Date of Award

11-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Cancer and Developmental Biology

Research Advisor

Tiffany N. Seagroves, PhD

Committee

Kevin W. Freeman, PhD; Wei Li, PhD; Duane D. Miller PhD; Gustavo Miranda-Carboni PhD; Ramesh Narayanan PhD; Daniel Savic PhD; Tiffany N. Seagroves PhD

Keywords

Breast Cancer; Colchicine Binding Site Inhibitors; Chemoresistance; Metastasis; Bromodomain 4; VERU-111

Abstract

Triple negative breast cancer (TNBC) has limited treatment options due to a lack of targetable markers, i.e., estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor 2 (HER2). For this reason, hormone receptor negative (HR-) breast cancers, such as TNBC and HER2+ breast cancers, typically have worse overall prognosis than HR+ cancers. TNBC frontline therapy involves a combination of cytotoxic chemotherapies, including tubulin inhibitors like taxanes and vinca alkaloids, whereas HER2+ cancers are treated with antibody-drug conjugates in conjunction with a taxane. However, taxanes are subject to several multidrug resistance mechanisms, including drug efflux through P-gp and inhibition from β-tubulin overexpression. Taxanes also cause peripheral neuropathy and dose limiting toxicity in patients. As such, it remains critical to explore new anti-tubulin drugs that can overcome the challenges of taxane therapy. Colchicine binding site inhibitors (CBSIs) are an exciting class of tubulin inhibitors emerging as an alternative to taxanes. We have previously reported on VERU-111, an orally bioavailable, highly potent CBSI that overcomes taxane chemoresistance (TxR) in TNBC and has a beneficial safety profile in clinical trials. In this work, we report that VERU-111 is also potent against treatment-naïve and heavily pre-treated HER2-overexpressing breast cancers. Furthermore, VERU-111 can resensitize trastuzumab-resistant HER2+ breast cancer to tyrosine kinase inhibition (lapatinib) in contrast to paclitaxel. We also report that a novel VERU-111 derivative, 60c, is highly effective against heavily pretreated TNBC and curtails distant metastases with unique metastatic tropism relative to VERU-111. Understanding the mediators of chemoresistance and chemosensitivity is key to providing cancer patients with timely, effective care. Although VERU-111 chemoresistance (VeruR) has not yet been encountered during clinical trials, our group has developed several models to proactively investigate mechanisms of VeruR. Herein, we identify breast cancer resistance protein (BCRP) as a major driver of VeruR. Further, using whole genome expression data from these models, we found a putative fingerprint for VeruR in TNBC that is distinct from TxR. Notably, we show that next-generation CBSIs, like 60c, are highly potent against VeruR TNBC. Finally, we present data derived from reverse phase protein arrays and X-ray crystallography studies that reveal that members of the bromodomain (BRD) and extraterminal domain (BET) protein family are novel binding partners of VERU-111, suggesting a role for VERU-111 in bromodomain-dependent gene expression. Overall, our data reveal a potential screening tool for patients of TNBC and identify a new binding partner and potential target for VERU-111f in TNBC.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

https://orcid.org/0000-0002-6298-9550

DOI

10.21007/aetd.cghs.2024.0013

Additional Files
2024-013-Oluwalana-AETD-DOA.pdf (361 kB)
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