Title: Combining Minimally Invasive Interventions with Radiotherapy to Improve Outcomes and Reduce Treatment Toxicity and Side-Effects in Locally Advanced Prostate Cancer.
Funder: Cancer Research UK

Abstract: Background: One third of men with radically treated intermediate- or high-risk prostate cancer (PCa) relapse within 5 years. Men with locally advanced PCa (LAPCa) usually receive combined androgen deprivation therapy and external beam radiotherapy, but some tumours relapse, and those patients who are cured may suffer significant treatment side effects. Local control is important in LAPCa, and radical surgery is increasingly being performed in this setting despite a lack of high quality evidence. There is an unmet need for improved therapeutic strategies for LAPCa, and novel surgery combined with other treatments may be beneficial. An additional major challenge is to improve treatment for oligometastatic PCa (OMPCa), and there is increasing interest in the role of cytoreductive surgery to improve outcomes. Radiotherapy has direct effects on tumour cells and stromal components including vasculature. A minimally invasive surgical technique, TOOKAD-soluble® vascular-targeted photodynamic therapy (TS-VTP®), focally ablates solid cancers. TS-VTP® targets tumour vasculature by focally generating reactive oxygen and nitrogenous species upon targeted near-infrared illumination of intravenous photosensitiser. This causes tumour micro-vessel thrombosis and obliteration, and pre-clinical evidence also suggests that TS-VTP®-mediated tumour ablation induces immunological anti-tumour effects. This proposal will investigate whether optimally combined radiotherapy and TS-VTP® has synergistic effects. Aims: To explore whether an optimal temporal sequence of TS-VTP® and radiotherapy results in a synergistic increase in the probability of local control in LAPCa in pre-clinical models. Experiments will also investigate whether combined TS-VTP® and radiotherapy is more effective with immunomodulation, and whether combination treatment of primary tumours in OMPCa causes immunological metastasis reduction. Methods: PCa tumours in pre-clinical models will be treated with sequential combinations of TS-VTP® and radiotherapy, along with immunomodulation. Effects on tumour burden, vascularity and tumour immunology will be investigated using in vivo imaging, MRI, FACS, and immunology studies. Further experiments in models of OMPCa will explore whether combined treatment of the primary lesion causes an immune-mediated reduction in the metastatic burden. How the results of this research will be used: If synergy from combined treatment is demonstrated in these pre-clinical models, this could be clinically relevant and may lead to clinical trials in the short-term (3-5 years). In the longer-term (5-10 years) these treatment combinations may become a recognised alternative treatment if they demonstrate effectiveness, cost-effectiveness, and safety in men with LAPCa or OMPCa. This proposal is innovative as these therapeutic combinations of TS-VTP® and radiotherapy are hitherto untested.


Research activity codes: 5.1 PHARMACEUTICALS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS