Defining how cancer cells acquire resistance to microtubule-based drugs

Interested individuals must follow Steps 1, 2 and 3 at this link on how to apply
http://www.ed.ac.uk/biology/prospective-students/postgraduate/pgr/how-to-apply

Taxol (paclitaxel) is a major drug used in the treatment of cancers, in particular breast cancers. However, resistance to taxol arises regularly and thus it is critical to find ways to circumvent this resistance. Our lab works on a family of proteins, Kinesin-13, that can destabilize taxol-stabilized microtubules and are overexpressed in certain cancers resistant to taxol (Ganguly et al., 2011). We want to understand the mechanism that causes resistance to taxol and develop assays to identify taxol-resistant cancers that would become sensitive to the presence of Kinesin-13 protein. This could then be used to design drugs that may block the activity of Kinesin-13, based on our structural knowledge of the protein. Other pathways and candidates that change during the acquisition of resistance to taxol will also be studied and evaluated as future drug targets. This project will contribute to working towards personal medicine and personalized treatments following resistance to cancer.
We have generated multiple cell lines that are sensitive and resistant to taxol. Upon acquisition of taxol resistance, the cell shape becomes more elongated. The project will involve inserting fluorescent markers (H2B, tubulin) stably into these various cell lines. The student will also generate cell lines with fluorescent markers that lack or/and overexpress MCAK using CRISPR technology and tissue culture approaches. The student will then use live-cell imaging and fluorescence microscopy to examine the dynamics of cell division and general cytoskeletal organization. He will characterize the cell cycle behavior and cytoskeleton changes linked to cell morphology using image analysis. Using RNAi and cell biology approaches, the student will examine whether cells that are resistant to taxol become dependent on MCAK levels.
In collaboration with Neil Carragher at the IGMM, the student will also use reverse phase protein array technology to examine which pathways are up- and downregulated during the stages of acquisition to taxol (Akbani et al., 2014; Hearn et al., 2015). The student will also perform genome-wide mRNA sequencing which will help us identify other candidates that support resistance to taxol. These data will indicate which pathways can be targeted in taxol-resistant cells and give leads for small molecule inhibitor screens, then performed at the IGMM or with CRUK drug discovery unit.