Date of Graduation

5-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Engineering (PhD)

Degree Level

Graduate

Department

Biomedical Engineering

Advisor/Mentor

Muldoon, Timothy J.

Committee Member

Tipton, John R.

Second Committee Member

Rajaram, Narasimhan

Third Committee Member

Nelson, Christopher E.

Keywords

5-fluorouracil; azoxymethane; colorectal cancer; diffuse reflectance spectroscopy; generalized additive models; metronomic chemotherapy

Abstract

Colorectal cancer (CRC) continues to be one of the most incident and deadliest types of cancer worldwide. Chemotherapy has proven effective to reduce tumor burden for CRC patients, but there are several disadvantages associated with the use of mainstay maximtolerated dose (MTD) chemotherapeutic strategies. Metronomic chemotherapy (MET) has been developed as an alternative that addresses the shortcomings of maximum-tolerated dose chemotherapy but so far its effectiveness as a neoadjuvant strategy for CRC has not been explored.

This dissertation uses a combined optics and molecular biology approach (using diffuse reflectance spectroscopy and mRNA expression) to study the changes in angiogenesis and metabolism in primary colorectal tumors receiving MTD and MET. In Chapter 2, we first developed and validated a miniaturized spectroscopy probe that enabled the longitudinal investigation of changes in perfusion in primary tumors. Our results showed that an increase in oxygenation occurs in MET and MTD-treated tumors. In Chapter 3, we presented generalized additive models as an appropriate methodology to analyze the non-linear trends in longitudinal data that are commonly found in biomedical research. In Chapter 4, we sought to provide molecular context to the observed changes in perfusion from Chapter 2 by quantifying relative changes the expression of genes associated with angiogenesis. We found that despite eliciting a similar response, the molecular mechanisms behind increases in perfusion in MET and MTD-treated tumors are different. Specifically, tumors treated with MET presented higher Hif-1a, Aldoa and Pgk1 expression, indicating increased glycolytic activity. Taken together, this work highlights that the opportunities and challenges of MET to treat CRC can be better understood by using combined modalities that complement the information of changes caused by chemotherapy.

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