Targeting tubulin isotypes in cancer

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Tubulins are a family of cellular proteins, including a- and B-tubulin, which go on to form microtubules; microtubules perform a variety of functions in the cell, such as coordinating transport within the cell and regulating cell division. Isotypes exist in both a- and B-tubulins, which can differ in their cellular localisation or level of expression. BIII-tubulin is an example of a tubulin isotype. Since microtubules are able to regulate processes such as cell division, microtubules have become an important target for various chemotherapies and anti-cancer drugs. Many are known to bind to pockets found on both the a- and B-tubulins to induce microtubule stabilisation or depolymerisation in order to halt cell division. For instance, Paclitaxel, otherwise known as Taxol, is a chemotherapeutic drug derived from the pacific yew tree, that binds to a taxane binding pocket located on B-tubulins, inducing microtubule stabilisation. However, it has also now been established that certain tubulin isotypes can become upregulated in cancer cells - BIII-tubulins has been found to be upregulated in breast cancer cells. Moreover, these cells have also shown to be more resistance to drugs such as Paclitaxel, thereby leading to the question of whether specific tubulin isotypes play a role in cancer drug resistance. Furthermore, there is a lack of characterisation on the binding affinities of different tubulin isotypes to cancer drugs. This project aims to determine the binding affinities of tubulin isotypes to cancer drugs, and study how cancer drugs affinity could be improved for different tubulin. In the long term, this may potentially lead to more specific and effective prescription of cancer drugs to patients depending on the expression of tubulin isotypes in cancer cells.