Title: MAnchester RESearch Transforming Radiation Oncology (MAESTRO) programme as part of CRUK RadNet
Funder: Cancer Research UK

Abstract: Background: Radiotherapy is a mainstay of cancer treatment and research on improving, optimising and personalising approaches is required to improve survival rates. The cancer burden is high in Manchester where incidence and mortality rates exceed the English average. Cancer patients in Manchester often suffer from multiple comorbidities and exemplify real-world individuals often excluded from clinical trials. Programme-wide changes dealing with complex patients must occur to demonstrate improved outcomes regionally before being applied nationally and beyond. Aims: Our vision as an integrated world-leading translational radiation oncology programme is to address the challenges of diverse patient characteristics to achieve individualised physical and biological targeting based on real-time outcomes and a deep mechanistic understanding of immune response, comorbidity and genomics. We aim to: (1) define radiotherapy-induced immunomodulatory changes that dictate tumour and normal tissue inflammatory responses to inform clinical interventions to improve therapeutic ratios; (2) develop decision support systems and use animal models of comorbidity to understand mechanisms and identify strategies for individualising radiotherapy for ‘real-world’ patients; and (3) investigate the complex interactions between the tumour microenvironment, immune-landscape and genetic instability in primary and metastatic lesions to inform novel radiotherapy and drug combined modality trials and overcome tumour resistance. Methods: Our programme will use pre-clinical models and clinical specimens to interrogate scientific paradigms and address key areas in radiobiology and radiation oncology. Methods will include: integrating immunology, genomics and radiotherapy in pre-clinical models and patient samples; using pre-clinical models recapitulating comorbidities to understand mechanisms and identify actionable targets; computational and statistical oncology analyses of real-time real-world large clinical datasets; interrogating the effects of hypoxia on the genesis of mitotic abnormalities; investigating effects on the immune system on protons versus photons; studying the effects of radiotherapy on barrier mucosa immunology and local and chronic inflammation. Our programme includes collaborative hubs for: national proton biology research; clinical informatics and distributed learning methods to learn from every patient treated; and biomarkers capabilities for both leading practice-changing biomarker-driven trials and embedding radiotherapy-relevant biomarker discovery and validation research in studies across the UK. How the results of this research will be used: We will drive new approaches for patient stratification to improve outcomes; develop new technologies (protons, MR-linac); increase the physical and biological precision of radiotherapy; identify new agents to combine with radiotherapy; generate high-quality biorepositories from patients and preclinical models for use by other UK researchers and linked to dense translational and clinical data.

Lay abstract: Background: Radiotherapy is a mainstay of cancer treatment and research on improving, optimising and personalising approaches is required to improve survival rates. The cancer burden is high in Manchester where incidence and mortality rates exceed the English average. Cancer patients in Manchester often suffer from multiple comorbidities and exemplify real-world individuals often excluded from clinical trials. Programme-wide changes dealing with complex patients must occur to demonstrate improved outcomes regionally before being applied nationally and beyond. Aims: Our vision as an integrated world-leading translational radiation oncology programme is to address the challenges of diverse patient characteristics to achieve individualised physical and biological targeting based on real-time outcomes and a deep mechanistic understanding of immune response, comorbidity and genomics. We aim to: (1) define radiotherapy-induced immunomodulatory changes that dictate tumour and normal tissue inflammatory responses to inform clinical interventions to improve therapeutic ratios; (2) develop decision support systems and use animal models of comorbidity to understand mechanisms and identify strategies for individualising radiotherapy for ‘real-world’ patients; and (3) investigate the complex interactions between the tumour microenvironment, immune-landscape and genetic instability in primary and metastatic lesions to inform novel radiotherapy and drug combined modality trials and overcome tumour resistance. Methods: Our programme will use pre-clinical models and clinical specimens to interrogate scientific paradigms and address key areas in radiobiology and radiation oncology. Methods will include: integrating immunology, genomics and radiotherapy in pre-clinical models and patient samples; using pre-clinical models recapitulating comorbidities to understand mechanisms and identify actionable targets; computational and statistical oncology analyses of real-time real-world large clinical datasets; interrogating the effects of hypoxia on the genesis of mitotic abnormalities; investigating effects on the immune system on protons versus photons; studying the effects of radiotherapy on barrier mucosa immunology and local and chronic inflammation. Our programme includes collaborative hubs for: national proton biology research; clinical informatics and distributed learning methods to learn from every patient treated; and biomarkers capabilities for both leading practice-changing biomarker-driven trials and embedding radiotherapy-relevant biomarker discovery and validation research in studies across the UK. How the results of this research will be used: We will drive new approaches for patient stratification to improve outcomes; develop new technologies (protons, MR-linac); increase the physical and biological precision of radiotherapy; identify new agents to combine with radiotherapy; generate high-quality biorepositories from patients and preclinical models for use by other UK researchers and linked to dense translational and clinical data.

Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS