Incidence of Oesophageal Adenocarcinoma (OAC) has increased by 48% over the past 15 years and the cure rate is dismal. Current therapeutic regimes focus on neoadjuvant treatment (prior to surgery) with chemotherapy alone or chemoradiation (CRT) for locally advanced tumours. Unfortunately 70-80% of patients show no benefit, with a delay to surgery. Our Department is leading a phase III randomised controlled trial comparing chemotherapy versus chemoradiotherapy regimes (NeoAEGIS;ICORG10-14), and consented biological samples from this trial will be central in this research programme. Improving radiation response is the key research focus of this multidisciplinary team consisting of translational scientists, surgeons and nanobiologists.
We have developed, validated and patented a novel small molecule inhibitor, the Quininib analog CC8, as an anti-angiogenic and anti-metabolic drug. Our proprietary radiosensitiser CC8 improves radiation treatment response by stabilising tumour vasculature and reducing metabolic profiles, and thus blocking two key radioresistance mechanisms. Gold nanoparticles offer benefits for cancer treatments as not only can they drive tumour-targeting through the leaky vasculature structure of tumours, they can also target the mitochondrial organelle of cells.
Hypothesis: Gold-nanoparticle targeting of the radiosensitiser CC8 will allow for targeting mitochodrial function and energy metabolism in tumour cells to ensure greater tumour response
Objective 1: Using an isogenic model of OAC radioresistance, assess the effects of gold nanoparticle-packaged CC8 on metabolic reprogramming and radiosensitivity.
Objective 2: Using a human ex vivo explant model, assess the effect of this novel combination treatment on mitochondrial/inflammatory/angiogenic protein secretions.
Objective 3: Using a mouse xenograft model with targeted image-guided exposures, determine the effect of the combination treatment on tumour regression and radiosensitivity.
