Fungus-derived toxin studied as potential treatment for deadly brain tumor
Jayme Blaschke | April 23, 2019
Alexander Kornienko, a professor in the Department of Chemistry and Biochemistry at Texas State University, has been awarded a National Institutes of Health (NIH) grant to study the potential of a fungus-derived treatment for an aggressive, deadly form of brain cancer.
The three-year, $460,000 grant from the National Cancer Institute within the NIH will support Kornienko's study, "Acid-Sensitive Glioblastoma Prodrugs Derived from Ophiobolin A," with the goal of enhancing the potential treatment's selectivity in targeting tumors.
Glioblastoma multiforme is the most common form of malignant brain tumor and is resistant to current forms of chemotherapy. Following surgery and radiation treatments, patients suffering from glioblastoma have a life expectancy of approximately 12 months, Kornienko said. The addition of current chemotherapy treatments only increases life expectancy of patients to 14 months. The potential effectiveness of Ophiobolin A as a new, front-line chemotherapy treatment is promising.
"Ophiobolin A is produced by a fungus that affects agricultural crops," Kornienko said. "Thus, it was originally investigated for its effect on plants. But then it was found that this toxic molecule works by a different mechanism than modern chemotherapy."
Modern chemotherapy kills cancer cells by inducing a type of cell death known as apoptosis. Glioblastoma cells, however, have developed mechanisms to resist this type of cell death, rendering current chemotherapy ineffective against them. Ophiobolin A induces cell death using a mechanism unrelated to apoptosis, one that has been shown to kill glioblastoma cells. The trouble is, Ophiobolin A is also toxic to healthy cells, leaving researchers with the challenge of how to target glioblastoma cells while leaving the normal cells unharmed.
"The idea is to make this molecule more selective, and kill cancer cells in the presence of normal cells. To do that, we hope to take advantage of the specific tumor microenvironment," Kornienko said. "The molecule itself is what's known as a prodrug –inactive – but when it goes into a tumor microenvironment, it is sort of uncaged and becomes an active drug that kills glioblastoma cells.
"A tumor microenvironment is more acidic than that of normal tissue," he said. "The compound remains in prodrug form, until it finally gets into the tumor tissue, where it will undergo the release of the toxic agent and the tumor cells will undergo cell death. The acid present in a tumor microenvironment will allow the prodrug to release the active drug."
In the first year of the study, Kornienko will research the most promising prodrugs that are stable at a pH of 7.4, but will undergo hydrolysis – a reaction with water causing a chemical breakdown – at a pH of 6.2-6.4 in the tumor microenvironment and release Ophiobolin A. In the second year of the study, the most effective prodrugs will be introduced to cancerous cell cultures at low pH in a laboratory environment, demonstrating that acidic conditions facilitate the death of the targeted tumor cells. If all goes well, the third year will involve testing in laboratory mice by collaborators at the University of Pittsburgh.
"We have very strong preliminary data which shows the feasibility of what we're proposing," Kornienko said. "When used in the prodrug form, they don't release the active agent, but at low acidity, they do. We have identified molecules which do exactly that."