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1.
Mol Cancer Ther ; 14(4): 931-40, 2015 Apr.
Article de Anglais | MEDLINE | ID: mdl-25637314

RÉSUMÉ

Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, ß, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents.


Sujet(s)
Antinéoplasiques/pharmacologie , Inhibiteurs des phosphoinositide-3 kinases , Quinoxalines/pharmacologie , Sulfonamides/pharmacologie , Animaux , Antinéoplasiques/administration et posologie , Lignée cellulaire tumorale , Mouvement cellulaire/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Humains , Mâle , Souris , Souris nude , Néovascularisation pathologique/traitement médicamenteux , Phosphorylation , Protéines proto-oncogènes c-akt/métabolisme , Quinoxalines/administration et posologie , Ribosomal Protein S6 Kinases/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Sulfonamides/administration et posologie , Tests d'activité antitumorale sur modèle de xénogreffe
2.
J Clin Invest ; 119(6): 1524-36, 2009 Jun.
Article de Anglais | MEDLINE | ID: mdl-19411762

RÉSUMÉ

Tumor infiltration with Valpha24-invariant NKT cells (NKTs) associates with favorable outcome in neuroblastoma and other cancers. Although NKTs can be directly cytotoxic against CD1d+ cells, the majority of human tumors are CD1d-. Therefore, the role of NKTs in cancer remains largely unknown. Here, we demonstrate that CD68+ tumor-associated monocytes/macrophages (TAMs) represented the majority of CD1d-expressing cells in primary human neuroblastomas. TAMs stimulated neuroblastoma growth in human cell lines and their xenografts in NOD/SCID mice via IL-6 production. Indeed, TAMs produced IL-6 in primary tumors and in the BM of patients with metastatic neuroblastoma. Gene expression analysis using TaqMan low-density arrays of 129 primary human neuroblastomas without MYCN amplification revealed that high-level expression of TAM-specific genes (CD14, CD16, IL6, IL6R, and TGFB1) was associated with poor 5-year event-free survival. While NKTs were not cytotoxic against neuroblastoma cells, they effectively killed monocytes pulsed with tumor cell lysate. The killing of monocytes was CD1d restricted because it was inhibited by a CD1d-specific mAb. Cotransfer of human monocytes and NKTs to tumor-bearing NOD/SCID mice decreased monocyte number at the tumor site and suppressed tumor growth compared with mice transferred with monocytes alone. Thus, killing of TAMs reveals what we believe to be a novel mechanism of NKT antitumor activity that relates to the disease outcome.


Sujet(s)
Macrophages/immunologie , Cellules T tueuses naturelles/immunologie , Neuroblastome/immunologie , Récepteurs aux antigènes des cellules T/immunologie , Animaux , Antigène CD1d/immunologie , Régulation de l'expression des gènes tumoraux/génétique , Glycolipides/métabolisme , Humains , Nourrisson , Interleukine-6/biosynthèse , Souris , Métastase tumorale/anatomopathologie , Neuroblastome/métabolisme , Neuroblastome/anatomopathologie , Tests d'activité antitumorale sur modèle de xénogreffe
3.
Clin Cancer Res ; 13(12): 3713-23, 2007 Jun 15.
Article de Anglais | MEDLINE | ID: mdl-17575237

RÉSUMÉ

PURPOSE: Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non-small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo. EXPERIMENTAL DESIGN: The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors. RESULTS: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors. CONCLUSIONS: These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.


Sujet(s)
Antinéoplasiques/pharmacologie , Composés azabicycliques/pharmacologie , Récepteurs ErbB/effets des médicaments et des substances chimiques , Récepteurs ErbB/génétique , Inhibiteurs de protéines kinases/pharmacologie , Quinazolines/pharmacologie , Animaux , Apoptose/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Résistance aux médicaments antinéoplasiques/génétique , Chlorhydrate d'erlotinib , Femelle , Géfitinib , Humains , Immunohistochimie , Méthode TUNEL , Souris , Souris nude , Souris SCID , Mutation , Phosphorylation/effets des médicaments et des substances chimiques , Tests d'activité antitumorale sur modèle de xénogreffe
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