Cancer Risk Reduction Through Active Management of Genotoxicity

• Main Author: Davoren, Michael Joshua
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2018
• Subjects: Microbiology; Toxicology
• ISBN: 9780355811483; 0355811480

Cancer is the second leading cause of death in developed countries. Despite advances in both therapies and our understanding of the carcinogenesis process itself, consistently effective treatments remain elusive for a large number of cancer subtypes. For this reason, the minimization of cancer risk is a high priority subject. At the moment, cancer risk management is generally characterized by abstention rather than active engagement. The importance of avoiding activities associated with carcinogenesis-inducing genotoxicity, such as smoking, is well ingrained in the public consciousness as an anticancer strategy. The development of treatments that positively reduce genotoxicity poses a novel method of protection against general cancer risk, as well as the mitigation of risk from scenarios such as inflammation-inducing infections or genotoxic radiation exposure. The first part of this thesis describes the development of a genotoxicity mitigating compound, Yel002. In yeast and mouse models, Yel002 reduced both genotoxicity and lethality resulting from radiation exposure. Administration of this compound up to 24 hours after an otherwise lethal dose of ionizing radiation reduced radiation-induced hematopoietic depletion and systemic DNA damage markers. Although issues with compound stability made it difficult to use consistently, its development establishes a pipeline for the testing and use of similar compounds. The second part of this thesis work describes the characterization of a Lactobacillus strain, L. johnsonii 456, associated with anti-inflammatory and anti-genotoxic outcomes in mice. Although originally derived from a murine host, the strain survives in both in vivo and in vitro models of the human gut, suggesting that these protective effects could be applicable to humans as well. Importantly, the strain’s ability to inhibit pathogen growth and binding to human gut monolayer cells was demonstrated experimentally. As pathogenic bacteria are a major source of inflammation in the gastrointestinal tract, future probiotic intervention with this strain could result in active intervention strategies to manage local and systemic genotoxicity. The third part of this work is a reprint of the previously published review article, Mouse models for radiation-induced cancers, included with the gracious approval of Mutagenesis. The mouse models described represent important animal models for the testing of active genotoxicity management interventions. Finally, two appendices are included to describe subtle factors that influence the carcinogenesis pathway. Appendix I is a version of the article in submission Glyphosate Based Herbicides and Cancer Risk: A Post IARC Decision Review of Potential Mechanisms, Policy, and Avenues of Research, describing the heavily debated carcinogenic potential of the pesticide glyphosate and how it might exert effects through the microbiome. Appendix II is a reprint of the article BALR-6 regulates cell growth and cell survival in B-lymphoblastic leukemia, and elucidates a novel lncRNA-based mechanism of gene dysregulation in leukemic progression, to which I contributed bone marrow data analysis. As Yel002 suppresses leukemic progression in DBA/2 mice by an unknown mechanism, lncRNAs should be considered as a potential mechanism by which radiation mitigators affect hematopoietic stem cells. The active management of systemic genotoxicity by both probiotic and pharmaceutical methods is a relatively untapped area in cancer risk reduction. This work describes the characterization process of two potential mitigators of genotoxicity-induced cancer risk, and establishes baseline criteria by which future interventions of these types can be identified and tested.