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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Phage display to identify functional resistance mutations to Rigosertib

Filipovic, Nedim 01 January 2017 (has links)
In vitro protein selection has had major impacts in the field of protein engineering. Traditional screens assay individual proteins for specific function. Selection, however, analyzes a pool of mutants and yields the best variants. Phage display, a successful selection technique, also provides a reliable link between variant phenotype and genotype. It can also be coupled with high throughput sequencing to map protein mutations; potentially highlighting vital mutations in variants. We propose to apply this technique to cancer therapy. RAF, a serine/threonine kinase, is critical for cell regulation in mammals. RAF can be activated by oncogenic RAS, found in over 30% of cancers, to drive cancer proliferation. Rigosertib, a benzyl styryl sulfone in phase III clinical trials for myelodysplastic syndrome (MDS), is an inhibitor of the RAS binding domain (RBD) in RAF. Phage display can be used to select RAF mutants for RAS binding affinity, in the presence of Rigosertib. High-throughput sequencing of these variants can provide a means of anticipating, and mapping resistance to this anti-cancer drug.

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