"Developing a small molecule to inhibit HSF1 expression in cancer and e" by Michaela Kendal Foley

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.

Available for download on Sunday, May 10, 2026

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