Metabolomic Biomarkers of Response to Systemic Therapy in Colorectal Cancer
Date
2021-07-07
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Abstract
Colorectal Cancer (CRC) is the 2nd leading cause of cancer death in North America. Besides surgery and radiation, chemotherapy administration is one of the mainstay treatment options used to improve CRC prognosis, and ultimately patient outcomes. Chemotherapies are selected empirically by oncologists, and only a fraction of these patients will experience the benefit of these therapies. Response is assessed through radiographic imaging (CT/MRI scans). However, a myriad of challenges, including time-delays and obstacles in measuring response (such as in molecularly targeted agents), means a new method of assessment is required to prevent unnecessary administration of unbeneficial therapies or undue accumulation of severe toxicities. This work describes the identification and development of metabolomic biomarkers that distinguishes the biological changes associated with the development of cancer progression, hypertension, and fatigue. Metabolomic profiling, a method in which the measurement of biological systems by describing the changes in molecular components constituting the metabolic state, was used. The metabolome is known to change rapidly within pathophysiological contexts and was chosen for its close relationship to phenotype, and its capacity to detect subtle changes in metabolite concentrations. Chapter 2 describes the protocol methodology using gas chromatography-mass spectrometry (GC-MS) and multivariate statistical analysis used in the development of plasma biomarkers. In Chapter 3, a large study using serial plasma samples from 220 CRC patients from an international clinical trial by GC-MS, which resulted in the development of a metabolomic biomarker distinguishing progression from partial response within one week of chemotherapy administration. In Chapter 4, using 70 CRC patients treated with cetuximab and brivanib, we aimed to establish a signature identifying differences in metabolomic changes signifying the development of hypertension within 12 weeks of treatment initiation. Chapter 5 was dedicated to the exploration of metabolomic changes accompanying the complexities associated with severe fatigue in 72 CRC patients. While the concepts presented in this work are not validated, the novel approach and careful considerations taken provide a proof of concept that have the possibility of substantiating and improving upon current clinical methods used. Therefore, this thesis is focused on the understanding of metabolomic perturbations of systemic therapy in CRC and the adaption of this knowledge for the development of signatures of progression for the use of clinically viable biomarkers for therapeutic assessment.
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Keywords
Chemotherapy, Metabolomics, Colorectal Cancer, Gas Chromatography-Mass Spectrometry, Radiographic Imaging, Cancer Biomarker, Toxicity
Citation
Rattner, J. I. (2021). Metabolomic Biomarkers of Response to Systemic Therapy in Colorectal Cancer (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.