MAGNETIC RESONANCE IMAGING BIOMARKERS OF ANGIOGENESIS AND APOPTOSIS IN ADVANCED CANCER

Abstract

University: University of ManchesterName of candidate: Danielle Lisa ShawDegree title: Doctor of PhilosophyThesis title: Magnetic resonance imaging biomarkers of angiogenesis andapoptosis in advanced cancerDate of submission: April 2016This work explores the use of functional magnetic resonance imaging (MRI) scans toprovide biomarkers of angiogenesis and of apoptosis in advanced colorectal and ovariancancer. Dynamic contrast-enhanced MRI (DCE-MRI) and diffusion weighted MRI (DWMRI),can be used to quantify changes in tumour microvasculature and tumour cellularityrespectively and so have potential to provide biomarkers for use with molecularly-targetedagents. The ultimate aim is to use these biomarkers to accelerate clinical trials, torationalise therapy and to improve patient outcomes.The first paper in this thesis describes DCE-MRI and DW-MRI techniques used incombination with ELISA measurements of circulating markers of angiogenesis and celldeath in metastatic colorectal cancer treated with conventional, oxaliplatin-basedchemotherapy. The second project investigates the use of DW-MRI in the pre-clinicalsetting, using CRC xenografts that had been engineered to undergo synchronous caspasedrivenapoptosis when exposed to doxycycline. The DW-MRI results were compared withcirculating markers of cell death, measured by ELISA, and IHC markers of cell death. Thefinal project evaluates DCE-MRI and DW-MRI parameter changes with cytotoxicchemotherapy with or without the VEGF-inhibitor cediranib in platinum-sensitiveadvanced ovarian cancer. MRI parameters are compared with progression free and overallsurvival data to assess for prognostic biomarkers.Both clinical studies demonstrate significant early change in MRI parameters followingtwo cycles of treatment, reflecting treatment-induced alterations to the tumour size,microvasculature and cellularity. Following two cycles of chemotherapy, both studiesrevealed correlations between MRI parameters and survival. In the case of ovarian cancer,pre-treatment DCE-MRI markers were prognostic, regardless of treatment arm. In the preclinicalsetting, we have shown that DW-MRI can detect apoptosis in an in vivo model.Changes observed on DW-MRI reflected those changes observed usingimmunohistochemical and circulating marker analyses. The use of this highly controllablemodel provides a better understanding of the mechanisms and timing behind ADCalterations due to apoptosis. Taken together, these studies show that these DCE-MRI andDW-MRI techniques are feasible and safe in the pre-clinical and clinical settings and thatthey can provide clinically useful information that relates to outcome.This thesis is presented in an alternative format to incorporate the three separate studiesthat were carried out to explore this common theme. The thesis is constructed around thesethree studies, which are written as journal papers.

Date of Award	31 Dec 2016
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Caroline Dive (Supervisor), Gordon Jayson (Supervisor) & Geoff Parker (Supervisor)