Evaluation of Selective γ-Secretase Inhibitor PF-03084014 for Its Antitumor Efficacy and Gastrointestinal Safety to Guide Optimal Clinical Trial Design
| Autor: | Kosta Tsaparikos, Robert H. Denlinger, Marlena Walls, Sophia Randolph, Michelle Sands, Ping Wei, Anthony C. Wong, Ming Qiu, Natilie Hosea, Richard Ding, Tod Smeal, Jitesh P. Jani |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Time Factors Cell cycle checkpoint Tetrahydronaphthalenes Notch signaling pathway Down-Regulation Antineoplastic Agents Apoptosis Pharmacology Biology medicine.disease_cause Dexamethasone Downregulation and upregulation Cell Line Tumor medicine Humans Protease Inhibitors Receptor Cell Proliferation Clinical Trials as Topic Dose-Response Relationship Drug Receptors Notch Gene Expression Regulation Leukemic Cell growth Cell Cycle Cancer Valine medicine.disease Xenograft Model Antitumor Assays Protein Structure Tertiary Gastrointestinal Tract Treatment Outcome Oncology Amyloid Precursor Protein Secretases Carcinogenesis |
| Zdroj: | Molecular Cancer Therapeutics. 9:1618-1628 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | Aberrant regulation of Notch signaling has been implicated in tumorigenesis. Proteolytic release of the Notch intracellular domain (NICD) by γ-secretase plays a key role in Notch-dependent nuclear signaling. γ-Secretase is an attractive pharmaceutical target for therapeutic intervention in cancer. We describe the potent antitumor effects of PF-03084014, a small molecule that is a reversible, noncompetitive, and selective γ-secretase inhibitor. The ability of PF-03084014 to inhibit γ-secretase activity was shown by the reduction of endogenous NICD levels and by the downregulation of Notch target genes Hes-1 and cMyc in the T-cell acute lymphoblastic leukemia (T-ALL) cell line HPB-ALL. PF-03084014 caused cell growth inhibition of several T-ALL cell lines via cell cycle arrest and induction of apoptosis. PF-03084014 treatment also resulted in robust NICD reduction in HBP-ALL xenograft models. Broad antitumor efficacy at well-tolerated dose levels was observed in six Notch-dependent models. Additional mechanism-of-action studies showed inhibition of tumor cell proliferation and induction of apoptosis in HPB-ALL tumors, suggesting that the antitumor activity of PF-03084014 may be mediated by its direct effects on tumor cell growth or survival. Further studies on PF-03084014–induced gastrointestinal toxicity identified an intermittent dosing schedule that displayed reduced body weight loss and sustained antitumor efficacy. We also showed that glucocorticoids abrogated PF-03084014–induced gastrointestinal toxicity and delayed administration of glucocorticoids did not compromise its protection effect. Collectively, the results show that inhibition of Notch signaling by PF-03084014 while minimizing gastrointestinal toxicity presents a promising approach for development of therapies for Notch receptor–dependent cancers. This compound is being investigated for the treatment of T-ALL and advanced solid tumors in phase I clinical trials. Mol Cancer Ther; 9(6); 1618–28. ©2010 AACR. |
| Databáze: | OpenAIRE |
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