Date of Award
5-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical Engineering and Sciences
First Advisor
Timothy A. Crombie
Second Advisor
Melissa Borgen
Third Advisor
Venkat Keshav Chivukula
Fourth Advisor
Jessica Smeltz
Abstract
Each year cancer affects nearly 20 million people worldwide and genetic differences across populations can impact cancer onset and progression. Specifically, tumors with high levels of HSF1, the master regulator of the cytoprotective heat shock response (HSR), are correlated with poor patient outcomes in multiple cancers such as prostate, breast, and melanoma. Subsequently, the development of pharmacological inhibitors of HSF1 represents a promising strategy for anticancer therapeutics. Using a luciferase-based transcriptional reporter, two small molecule libraries were screened for inhibitors of HSF1 expression in human embryonic kidney cells, yielding ten compounds that decrease HSF1 expression. To identify if cancer lines are sensitive to these compounds, ten cancer cell lines with high HSF1 expression were treated with the hits from the screen. We found that multiple cancer lines were susceptible to two compounds at low doses, suggesting these molecules might be developed into useful targeted anticancer therapies. However, genetic differences among individuals can cause inconsistent responses to drugs, which can lead to disparities in the efficacy of treatment. Precision medicine offers a solution to these disparities by tailoring patient treatments to maximize efficacy and minimize adverse drug responses (ADRs). To better understand how small molecule responses vary across natural populations, we measured responses of wild Caenorhabditis elegans strains to chlorfenapyr, a small molecule pyrrole related to many anticancer treatments. Using a quantitative genetic approach, we found a genomic region on chromosome V that modulates response to chlorfenapyr. Identifying specific genetic variants that influence adverse responses to chlorfenapyr can provide insight into the molecular mechanisms that drive detoxification of small molecule therapeutics. Using long-read sequencing, we explored the gene content in the region for insight into the specific natural variants that drive differential responses to chlorfenapyr. Overall, this work provides a framework for developing novel anticancer treatments using principles of precision medicine to target specific cancers and predict ADRs.
Recommended Citation
Foley, Michaela Kendal, "Developing a small molecule to inhibit HSF1 expression in cancer and evaluating natural genetic variation in small molecule toxicity." (2025). Theses and Dissertations. 1561.
https://repository.fit.edu/etd/1561
Included in
Cancer Biology Commons, Cell Biology Commons, Cells Commons, Chemicals and Drugs Commons, Computational Biology Commons, Developmental Biology Commons, Genetic Processes Commons, Genetics Commons, Genomics Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Molecular Biology Commons, Molecular Genetics Commons, Therapeutics Commons, Toxicology Commons
