University of Texas team studies compounds aimed at brain cancer treatment
Mays Cancer Center Annual Report
$3M National Cancer Institute grant to make compounds to treat glioblastoma multiforme (GBM) tumors, an aggressive brain cancer associated with the worst overall survival rates among all human cancers
Scientists from Mays Cancer Center and from the Department of Obstetrics and Gynecology at The University of Texas Health Science Center at San Antonio, along with the Department of Chemistry at The University of Texas at San Antonio (UTSA), are using a $3 million National Cancer Institute grant to make compounds they hope will treat glioblastoma multiforme (GBM) tumors, an aggressive brain cancer associated with the worst overall survival rates among all human cancers.
The grant follows previous NCI funding of $2 million that supported lab studies yielding fundamental understandings needed to progress to drug development.
The new compounds mimic the 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. More men are diagnosed with GBM than women.
ER-beta suppresses cancer by activating thousands of genes that collectively have tumor-stunting effects. The small molecule that the research team is developing will uniquely bind, or attach to, ER-beta and enhance the activation of genes that suppress glioblastoma growth.
Neuro-oncologist Andrew Brenner, MD, PhD, a professor of medicine at the health science center who treats patients at the Mays Cancer Center, noticed the pattern of more men with GBM. To explore this further, Brenner approached Ratna K. Vadlamudi, PhD, a professor in the Department of Obstetrics and Gynecology and co-leader of the cancer development and progression program at Mays Cancer Center.
“Estrogen signaling is one of the main topics of study in the OB-GYN field. 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,” Vadlamudi said. Stanton McHardy, PhD, professor in the Department of Chemistry at UTSA, 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 the health science center that is supported by funding from the Cancer Prevention and Research Institute of Texas.
The University of Texas at San Antonio
“At UTSA, our role 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, which can be developed clinically.”
Brenner, co-leader of the Experimental and Developmental Therapeutics Program at the Mays Cancer Center, conducted studies that showed the compounds enter the brain. This is an important consideration, given that the brain is protected from foreign substances by a blood-brain barrier, said Brenner. Any drug that treats GBM will have to penetrate this natural barrier.
“Dr. Brenner has proven that our compounds can do that. 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.”
The scientists will go through iterations of ER-beta agonists to develop a novel clinical strategy with a goal 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.
