ALK Inhibitors, a Pharmaceutical Perspective

In 2007, the ALK tyrosine kinase was described as a potential therapeutic target for a subset of non-small-cell lung cancer patients. Clinical proof of concept, culminating in the recent approval by the Food and Drug Administration of the Pfizer drug crizotinib followed in record time. The drug was approved together with a companion diagnostic for detection of patients eligible for therapy. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in a rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib was observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may additionally occur through ALK-independent mechanisms, which still need to be elucidated in detail. Here we discuss the factors that led to such a rapid approval of a targeted agent, and we describe the second-generation compounds currently in development

Sensitivity to Entrectinib Associated with a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer

In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangement is a recurring event in CRC that renders tumors sensitive to TRKA kinase inhibitors in preclinical models. We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2cm in longest diameter to 4.7 and 4.3cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib

Morphology of antennal sensilla in doeringiella nobilis (Hymenoptera: Apidae)

The distribution and morphology of antennal sensilla were investigated in females of Doeringiella (Triepeolus) nobilis (Friese) (Apidae, Epeolini) using scanning-electron microscopy. Sensilla campaniformia and three different types of sensilla trichodea were observed in the scape and pedicel. Sensilla trichodea and placodea were the most abundant types in all the flagellomeres. Variability in terms of length was observed in sensilla trichodea and to a lesser extent in sensilla basiconica, allowing further classification of these cuticular structures into types. Sensilla ampullacea, coeloconica and coelocapitula displayed a similar morphology to that reported for other hymenopterans. A previously unknown type of sensilla basiconica was observed in flagellomere nine.Fil: Galvani, Gerónimo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; ArgentinaFil: Settembrini, Beatriz Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; ArgentinaFil: Roig Alsina, Arturo Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentin

Mutti L: Bortezomib inhibits nuclear factor-kappaB dependent survival and has potent in vivo activity in mesothelioma. Clin Cancer Res 2007

Abstract Purpose: Purpose of this study has been the assessment of nuclear factor-nB (NF-nB) as a survival factor in human mesothelial cells (HMC), transformed HMC and malignant mesothelioma (MMe) cells.We aimed at verifying whether the proteasome inhibitor Bortezomib could abrogate NF-nB activity in MMe cells, leading to tumor cell death and may be established as a novel treatment for this aggressive neoplasm. Experimental Design: In HMC and MMe cells, NF-nB nuclear translocation and DNA binding were studied by electrophoretic mobility shift assay, following treatment with tumor necrosis factor-a (TNF-a). The IKK inhibitor Bay11-7082 was also tested to evaluate its effects on HMC, transformed HMC, and MMe cell viability upon exposure to asbestos fibers. Following Bortezomib treatment, cytotoxicity of MMe cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, whereas apoptosis and cell-cycle blockade were investigated by high-content analysis. Bortezomib was also given to mice bearing i.p. xenografts of MMe cells, and its effects on tumor growth were evaluated. Results: Here, we show that NF-nB activity is a constitutive survival factor in transformed HMC, MMe cells, and acts as a survival factor in HMC exposed to asbestos fibers. Bortezomib inhibits NF-nB activity in MMe cells and induces cell cycle blockade and apoptosis in vitro as well as tumor growth inhibition in vivo. Conclusions: Inhibition of NF-nB constitutive activation in MMe cells by Bortezomib resulted in in vitro cytotoxicity along with apoptosis and in vivo tumor regression. Our results support the use of Bortezomib in the treatment of MMe and has led to a phase II clinical trial currently enrolling in Europe