DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

A Novel Tubulin Inhibitor to Overcome Taxane Resistance in Metastatic Breast Cancer

Posted January 25, 2023

Wei Li, Ph.D., and Tiffany Seagroves, Ph.D.,
University of Tennessee Health Science Center (UTHSC)

Triple-negative breast cancer (TNBC) is a particularly aggressive molecular subtype of breast cancer, associated with early recurrence, a high rate of metastasis, and a lack of targeted therapies for use in treating patients. Treatment for TNBC commonly includes tubulin inhibitors (or taxane drugs) such as paclitaxel and docetaxel, which target the proteins essential for the division and proliferation of both cancer and healthy cells. Major limitations associated with prolonged clinical use of paclitaxel and docetaxel, however, include development of chemotherapy resistance and dose-limiting toxicities.

Wei Li, PhD Dr. Wei Li
(Photo by Caleb Jia, UTHSC Communications and Marketing Department)
Tiffany Seagroves, PhD Dr. Tiffany Seagroves
(Photo by Caleb Jia, UTHSC Communications and Marketing Department)

To overcome these challenges, Drs. Li and Seagroves at the University of Tennessee Health Science Center (UTHSC) have identified a novel class of tubulin inhibitors, which appears to overcome mechanisms of taxane resistance and have lower toxicity based on preclinical studies. In animal models of TNBC (including taxane-resistant TNBC), the lead compound, sabizabulin (also called VERU-111), inhibited primary tumor growth and metastasis and also inhibited the growth of established metastases (present before initiation of treatment).

With support from a Fiscal Year 2019 Breast Cancer Research Program Breakthrough Award - Funding Level 2, Drs. Li and Seagroves aim to develop new analogs of sabizabulin, having improved potency and metabolic stability for potential use in treating patients with metastatic breast cancer, including those who progress on taxanes. Through structure-based optimization of sabizabulin, an analog called CH-2-77 was identified and subsequently evaluated for anticancer activity in TNBC models. When tested in a panel of TNBC cell lines, including paclitaxel-resistant TNBC cells, nanomolar concentrations of CH-2-77 were shown to inhibit cellular proliferation across all cell lines and, importantly, CH-2-77 was able to overcome paclitaxel resistance. The researchers demonstrated that effects observed in TNBC cells also included disruption of microtubule assembly, inhibition of migration and invasion (two markers of a metastatic capability), and induction of cellular death pathways. Additionally, when studied in an animal model of TNBC, CH-2-77 significantly inhibited primary tumor growth and the number of lung metastases, with no obvious signs of toxicity. Effects seen in the animal model with CH-2-77 were comparable to those of fosbretabulin, another inhibitor that targets tubulin that has previously been tested in clinical trials.

Through their work, Drs. Li and Seagroves have demonstrated that CH-2-77 overcomes taxane resistance and inhibits growth of TNBC at nanomolar concentrations in vitro and in an animal model of TNBC as well. Taken together, findings from their work support further development of CH-2-77 as well as continued identification of other analogs to address current clinical challenges associated with treatment of patients with TNBC.

Dr. Li Research Team and Dr Miller Li Research Team and Dr. Miller:  Wei Li, Ph.D., fifth from the right, stands with members of his research team and Duane Miller, Ph.D., (Co-Investigator, sixth from the right) at UTHSC, where they are conducting research to discover novel tubulin inhibitors to overcome taxane resistance in triple-negative breast cancer. (Photo by Caleb Jia, UTHSC Communications and Marketing Department)
Dr. Seagroves Team Seagroves Research Team:  Tiffany Seagroves, Ph.D., center, stands with members of her research team at UTHSC. (Photo by Caleb Jia, UTHSC Communications and Marketing Department)





















Publications:
Deng S, Krutilina RI, Hartman KL, et al. 2022. Colchicine-binding site agent CH-2-77 as a potent tubulin inhibitor suppressing triple-negative breast cancer. Molecular Cancer Therapeutics 21(7):1103-1114. doi: 10.1158/1535-7163.MCT-21-0899. PMID: 35499388; PMCID: PMC9256790.

Links:
Public and Technical Abstracts: Discovery of Orally Bioavailable Tubulin Inhibitors to Overcome Taxane Resistance in Metastatic Breast Cancer



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Last updated Sunday, January 22, 2023