Advancing SULT2B1b Inhibitors and Ferroptocide as Innovative Cancer Treatment Strategies

Small molecules play an important role in the treatment of cancer via the induction of cell death within tumors. Given the ever-changing landscape of cancer resistance, the development of compounds that elicit cell death through a variety of mechanisms and pathways is of utmost importance. Ferroptocide is a ferroptosis-inducing compound whose unique mechanism of action has shown promise for administration in transarterial chemoembolization (TACE) therapy, a technique where chemotherapy is delivered through liver tumor feeding arteries and embolization reduces its systemic distribution. Ferroptocide’s rapid induction of ferroptosis aids in the treatment of apoptosis resistant cells, and its immunomodulatory properties recruits immune cells to reinforce tumor cell death. While a limiting factor in systemic administration, ferroptocide’s rapid clearance makes it well suited for TACE since high doses can be administered locally, and compound that escapes the tumor can be quickly removed. Preclinical models to test this in vivo are lacking due to the technical challenges of the procedure in traditional mouse models. Thus, steps were taken to assess the feasibility of using canine liver cancer patients as a bridge between preclinical models and human TACE patients. These results recommend this approach to improve the preclinical pathway in the development of TACE-specific chemotherapies. Beyond compounds that directly elicit cell death, small molecules that improve the immune system’s natural ability to kill cancer cells greatly aid in the cancer treatment arsenal. SULT2B1b is an enzyme known to produce cholesterol sulfate (CS), a metabolite which inhibits T cell migration. Cancers expressing high levels of SULT2B1b thus generate an immunosuppressive microenvironment that excludes T cells, which leads to increased tumor growth and renders immune checkpoint blockade (ICB) therapy ineffective. A collection of SULT2B1b inhibitors have been synthesized and tested herein, and they are shown to be more potent and selective compared to the current leading alternatives. These compounds effectively reduce CS levels in vivo and are well-suited for further studies as cancer therapeutics in combination with ICB therapy.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Smith, Amanda Janelle

Contributors dc:contributor

• Hergenrother, Paul J
• Fan, Timothy M
• Mehta, Angad P
• Ranoa, Diana RE

• SULT2B1b
• cholesterol sulfate
• ferroptosis
• ferroptocide
• cell death
• cancer
• immune checkpoint blockade

Statement dc:rights

• Copyright 2025 Amanda Smith

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/129700

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F129700