Michael Mulligan, a Ph.D. student in the lab of Cancer Center at Illinois (CCIL) Deputy Director Paul Hergenrother, recently discovered that a small molecule called ErSO-TFPy has the ability to drastically reduce the size of large breast tumors in mice. Even more impressive, this occurs after only a single dose of ErSO-TFPy. If translated to human cancer patients, such a discovery could dramatically improve breast cancer treatment.
In 2021, the research team discovered the parent molecule to this new compound, ErSO, a collaboration between CCIL scientists Hergenrother, David Shapiro, Erik Nelson and Timothy Fan.
“One of the things that really excited us about the ErSO originator molecule was the really rapid cell death that we saw in cell culture and tumor models,” says Mulligan, first author of the collaborative research team’s initial ErSO paper reported in the journal ACS Central Science.
“In standard preclinical experiments, ErSO even killed cancer cells at low concentrations, and it’s also selective, so it’s not broadly toxic to other cells.”
“Once we saw the single dose efficacy with tumor models, we knew that was an important discovery. I have never seen a paper with a single dose efficacy, and that’s what I find extremely novel about this; a single dose and the subsequent regression is remarkable.”
However, the team had their sights set on further improved versions of ErSO. “In the original paper, we showed the ErSO molecule was very effective, but we treated those mice multiple times,” said collaborator Dr. Timothy Fan, regarding the published 2021 study. “ErSO-TFPy, however, is a safer compound and it’s more selective, meaning you only have to administer it once.”
The new publication explores the idea of using the ErSO derivative, ErSO-TFPy, in single dose treatment mode, demonstrating the same dramatic tumor eradications in mice observed with ErSO are retained with ErSO-TFPy, only now with minimal dosing. This, if able to translate from mice to humans, could drastically change the treatment outlook for breast cancer patients across the globe.
A diagram displaying the process of patient-derived xenografts, consisting of taking human tumor cells and implanting them into a mouse. This allows researchers to observe how a drug reacts to human cancer cells before patients are entered into a Phase 1 Clinical Trial.
Though the journey from mice models to human models is an arduous one, the collaborators aimed to find mouse models that could best represent the human disease. “One of the options is patient derived xenografts, which are becoming increasingly common in breast cancer research and seem to be more representative of clinical disease,” says Mulligan, describing the transfer of human tissue into mice. “We’ve seen efficacy in patient derived xenografts for this molecule, which is a good sign that this molecule could also induce regression of tumors in humans.”
If the ErSO-TFPy molecule does successfully translate its tumor reducing abilities to human breast cancer, women with the disease could have a much more positive outlook. “Many women with breast cancer are treated with cytostatic drugs, meaning that they don’t typically make tumors smaller— they just prevent them from getting much bigger,” says Fan. “These women are also treated chronically for years and years, and there are quite a few side effects associated with some of those chronic therapies.”
By reducing breast cancer treatment to a single dose, treatment outcomes for patients could vastly improve. Currently, 20-30% of breast cancer patients undergoing years-long endocrine therapy (one of the most widely-used modern methods of breast cancer treatment) will eventually discontinue their treatment due to the harsh side effects of such a long exposure— ranging from musculoskeletal pain to increased risk for endometrial cancers. This often decreases how effective endocrine therapy is for patients, potentially leading to later recurrence of the cancer.
Experiments so far suggest that ErSO-TFPy is safe and potent enough for single dose efficacy, possibly eliminating the need for chronic treatment. In addition to this impressive fact, the drug is also incredibly powerful even against large, late-stage tumors in mice.
A diagram depicting the difference between cytostatic and cytotoxic drugs in cancer treatment; while cytostatic drugs prevent a tumor from further growth, cytostatic cells lead to cancer cell death, shrinking the tumor.
“When we got to the point that we were ready to finish the study, we decided to take our control (non-treated) mice and give them a dose of ErSO-TFPy when the tumors were very large—around 10 times larger than when most tumor models would begin dosing. The profound tumor reduction we observed in these large tumors was surprising, as that mimics such an advanced stage of the disease,” describes Mulligan.
In the future, the Hergenrother lab and its collaborators are looking forward to expanding the reach of ErSO-TFPy and pushing the limits of its tumor shrinking abilities. “Finding something shocking and new, I think, is the hardest part of any scientific story,” ends Mulligan as he retells his experience with the study. “But once we saw the single dose efficacy with tumor models, we knew that was an important discovery. I have never seen a paper with a single dose efficacy, and that’s what I find extremely novel about this; a single dose and the subsequent regression is remarkable.”
A diagram from the 2025 ErSO-TFPy paper about how a single dose of the anticancer drug leads to complete tumor regressions in mice.
Editor’s notes:
Michael Mulligan is a graduate student working under Paul Hergenrother and is a member of the National Institute of Health (NIH) Chemistry-Biology Interface Training Program. He can be reached at mpm12@illinois.edu.
Paul Hergenrother is the Kenneth L. Rinehart Jr. Endowed Chair in Natural Products Chemistry and the Deputy Director of the Cancer Center at Illinois. Professor Hergenrother is also the leader of the Carl R. Woese Institute for Genomic Biology’s Theme, “Anticancer Discovery from Pets to People,” as well as the Director of the NIH Chemistry-Biology Interface Training Program. He can be reached at hergenro@illinois.edu.
Timothy Fan is the CCIL Associate Director of Translational Research and Development, as well as a Professor of Clinical Veterinary Medicine. Dr. Fan also serves as a principal investigator for the Comparative Oncology Research Laboratory and is a core member of the Anticancer Discovery from Pets to People project at the Carl Woese Institute for Genomic Biology. He can be reached at t-fan@illinois.edu.
Erik Nelson is an Associate Professor of Molecular and Integrative Physiology, Nutritional Sciences, and at the Beckman Institute for Advanced Science and Technology. Professor Nelson is also an affiliate of the Personalized Nutrition Initiative at the Carl Woese Institute for Genomic Biology (IGB), along with the IGB as a whole. He is also a Research Program Leader at the Cancer Center at Illinois. He can be reached at enels@illinois.edu.
The 2025 ErSO paper, entitled “Single dose of a small molecule leads to complete regressions of breast tumors in mice” can be accessed online here.
The 2021 ErSO paper, entitled “A small molecule activator of the unfolded protein response eradicates human breast tumors in mice” can be accessed online here.
This story was written by Chloe Zant, CCIL Communications Intern.