Laura Hawkins is researching the most common intraocular tumour in adults in her ongoing PhD research. With a poor median survival of 4-6 months following metastasis, radiotherapy is the mainstay of treatment, with majority of patients receiving proton beam therapy. However, approximately 50% of patients will progress to metastasis. Laura aims to further understand and optimise the radiation response of this cancer to conserve eyesight and prevent progression of the disease, impacting the future of cancer treatment.
It is hoped that my work will show that targeting the DNA damage response is a viable non-toxic approach to enhance the radiation treatment that patients receive. There would then be the potential for this to be translated in the clinic to hopefully impact uveal melanoma patients to improve their response to initial radiation treatments to prevent metastatic development, with less adverse effects that they currently experience.
Spheroids are a 3D model which naturally form oxygen and nutrient gradients to better mimic the tumour microenvironment, as compared to monolayers. Through the use of this model, we aim to evaluate radiation response to both photon and proton radiations in cell lines derived from primary tumour and metastatic tumours, through growth and viability assays and the comet assay, to measure DNA damage. We are currently investigating whether key DNA repair proteins essential for homologous recombination (HR) and non-homologous end joining (NHEJ) are required for the repair of DNA damage induced by either form of ionising radiation; including ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), and DNA dependent protein kinase catalytic subunit (DNA-PKcs).
I have shown that inhibitors for all three kinases sensitised UM spheroids to photon and proton radiation, with the ATM inhibitor in particular creating persistent DNA damage which correlated to the reduced growth phenotype. Overall, I have shown that key DNA repair proteins are required for efficient repair of IR-induced lesions and could be targetable for the enhancing the effectiveness of UM treatment.
The 3D model of uveal melanoma spheroids show varied response to IR regardless of tissue origin, there is no difference in inherent sensitivity with metastatic cell lines vs primary cell lines.
Targeting the DDR appears to be a promising therapeutics option. ATM, ATR and DNA-PKc inhibitors are showing to be well tolerated (low toxicity) but show a significant growth reduction and viability when used in combination with radiation treatment. This is coupled with persistent DNA damage, suggesting this is the main mechanism driving this reduction in growth and survival.