By Ian Bennett
Brian K. Law, Ph.D., an associate professor in the department of pharmacology & therapeutics in the University of Florida College of Medicine, has been awarded two grants from the Florida Department of Health for breast cancer studies.
For one project, he received a $570,000 grant from the James and Esther King Biomedical Research Program to increase the value and translational potential of disulfide bond disrupting agents, DDAs, as a novel therapy for breast cancer.
Triple-negative breast cancer is a subtype of breast cancer in which the cancer cells lack the three receptors commonly targeted by breast cancer therapeutics. This subtype accounts for only about 20% of all breast cancer cases but carries the highest mortality rate. It disproportionately affects younger and Black women in the United States, according to the American Cancer Society.
The Law lab has developed a novel class of DDAs to treat breast cancer, but their mechanisms of action are not fully understood. At the same time, the biological mechanisms that differ between African American and European American patients with breast cancer are unknown. Understanding both topics has the potential to reduce the survival disparity and improve treatment for patients.
The grant will allow Law and his team, including Ronald K. Castellano, Ph.D., a professor in the department of chemistry in the UF College of Liberal Arts & Sciences, and Coy D. Heldermon, M.D., Ph.D., an associate professor in the division of hematology & oncology in the UF College of Medicine, to use DDA molecules to study and selectively target the mechanisms involved in triple-negative breast cancer.
“This generous award from the Florida Department of Health James and Esther King Biomedical Research Program will bring together the expertise of the Castellano, Heldermon and Law laboratories to further the development of DDAs, which may be useful in the treatment of a breast cancer subtype that disproportionately impacts women of African descent,” said Law, a member of the Cancer Center’s Cancer Therapeutics & Host Response research program.
The protein death receptor 5, or DR5, is well known to selectively kill cancer cells without harming healthy tissues. While previous efforts that have used protein drugs have failed, this new class of DDAs increases DR5 levels. This is an important indicator that DDAs could promote the death of cancer cells.
Law and his team aim to understand how DDAs increase DR5 levels. Then, they will evaluate the efficacy of DDA-based therapy against triple-negative breast cancer in African American or European American patients by using animal models.
In addition, Law received a $100,000 grant from the Florida Department of Health Bankhead-Coley Cancer Research Program to increase the commercial value and translational potential of DDAs as a novel therapy for breast cancer.
DDAs act by inhibiting a subset of protein disulfide isomerases, or PDIs. DDA-mediated inhibition of PDIs causes changes in disulfide bonding. Along with controlling the stability and signaling functions of key receptors, which are rich in disulfide bonds, inhibiting these PDI receptors can control the life of cancer cells. Specifically, DDAs cause cancer cell death through two mechanisms: downregulation of the epidermal growth factor receptor, or EGFR, family proteins EGFR/HER1, HER2 and HER3, or the upregulation and activation of the DR5 protein independently of the DR5 ligand TRAIL.
Together, the Law, Castellano and Heldermon labs aim to unlock the potential of DDAs as a therapy for breast cancer by evaluating the stability and metabolism of promising DDAs. Then, they will examine potential markers of DDA toxicity to normal cells and tissues and evaluate how DDAs engage their target proteins in tumors in vivo. The team will also study the effects of DDAs on the levels and signaling functions of HER1-3 and DR4 and DR5 in tumors.
“Despite improvements in the treatment of breast cancer, it remains the second largest cancer killer of women,” Law said. “It is a real pleasure to work with such an outstanding team of investigators toward translating our basic science discoveries into new therapeutic options for breast cancer patients.”