*4 Year MRC PhD Programme* Developing a mathematical model to explain paclitaxel uptake in vivo

The bestselling anti-cancer drug, paclitaxel™ (or taxol), works by stabilising microtubules and preventing cell division during mitosis. In an effort to produce drugs with fewer side-effects, billions of pounds have been spent on developing second generation anti-mitotic agents that only affect dividing cells (e.g. inhibitors of mitotic kinases and microtubule motors). It is currently unclear why these new drugs have so far been relatively ineffective in the clinic but it is critical to resolve this issue if current broad-spectrum chemotherapeutics are to be improved. An important property of taxol that has been somewhat overlooked, but which could account for its therapeutic efficacy, is its propensity to accumulate in cells and persist within tumours for many days/weeks after its blood plasma levels have fallen.

To explore this issue we have: (i) performed mass spec experiments that measure the extent of taxol accumulation within cultured cells; and (ii) developed a microfluidic system that allows cell division to be monitored following taxol treatment. (iii) shown that inhibiting microtubule polymerization prevents taxol accumulation, which implies that the abundance of taxol binding sites on polymerised microtubules acts as a sink to prevent drug release from cells.

The aims of this project are:

1) to develop mathematical models that describe taxol uptake and diffusion,

2) to perform microscopy experiments to test and validate these models,

3) to develop the models to simulate taxol uptake in 3D tissue environments.

The first set of models will describe Taxol uptake in cells that are cultured in a well-mixed medium and parameterized using measurements of taxol accumulation in cells. These models will be generalized to account for Taxol diffusion and parameterized using data from the microfluidic chambers in which taxol gradients are present. Hence key parameters about the diffusion length of taxol in tissue will be inferred. Finally, we will use Chaste to implement the developed models in a 3D tissue environment. The mathematical models will be used to address fundamental questions about how efficiently taxol penetrates tissues in vivo, which could have implications for dosage regimens (for example, lower doses given more frequently may preserve immune function to allow the clearance of dead cells to aid drug penetration).



Research training: The student will learn a combination of mathematical modelling, microscopy and cell biology.