Date of Graduation

12-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Engineering (PhD)

Degree Level

Graduate

Department

Biomedical Engineering

Advisor/Mentor

Narasimhan Rajaram

Committee Member

Timothy J. Muldoon

Second Committee Member

Magda O. El-Shenawee

Third Committee Member

Kyle P. Quinn

Keywords

Cancer Research, Head and neck cancer, Optical spectroscopy, Radiation resistance, Tumor Hypoxia

Abstract

Each year, 800,000 new patients are diagnosed with head and neck squamous cell carcinoma (HNSCC), a majority of whom are treated with a combination of daily fractions of radiation and weekly chemotherapy sessions for up to seven weeks. Current methods to evaluate treatment response of individual patients are limited to anatomical measurements of tumor burden using CT scan or MRI 4-8 weeks after completion of treatment. However, earlier knowledge of radiation-response prior to or at early days after commencement of therapy can aid oncologist with escalating and de-escalating treatment plans for exceptionally non-responding and responding patients. Such a knowledge can be only be gained if proper understanding of radiation-induced physiological and biomolecular changes is established and associated with treatment response.

This dissertation presents two quantitative optical spectroscopic methods that can provide snapshots of tumor physiology and biomolecular content which can be used as biomarkers of treatment response. Because tumor hypoxia has been linked to poor treatment outcome, we employed diffuse reflectance spectroscopy to measure vascular oxygen saturation. In chapter 2, we first investigated the sensitivity of diffuse reflectance spectroscopy to tumor hypoxia and determined that optical measurement of tumor vascular oxygen saturation is negatively correlated with tumor hypoxia. In chapter 3, we utilized this technique to study radiation-induced kinetics of tumor oxygenation among radiation-resistant and -sensitive tumors. We established tumor xenografts from two human head and neck cancer cell lines in mice which were treated with 4 doses of 2 Gy twice weekly for two weeks. We observed greater rate of reoxygenation in radiation-resistant tumors which was accompanied with greater content of hypoxia inducible factor-1α (HIF-1α). Our results indicate that reduced oxygen consumption rate can potentially play a significant role in promoting radiation resistance. In addition, the radiation-induced changes in tumor optical properties were used to train a logistic regression model which successfully differentiated local-control and treatment-failure tumors.

In addition to changes in reoxygenation, radiation treatment has also been known to induce microenvironmental changes within tumor. Thus in chapter 4, we used Raman spectroscopy to investigate early radiation-induced biomolecular changes in tumor microenvironment of radiation-resistant and -sensitive tumors. Raman spectra of head and neck tumor xenografts 1, 24, and 48 hours after radiation was collected and the spectra were analyzed using multivariate curve resolution-alternating least squares (MCR-ALS) and pure spectral profiles of biological specimen were extracted. We observed higher contributions to Raman spectra from lipid- and collagen-like species respectively in radiation-sensitive and -resistant tumors. Our results indicate the sensitivity of Raman spectroscopy to radiation-induced microenvironmental changes at early time points after radiation. The association between the observed functional and biomolecular changes with the radiosensitivity of the utilized tumors motivate further clinical studies to investigate whether such changes can be used as potential biomarkers of radiation response.

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