ABSTRACT: Multicenter, open-label, phase 1, cohort dose escalation study to determine the maximum tolerated dose (MTD) of 3 intermittent OSI-906 dosing schedules.
Project description:Multicenter, open-label, phase 1, cohort dose escalation study to determine the Maximum Tolerated Dose (MTD) on both Once Daily (QD) and Twice Daily (BID) schedules.
Project description:Multicenter, open-label, phase 1, cohort dose escalation study to determine the Maximum Tolerated Dose (MTD) of OSI-906 in combination with erlotinib
Project description:The purpose of this study is to determine the maximum tolerated dose (MTD) of the combination of OSI-906 and everolimus for the treatment of patients with refractory metastatic colorectal cancer.
Project description:Melanoma patients receiving drugs targeting BRAFV600E and MKK1/2 invariably develop resistance and continue progression, limiting the efficacy of treatment. As an alternative to continuous dosing schedules, intermittent treatment strategies involving intervening periods of drug withdrawal have been proposed to delay resistance. The efficacy of this treatment strategy has been supported by preclinical findings and several clinical case reports. The beneficial effect of intermittent treatment has been attributed to “drug addiction”, in which the cell viability of resistant cells is compromised during periods of drug removal, presumably due to MAPK pathway hyperactivation. However, the cellular and molecular responses to intermittent treatment are still incompletely understood. Here, we investigate effects of intermittent treatment with the BRAFV600E inhibitor, encorafenib, in a metastatic melanoma cell line engineered to express genes conferring resistance to BRAF inhibition. We show that intermittent treatment shows superior growth suppression compared to continuous treatment for resistant cells that substantially reactivate the MAPK pathway. While drug addiction is clearly observable in these cells, it fails to account for the advantageous effects of intermittent treatment. Instead, growth suppression can mainly be explained by resensitization as most cell death is observed upon readdition of drug following periods of drug removal. Gene expression analysis shows that a unique and reversible transcriptional state is induced in intermittently treated cells following periods of drug removal. Thus, we conclude that the beneficial effects of intermittent treatment in our model are best explained by adaptive, non-mutational changes in transcription which confer drug resensitization.
Project description:This study plans to learn more about an investigational drug called OSI-906. OSI-906 is being looked at to see if it could be a treatment for advanced cancer. "The FDA is the U.S. government agency that reviews the results of research of drugs and decides if it can be sold in the U.S. OSI-906 has been given to over 185 people with cancer.
Project description:The Toxicogenomics Project was a 5-year collaborative project (2002-2007) by a consortium comprising the Japanese government and several pharmaceutical companies. The project produced the 'Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system' (TG-GATEs), a large-scale database of transcriptomics and pathology data potentially useful for predicting the toxicity of new chemical entities. Conventional in vivo toxicology data was collected from single dose and repeat dosing studies on rats, and gene expression measured for the liver (and kidney in some cases). To provide information on species differences, gene expression was also measured in rat and human hepatocytes treated with the chemicals in vitro. Approximately 130 chemicals, primarily medicinal compounds, were tested at multipe doses. Gene expression was analysed using Affymetrix GeneChip arrays. The gene expression data has been submitted in four parts: in vivo single dose (E-MTAB-799), in vivo repeat dosing, in vitro rat (E-MTAB-797) and in vitro human (E-MTAB-798). This submission comprises the in vivo, repeat dosing studies. If publishing results based on this data, please cite the full project name 'Toxicogenomics Project and Toxicogenomics Informatics Project', the database name 'Open TG-GATEs' and the URL 'http://toxico.nibio.go.jp'. Please note that the European Bioinformatics Institute (EBI) was not involved in the Toxicogenomics Project in any way, acting only to submit the transcriptomics data to Array Express. Queries about the project can be addressed to the consortium directly via 'opentggates@nibio.go.jp'. This dataset is part of the TransQST collection.
Project description:A clinical study evaluating the dosing of an oral HDACi panobinostat in patient infected with HIV-1. Dosing was 20 mg orally, 3 times weekly, every other week for a total of 8 weeks. Gene expression was evaluated in whole PBMCs at baseline (Visit 2), after 3 doses (Visit 4), 4 weeks after dosing (Visit 12) and 6 months after dosing (Visit 13) using the Affymetrix HTA 2.0 gene expression chip
Project description:Mixed MCBA PBFM dosing of wild-type C57BL/6Crl mice. 80 mg/kg total bile acid dose (10 mg/kg individual MCBA). MCBAs included in the dosing included AlaCA, AspCA, GluCA, LeuCA, PheCA, SerCA, ThrCA, and TyrCA.
Project description:Expression data from mice exposed to intermittent hypoxia and mice reared for 12 months. We used microarrays to analyze the transcriptome of hippocampus from mice exposed to intermittent hypoxia or aged mice.