Development of a novel preclinical model to test immune-oncology – radiotherapy combinations in rectal cancer

Supervisors: Campbell Roxburgh, Colin Steele, Anthony Chalmers (University of Glasgow), Owen Sansom (CRUK Beatson Institute)

In clinical practice, radiotherapy (RT) is an important component of multi-modality treatment of rectal cancer. There are currently no reliable biomarkers of response to RT, however a proportion of patients (10-20%) will exhibit a complete response to treatment with chemoradiation (5-FU and long course radiotherapy). Better identification of tumours likely to respond to RT would enable a more precise allocation of treatment to patients most likely to benefit. It is also important to expand the proportion of patients exhibiting complete treatment responses by developing novel RT based strategies as this may result in more patients avoiding radical and potentially morbid surgery. Importantly, RT is associated with a variety of potentially desirable changes within the tumour immune microenvironment (e.g. antigen exposure, MHC1 expression, T cell infiltration, expression of immune checkpoint molecules including PD-1/ PD-L1). Therefore there is a strong rationale for the development of novel immune-oncology – RT combinations in rectal cancer including strategies to enhance lymphocytic responses or deplete harmful myeloid responses.

Current preclinical models including transplanted xenografts fail to recapitulate the human scenario of rectal cancer in that the tumours often grow at a site remote from the mouse pelvis and maintenance of a competent murine immune system in such models is impossible. Professor Sansom's lab have developed a series of genetically engineered mouse models in which tumours can be induced using tamoxifen injection directly to the mouse rectum via colonoscopy. These tumours closely relate to the molecular subtypes of colorectal cancer and importantly these models maintain immune competence.

The successful applicant for this PhD project will work to develop a platform for image guided irradiation of induced tumours in the mouse rectum. The project will have the following aims:

- To develop a platform for delivery of radiotherapy using a small animal radiotherapy research platform to rectal cancers in mice.
- To develop protocols for the delivery of low dose and high dose per fraction radiotherapy over multiple administrations with the aim of recapitulating short and long course RT regimens used in current clinical practice.
- To evaluate differences in treatment response according to molecular/ genetic make-up in different models.
- To evaluate immune changes in the tumour microenvironment after RT according to genetic make-up.
- To assess whether the irradiation of regional lymph nodes compromises the development of intratumoural immune responses in response to RT
- To develop a workflow and platform in which novel immune-oncology compounds can be tested in combination with RT in preclinical studies
- To apply novel technologies including mass spectrometry to discover novel biomarkers of response to RT within subtypes of colorectal cancer



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