A Phase I Study to Assess the Safety, Tolerability and Potential Therapeutic Dose of OMT-110 in Patients with metastatic colorectal cancer
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ABSTRACT:
DISEASE(S): Diseases Of The Digestive System
PROVIDER: 2513246 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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2016-02-10 | E-GEOD-77069 | biostudies-arrayexpress
Project description:It is very important to understand the mechanisms how bacteria become tolerant towards antibiotics during clinical therapy. In a previous study we showed that increased daptomycin (DAP) tolerance of Staphylococcus aureus was due to a point mutation in pitA (inorganic phosphate transporter) that led to intracellular accumulation of both inorganic phosphate (Pi) and polyphosphate (polyP). DAP tolerance in that pitA6 mutant differs from classical resistance mechanisms as there was no increase in minimal inhibitory concentration (MIC). In this study we demonstrate that DAP tolerance in the pitA6 mutant is not triggered by the accumulation of polyP. Transcriptome analysis revealed that about 234 genes were at least 2.0-fold differently expressed in the mutant. Particularly, genes involved in protein biosynthesis, carbohydrate and lipid metabolism as well as in replication and maintenance of DNA were downregulated. However, the most important change was the upregulation of the dlt-operon, which is induced by the accumulation of intracellular Pi. The GraXRS system, known as activator of both dlt and mprF, as well as surface charge, cell wall thickness or the content of wall teichoic acids (WTA) are not involved in DAP tolerance in the pitA6 mutant. In conclusion the DAP tolerance in the pitA6 mutant is due to an upregulation of the dlt-operon triggered directly or indirectly by the accumulation of Pi.
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Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma. We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.
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