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Investigating the Mechanisms and Kinetics of Circulating Tumour DNA Release to Improve Its Clinical Utility.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Investigating the Mechanisms and Kinetics of Circulating Tumour DNA Release to Improve Its Clinical Utility.
Author:	Rostami, Ariana.
Published:	Ann Arbor : ProQuest Dissertations & Theses, 2021
Description:	157 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-01, Section: B.
Notes:	Advisor: Bratman, Scott.
Contained By:	Dissertations Abstracts International83-01B.
Subject:	Molecular biology.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28261840
ISBN:	9798522942847

Investigating the Mechanisms and Kinetics of Circulating Tumour DNA Release to Improve Its Clinical Utility.
Rostami, Ariana.

Investigating the Mechanisms and Kinetics of Circulating Tumour DNA Release to Improve Its Clinical Utility. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 157 p.

Source: Dissertations Abstracts International, Volume: 83-01, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2021.

This item must not be sold to any third party vendors.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with distinct subtypes, molecular features and clinical behaviours. Significant advances to better define this heterogeneity have revealed new targets and attempted to stratify patients into clinically meaningful groups. Human papillomavirus (HPV)-positive HNSCC has been recognized as a distinct etiology with significantly better treatment response and overall survival compared to HPV-negative HNSCC. However, despite the improved prognosis of these patients, current therapies result in significant toxicities, and subtype-specific treatments are still lacking. Thus, there remains an urgent need for additional biomarkers of therapeutic sensitivity to better risk stratify these patients and enable personalized treatment regimens. Circulating tumour DNA (ctDNA) has sparked tremendous interest in the last decade as a non-invasive method to monitor dynamic changes in treatment response. However, the mechanisms that dictate ctDNA release kinetics have not been thoroughly investigated, hampering the interpretation of such ctDNA kinetic patterns. To address this gap, I first evaluated the biological underpinnings that dictate ctDNA release using preclinical models of HNSCC. To evaluate the generalizability of my findings, I simultaneously evaluated ctDNA release from other cell types including mesenchymal cells and lung adenocarcinoma. Through detailed mechanistic studies, I uncovered a complex interplay between apoptosis, necrosis and senescence in determining ctDNA release kinetics, where treatment type and timing from treatment exposure were key factors influencing release. I next investigated the longitudinal kinetics of ctDNA release in 70 HNSCC patients treated with definitive radiotherapy or chemoradiotherapy. Three patterns of ctDNA kinetics were observed, with HNSCC patients exhibiting frequent on-treatment spikes, with a strong dependence on treatment type. Lastly, utilizing the knowledge gained in regard to the underlying biology and longitudinal profiles of ctDNA release, I identified a cohort of 235 HPV-positive oropharyngeal carcinoma patients and discussed the next steps in evaluating the relationship between ctDNA kinetic changes and clinical response. These studies provide novel insights into the biological mechanisms and dynamic changes of treatment-induced ctDNA release. Overall, these findings highlight the potential clinical utility of dynamic ctDNA monitoring to facilitate biomarker-driven adaptive therapy, with the intent to maximize disease control and minimize current treatment related-morbidities.

ISBN: 9798522942847Subjects--Topical Terms:

188737
Molecular biology.
Subjects--Index Terms:

Cell death

Investigating the Mechanisms and Kinetics of Circulating Tumour DNA Release to Improve Its Clinical Utility.
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506 $a This item must not be sold to any third party vendors.
520 $a Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with distinct subtypes, molecular features and clinical behaviours. Significant advances to better define this heterogeneity have revealed new targets and attempted to stratify patients into clinically meaningful groups. Human papillomavirus (HPV)-positive HNSCC has been recognized as a distinct etiology with significantly better treatment response and overall survival compared to HPV-negative HNSCC. However, despite the improved prognosis of these patients, current therapies result in significant toxicities, and subtype-specific treatments are still lacking. Thus, there remains an urgent need for additional biomarkers of therapeutic sensitivity to better risk stratify these patients and enable personalized treatment regimens. Circulating tumour DNA (ctDNA) has sparked tremendous interest in the last decade as a non-invasive method to monitor dynamic changes in treatment response. However, the mechanisms that dictate ctDNA release kinetics have not been thoroughly investigated, hampering the interpretation of such ctDNA kinetic patterns. To address this gap, I first evaluated the biological underpinnings that dictate ctDNA release using preclinical models of HNSCC. To evaluate the generalizability of my findings, I simultaneously evaluated ctDNA release from other cell types including mesenchymal cells and lung adenocarcinoma. Through detailed mechanistic studies, I uncovered a complex interplay between apoptosis, necrosis and senescence in determining ctDNA release kinetics, where treatment type and timing from treatment exposure were key factors influencing release. I next investigated the longitudinal kinetics of ctDNA release in 70 HNSCC patients treated with definitive radiotherapy or chemoradiotherapy. Three patterns of ctDNA kinetics were observed, with HNSCC patients exhibiting frequent on-treatment spikes, with a strong dependence on treatment type. Lastly, utilizing the knowledge gained in regard to the underlying biology and longitudinal profiles of ctDNA release, I identified a cohort of 235 HPV-positive oropharyngeal carcinoma patients and discussed the next steps in evaluating the relationship between ctDNA kinetic changes and clinical response. These studies provide novel insights into the biological mechanisms and dynamic changes of treatment-induced ctDNA release. Overall, these findings highlight the potential clinical utility of dynamic ctDNA monitoring to facilitate biomarker-driven adaptive therapy, with the intent to maximize disease control and minimize current treatment related-morbidities.
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