Development of a high-throughput in-vitro radiobiology platform and evaluation of dose-rate, intra-fraction treatment breaks and drug-radiation effects in stereotactic radiotherapy

Stereotactic radiotherapy (SRT), which delivers ablative radiation doses, is increasingly becoming a standard of care in many clinical scenarios. Radiobiological studies help to understand clinical radiotherapy, including SRT, better. In-vitro radiobiological studies designed to explore complexities of SRT, and the large potential experimental space of radiation-drug combinations would require a high-throughput in-vitro system, which should be relevant to clinical radiotherapy. My programme of work led to the development of a high-throughput in-vitro radiobiology platform using an advanced clinical radiotherapy technique, intensity modulated radiotherapy (IMRT) using widely available clinical facilities to recapitulate clinical radiotherapy as close as possible. My work also examined some of clinically relevant radiation physics and clinical parameters that are related to SRT. My work, in contrast with other work showed that there might not significant biological implications of different radiation-doses rates and intra-fraction treatment breaks used in SRT. This could be due to ablative radiation doses used in SRT. Using in-vitro tumour models, I demonstrated a novel radiosensitisation strategy of using Notch inhibition that has a potential for clinical translation in melanoma where, because of its relative radioresistance phenotype could prove to be a successful strategy to widen the clinical application of radiotherapy. My work also showed that Notch inhibition could potentially reduce the risk of development of metastasis and demonstrated potential mechanistic basis for this combined approach. I also demonstrated a novel, first-in-class radiosensitisation approach with a folate depletion strategy based on sound biological rationale with various in-vitro tumour models differing in their radiosensitivities that would require in-vivo validation. My work would hopefully encourage other institutions to develop their own radiobiology programmes using clinical radiotherapy facilities to interrogate potential biological uncertainties of SRT and also expedite pre-clinical evaluation of radiation-drug combinations