , and c - Met ( SU11274 ) showed a significant improvement of GBM cell growth inhibition in vitro ( Stommel et al . , 2007 ) . However , when c - Met is amplified alone , crizotinib treatment , directed against ALK and c - Met activity ( Christensen et al . , 2007 ) , shows significant radiographic and clinical improvement in a case report ( Chi et al . , 2012 ) . A phase I clinical trial is ongoing ( A8081001 ) ."
[Show abstract][Hide abstract] ABSTRACT: Despite an increased emphasis on developing new therapies for malignant gliomas, they remain among the most intractable tumors faced today as they demonstrate a remarkable ability to evade current treatment strategies. Numerous candidate treatments fail at late stages, often after showing promising preclinical results. This disconnect highlights the continued need for improved animal models of glioma, which can be used to both screen potential targets and authentically recapitulate the human condition. This review examines recent developments in the animal modeling of glioma, from more established rat models to intriguing new systems using Drosophila and zebrafish that set the stage for higher throughput studies of potentially useful targets. It also addresses the versatility of mouse modeling using newly developed techniques recreating human protocols and sophisticated genetically engineered approaches that aim to characterize the biology of gliomagenesis. The use of these and future models will elucidate both new targets and effective combination therapies that will impact on disease management.
Advances in Cancer Research 06/2014; 121:261-330. DOI:10.1016/B978-0-12-800249-0.00007-X · 5.32 Impact Factor
"Currently crizotinib is the “drug of choice” for the NSCLCs [49,11,129]. The clinical response rates with crizotinib and the newer ALK inhibitors are roughly 30% more effective than conventional chemotherapeutic treatments [122-128,138-145]. Thus, although ALK-rearrangement targeted treatments offer a better treatment regimen, advanced ALK-rearranged NSCLC still carries a poor prognosis. "
[Show abstract][Hide abstract] ABSTRACT: The anaplastic lymphoma tyrosine kinase (ALK) gene was first described as a driver mutation in anaplastic non-Hodgkin's lymphoma. Dysregulated ALK expression is now an identified driver mutation in nearly twenty different human malignancies, including 4-9% of non-small cell lung cancers (NSCLC). The tyrosine kinase inhibitor crizotinib is more effective than standard chemotherapeutic agents in treating ALK positive NSCLC, making molecular diagnostic testing for dysregulated ALK expression a necessary step in identifying optimal treatment modalities. Here we review ALKmediated signal transduction pathways and compare the molecular protocols used to identify dysregulated ALK expression in NSCLC. We also discuss the use of crizotinib and second generation ALK tyrosine kinase inhibitors in the treatment of ALK positive NSCLC, and the known mechanisms of crizotinib resistance in NSCLC.
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