Evaluation of a panel of angiogenesis biomarkers in patients with colorectal cancer.

Abstract

Background: The introduction of anti-angiogenic drugs to the management of many solid tumours has resulted in improved outcomes for many patients. In colorectal cancer, several anti-angiogenic drugs have been incorporated to the therapeutic options for patients with metastatic disease. Unfortunately, the benefit provided by these drugs is not universal and many patients are exposed as a consequence to ineffective treatment at the expense of potential toxicity and at a great financial cost. The definition of predictive biomarkers for this type of drug would help distinguish those patients who are likely to benefit from these drugs from those who are not. Unfortunately, no robust predictive biomarker is available for these drugs yet. One confounding factor is the fact that these drugs are usually delivered in combination with cytotoxic chemotherapy and little is known about the effect of such treatment on biomarker values. This project was designed to systematically explore the influence of standard-of-care therapies on a panel of angiogenesis-related and cell death biomarkers, aiming to aid future studies designed to identify potential predictive biomarkers for anti-angiogenic drugs. The main hypothesis of the thesis was that standard-of-care treatment modulates the level of a panel of angiogenesis-related biomarkers. Methods: A clinical protocol was developed and granted ethical and R&D approval. 120 patients were recruited to four different cohorts (chemoradiotherapy, adjuvant, neo-adjuvant and palliative cohorts) as well as 50 healthy volunteers. A panel of circulating angiogenesis-related and cell death biomarkers was studied at baseline and during treatment with either chemotherapy or chemoradiotherapy in all patients and at a single time point in healthy volunteers. The analyses were carried out using multiplex ELISA platforms, single plex ELISAs and rare cell identification technology. In addition, the same panel of biomarkers was studied in a phase I trial of cediranib (an anti-angiogenic drug) in combination with chemoradiotherapy. Results: A group of biomarkers, namely Ang2, FGFb, HGF, PDGFbb, VEGF-A, VEGF-C, Ang1, CD105 and Tie2 exhibited consistent changes during treatment with cytotoxic chemotherapy in the adjuvant, neo-adjuvant and palliative cohorts, confirming the main hypothesis of this thesis. In addition and as a result of the systematic analysis of these biomarkers in patients with different stages of colorectal cancer, several biomarkers were identified as having potential prognostic value (tCK18) or being potential surrogate markers of tumour burden (sVEGFR1,sVEGFR2, IL-6, tCK18 and SDF-1β). Moreover, pre-treatment levels of sVEGFR2 and tCK18 were associated with progression free survival and levels of sVEGFR2, sVEGFR1 and tCK18 with overall survival. In the phase I trial combining cediranib with standard chemoradiotherapy, a group of proof of mechanism biomarkers was defined (SDF-1β, PlGF, Ang, Tie2 and sVEGFR2). Several other biomarkers were proposed as surrogate biomarkers of response and toxicity. Conclusions: This study demonstrated the existence of drug-induced changes in a panel of angiogenesis-related biomarkers caused by cytotoxic chemotherapy which highlights the importance of knowing the changes associated to the standard of care treatment prior to studying the changes produced by the experimental drug. In addition, several biomarkers showed potential value as a predictor of outcome in colorectal cancer.

Date of Award	1 Aug 2016
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Caroline Dive (Supervisor) & Gordon Jayson (Supervisor)