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.
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 tumours.
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 oestrogen on a cell protein called oestrogen receptor-beta (ER-beta).
This critically important receptor is known to suppress cancer.
Both males and females have oestrogen, 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 tumour-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 oestrogen activity at ER-beta without the known side effects associated with increased oestrogen, such as breast tenderness and vaginal bleeding in women and fatigue and sweating in men.
“My lab will design, synthesise and optimise 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 oestrogen, that can be developed clinically.”
McHardy’s involvement in the project is personal. His older sister died of an inoperable GBM tumour 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 programme. Nieves-Merced assisted in the early compound design stages of the programme, and Tidwell synthesised the compounds and characterised their structure.
“This research proposal is based on strong preliminary data showing that ER-beta exerts tumour-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 tumour 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.”
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