Modelling tumour initiating cells and their differentiation cascade, with the effects of photon irradiation and temozolomide, to optimise treatment

Glioblastoma murtiforme (GBM) is the most aggressive form of glioma, classified by the Wor1d Health Organisation (WHO) as a grade III or IV tumour [1]. Despite receiving a combination of radiotherapy, chemotherapy and surgical treatment, average survival is poor of 14•6 months and only a two year survival of 27•2% [2]. Present studies on cell surface markers, such as CD15, suggest that GBM is composed of a heterogeneous population of cells, derived from a brain tumour stem cell (BTSC). BTSC cells play an essential role in the growth of tumours and thus treatment therapies may be more beneficial if adapted to inhibit the development of these cells. R10 cells are a patient derived GBM cell line provided by the Addenbrooke's Hospital in Cambridge. Isolating the R10 cell line for the CD15 marker can allow for the sensitivity of the subpopulations within the tumour to be determined. A better understanding of these sensitivities could allow for a more optimal treatment to be developed, which exploits the different sensitivities of each subpopulation. Experimental results showed that each subpopulatian af the R10 cell line has significantly different doubling times and sensitivities to drug and irradiation. A population balance equation is used to model the growth of a BTSC cell. The aim was to model a new fractionation schedule, which improves the treatment of GSM. This was achieved by means of predicting the number of cells killed in each cell line using the data from the R10 cell line. The model implements an asymmetric radiotherapy (ART) treatment that gives two initial low doses followed by a third dose that delivers a total daily dose of 2 Gy. All doses and the inter-fraction intervals could be varied to find the optimum treatment schedule. The optimum schedule from ART delivers two initial doses of 0•7 Gy, followed by a dose of 0-6 Gy with intervals of 1 hour, for 5 days a week for 6 weeks. A daily dose of 2 Gy and a total dose of 60 Gy were given to ensure that jf a patient were to show no signs of hyper-radiosensitivty (HRS) they would still be treated efficiently. However, it was found that the standard radiotherapy treatment was more beneficial with this scenario.EThOS - Electronic Theses Online ServiceProf. Norman KirkbyGBUnited Kingdo