Metabolomic Biomarkers of Response to Systemic Therapy in Colorectal Cancer

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dc.contributor.advisorBathe, Oliver
dc.contributor.advisorVogel, Hans
dc.contributor.authorRattner, Jodi Ilana
dc.contributor.committeememberKopciuk, Karen
dc.contributor.committeememberTang, Patricia
dc.date2021-11
dc.date.accessioned2021-07-12T21:34:12Z
dc.date.available2021-07-12T21:34:12Z
dc.date.issued2021-07-07
dc.description.abstractColorectal 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.en_US
dc.identifier.citationRattner, 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.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/39005
dc.identifier.urihttp://hdl.handle.net/1880/113624
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectChemotherapyen_US
dc.subjectMetabolomicsen_US
dc.subjectColorectal Canceren_US
dc.subjectGas Chromatography-Mass Spectrometryen_US
dc.subjectRadiographic Imagingen_US
dc.subjectCancer Biomarkeren_US
dc.subjectToxicityen_US
dc.subject.classificationMedicine and Surgeryen_US
dc.subject.classificationOncologyen_US
dc.subject.classificationBiochemistryen_US
dc.subject.classificationEngineering--Biomedicalen_US
dc.titleMetabolomic Biomarkers of Response to Systemic Therapy in Colorectal Canceren_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineMedicine – Medical Sciencesen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrueen_US
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