Abstract

Cancer is among the leading causes of death worldwide. Chemotherapy remains a cornerstone in the treatment of various cancers; however, it often leads to a range of debilitating side effects that compromise its efficacy and profoundly impact patients' quality of life and psychosocial well-being. These side effects can be broadly categorized into short-term effects, such as nausea, vomiting, fatigue, hair loss, and neutropenia, and long-term effects which can persist months or even years after treatment, including peripheral neuropathies, cognitive impairment, cardiotoxicity, nephrotoxicity and ototoxicity. Among the most common and dose-limiting side effects are chemotherapy-induced peripheral neuropathy (CIPN) and cardiotoxicity (CTX). Another life-threatening condition typically associated with cancer and chemotherapy is cachexia, a wasting syndrome causing significant loss of body mass, affecting up to two-thirds of patients with advanced cancer. Despite their prevalence and severity, the underlying mechanisms are not fully understood, limiting the development of early diagnostic markers and effective therapeutic interventions. This thesis focuses on developing models and elucidating mechanisms of CIPN, CTX, and chemotherapy-induced cachexia-like syndrome. Specifically, the research is centered around oxaliplatin, a third-generation platinum-based chemotherapeutic drug commonly used in the treatment of various cancers primarily colorectal cancers as well as gastric, pancreatic, and ovarian cancers in combination of other agents. The study aims to enhance the understanding of these adverse effects and to improve patient outcomes and tolerability of chemotherapy by establishing pre-clinical models that closely mimic the clinical symptoms observed in patients, developing behavioral and imaging measurements to quantify the progression of these conditions, and identifying potential biomarkers and targets for early diagnosis, prevention, and treatment. The first aim investigates mechanisms underlying oxaliplatin-induced peripheral neuropathy with emphasize on the chronic phase of pain. We established in vivo and ex vivo models of the chronic CIPN and explored the role of oxidative stress in CIPN. Though RNA-sequencing (RNA-seq), we further identified Thioredoxin-interacting protein (Txnip), which plays a central role regulating reactive oxygen species (ROS), as a potential therapeutic target. Pharmaceutical inhibition of Txnip demonstrated improvement in CIPN symptoms in both in vivo and in vitro models. Second, cardiotoxicity of oxaliplatin is studied with a rodent model of cardiotoxicity (CTX), where a decrease in heart rate and abnormal ECG reads were observed in mice following oxaliplatin administration. RNA-seq revealed an energy metabolism shift from fatty acid oxidation to glycolysis in heart, accompanied by lactate accumulation, indicating an impaired energy supply necessary for normal heart function. Additionally, significant up-regulation of Nmrk2 gene and depletion of NAD+ were detected. Based on those results, supplementation of nicotinamide riboside (NR), a precursor of NAD+, may serve as potential treatment to restore NAD+ levels and improve cardiac function. The final aim explores the mechanisms of chemotherapy-induced cachexia, where a systematic metabolic disorder was observed in mice treated with oxaliplatin, characterized by severe body mass loss, skeletal muscle wasting and adipose tissue loss, reduced daily activity, and altered energy metabolism. RNA-seq data indicated inflammation as a key driver of muscle wasting, while decreased lipogenesis and adipogenesis contributed to white adipose tissue (WAT) loss. Moreover, we observed a dysregulation of adipokines – neuropeptides axes in WAT and hypothalamus which may serve as therapeutic targets to improve appetite and increase body mass. These findings suggested oxaliplatin alone can induce cachexic syndrome, highlighting the critical need for therapeutic interventions that target cachexia arising from both cancer progression and chemotherapy.

Degree

Doctor of Philosophy (PhD)

Author's Department

Interdisciplinary Programs

Author's School

McKelvey School of Engineering

Document Type

Dissertation

Date of Award

4-16-2025

Language

English (en)

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