Glioblastoma multiforme (GBM) is an aggressive brain cancer associated with the worst overall survival rates among all human cancers. Only 65% of GBM patients live one year past diagnosis and only 12% live five years. The late senators Ted Kennedy and John McCain both died of GBM on the same day (August 25) nine years apart (Kennedy in 2009; McCain in 2018).
Credit: The University of Texas at San Antonio
Glioblastoma multiforme (GBM) is an aggressive brain cancer associated with the worst overall survival rates among all human cancers. Only 65% of GBM patients live one year past diagnosis and only 12% live five years. The late senators Ted Kennedy and John McCain both died of GBM on the same day (August 25) nine years apart (Kennedy in 2009; McCain in 2018).
A San Antonio research team is working to give GBM survivors new hope. Scientists from the Department of Chemistry at The University of Texas at San Antonio (UTSA), Department of Obstetrics and Gynecology at UT Health San Antonio, and Mays Cancer Center at UT Health San Antonio are making compounds to hopefully one day treat GBM tumors. The team recently was awarded $3 million by the National Cancer Institute (NCI). The grant, which began on January 1, 2023, follows previous NCI funding of $2 million that supported laboratory studies yielding fundamental understandings needed to progress to drug development.
The new compounds mimic activity of the sex hormone estrogen on a cell protein called estrogen receptor-beta (ER-beta). This critically important receptor is known to suppress cancer. Both males and females have estrogen, but females have higher levels and it has been noted that more men are diagnosed with GBM than women.
ER-beta may be the answer to treating GBM; it suppresses cancer by activating thousands of genes that collectively have tumor-stunting effects. The small molecule that the San Antonio research team is developing will uniquely bind—or attach to—ER-beta and enhance activation of genes that suppress glioblastoma growth.
UTSA chemists including Stanton McHardy, a professor in the UTSA Department of Chemistry, are working to produce molecules that mimic estrogen activity at ER-beta without the known side effects associated with increased estrogen, such as breast tenderness and vaginal bleeding in women and fatigue and sweating in men.
“My lab will design, synthesize and optimize small-molecule inhibitors of ER-beta,” McHardy said. “Our ultimate goal is to identify a structurally novel ER-beta agonist, a molecule that acts like estrogen, that can be developed clinically.”
McHardy’s involvement in the project is personal. His older sister died of an inoperable GBM tumor for which there were no effective treatments. He says the project has been an extremely efficient and productive collaboration between his laboratory and his research partners.
McHardy is director of the Center for Innovative Drug Discovery (CIDD), a joint initiative of UTSA and UT Health San Antonio that is supported by funding from the Cancer Prevention and Research Institute of Texas (CPRIT). Grants provided by CPRIT were instrumental in offering support for preliminary data generation, which bolstered the team’s NCI-funded proposal.
CIDD is comprised of four collaborating core research facilities: a High-Throughput In Vitro Screening (HTSF) Facility and Computer-Aided Drug Design (CADD) Facility located at UT Health San Antonio and a Medicinal Chemistry Core Facility (MCCF) and a Pre-Clinical Pharmacology Core Facility (PCPC) at UTSA. The center’s mission is to provide a diverse array of core facilities and expertise to facilitate the translation of basic scientific discoveries into tangible pre-clinical candidate drugs that can be later developed into clinical therapies.
Karinel Nieves-Merced and Michael Tidwell, special research associates at CIDD and staff chemists at UTSA, have contributed to the research program. Nieves-Merced assisted in the early compound design stages of the program, and Tidwell synthesized the compounds and characterized their structure.
“This research proposal is based on strong preliminary data showing that ER-beta exerts tumor-suppressive functions in glioblastoma,” said Ratna K. Vadlamudi, professor in the Department of Obstetrics and Gynecology at UT Health San Antonio. “This proposal will develop novel ER-beta drugs that promote tumor suppression, leading to a new therapeutic modality to treat GBM.”
The scientists will go through iterations of ER-beta agonists to develop a novel clinical strategy and bring hope to patients and families affected by GBM. The goal is to move forward with completion of validation using preclinical models and then to test the molecules in clinical trials in two to three years.
“This is a great example of the drug discovery happening here at UTSA that will have real impact on cancer treatment,” said Audrey Lamb, professor and chair of the UTSA Department of Chemistry. “I am very excited by the work Dr. McHardy and his team are doing, which has clear potential for providing a therapeutic strategy in the near future.”
Other researchers who contributed to this study include, from the Department of Obstetrics and Gynecology in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio: Suryavathi Viswanadhapalli, Ph.D.; Gangadhara R. Sareddy, Ph.D.; Uday P. Pratap, Ph.D. and Rajeshwar Rao Tekmal, Ph.D.; and from the Mays Cancer Center: Andrew Brenner, M.D., Ph.D. and Henriette U. Balinda, Ph.D.