Basic science generates new drug for treating glioblastoma, the deadliest cancer
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 (Aug. 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 Obstetrics and Gynecology at UT Health San Antonio; the Mays Cancer Center at UT Health San Antonio; and the Department of Chemistry at The University of Texas at San Antonio (UTSA) 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 Jan. 1, 2023, follows previous NCI funding of $2 million that supported lab 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.
How the project began
Neuro-oncologist Andrew Brenner, MD, PhD, professor of medicine who treats patients at the Mays Cancer Center, noticed the pattern of more men with GBM and approached Ratna K. Vadlamudi, PhD, professor in the Department of Obstetrics and Gynecology at UT Health San Antonio. “Estrogen signaling is one of the main topics of study in the ob-gyn field,” Vadlamudi said. “Dr. Brenner said we need to study explanations for the gender difference. Over time, we narrowed it down to ER-beta, and we brought in UTSA chemists to make molecules that mimic estrogen activity at ER-beta without the estrogen side effects, which include breast tenderness and vaginal bleeding in women and fatigue and sweating in men.”
Stanton McHardy, PhD, professor in the Department of Chemistry at UTSA, said his involvement in the project is personal because his older sister died of an inoperable GBM tumor for which there were no effective treatments. He said the project has been an extremely efficient and productive collaboration between the Vadlamudi, Brenner and McHardy laboratories. McHardy is director of the Center for Innovative Drug Discovery, 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).
“At UTSA, my lab’s specific role on the grant will be to 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.”
Strong preliminary data
“This research proposal is based on strong preliminary data showing that ER-beta exerts tumor-suppressive functions in glioblastoma,” Vadlamudi said. “This proposal will develop novel ER-beta drugs that promote tumor suppression, leading to a new therapeutic modality to treat GBM.”
Brenner, co-leader of the Experimental and Developmental Therapeutics Program at the Mays Cancer Center — a National Cancer Institute-Designated Cancer Center — conducted studies that showed the compounds enter the brain. This an important consideration, given that the brain is protected from foreign substances by a blood-brain barrier. Any drug that treats GBM will have to penetrate this natural barrier. “For GBM, the drug must go into the brain. Dr. Brenner has proven that our compounds can do that,” Vadlamudi said.
Refining the small molecules
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, Vadlamudi said.
“This is a tremendous example of the collaborative translational science ongoing in our department,” said Randal D. Robinson, MD, professor and chair of the UT Health San Antonio Department of Obstetrics and Gynecology. “The work Dr. Vadlamudi and his team are undertaking is very exciting since the new class of ER-beta agonists will be helpful in treating brain and female cancers.”
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, PhD; Gangadhara R. Sareddy, PhD; Uday P. Pratap, PhD; Rajeshwar Rao Tekmal, PhD; from the Mays Cancer Center: Henriette U. Balinda, PhD; and from UTSA: Michael Tidwell, MS, and Karinel Nieves-Merced, PhD.