‘Terminator’ brain cancer faces judgement day
QUEENSLAND scientists believe they have found a new weapon in the fight against a brain cancer so deadly it's nicknamed The Terminator.
Patients typically survive just 12 to 15 months after a diagnosis of glioblastoma, but Griffith University researchers are hopeful they have developed a drug to extend life in patients with the aggressive brain cancer.
Medicinal chemist Sally-Ann Poulsen describes the discovery as the most exciting in her 20 years as a scientist, but has no funding to continue the research.
She needs a biotechnology company or philanthropist to come on board to further develop the drug and take it into human trials.
The compound her team has developed is designed to work as a "piggyback" drug with the chemotherapy temozolomide, commonly given to glioblastoma patients.
Glioblastoma is typically treated with surgery to remove as much of the tumour as possible, as well as radiotherapy and chemotherapy.
Professor Poulsen, the acting deputy director of the Griffith Institute for Drug Discovery, said that while the cancer may initially respond to chemotherapy, it quickly became resistant.
But researchers have found that by pairing temozolomide with the Griffith University-developed compound, the survival of mice with glioblastoma is significantly increased.
She said glioblastoma cells contained a "transporter" protein which acted like a pump, regurgitating foreign molecules once they entered the cell.
"I think of it like an electric pool pump. The drug gets into the cell but it gets pumped back out," Prof Poulsen explained. "Inside the cell you never get high enough concentration of the drug for it to be very effective."
Directly blocking the pump, known as P-glycoprotein, with a drug is not feasible, given the potential for severe side effects, because the protein is found in most cells of the body.
But working with researchers at Italy's University of Turin, Prof Poulsen found that by blocking an enzyme, known as carbonic anhydrase 12, which sits beside the P-glycoprotein on the surface of glioblastoma cells, the pump is disabled.
"It's sort of like pulling out the plug," she explained. "If you think of an electric pump, it's like turning the electricity to it off at the switch."
Prof Poulsen has worked for years in the laboratory studying different carbonic anhydrase enzymes, and developing compounds to block them.
Inhibiting the carbonic anhydrase 12 enzyme changes the pH level within glioblastoma cells, which blocks the function of the adjacent pump, preventing the cell from regurgitating the chemotherapy.
In mice experiments, giving the man-made compound in combination with temozolomide increases survival, compared with treating them with the chemotherapy or the enzyme inhibitor alone.
Prof Poulsen stressed the combination therapy was not a cure for glioblastoma but hoped to take the compound development further and then into human trials, believing it may improve life expectancy and quality of life.
The animal research is published in the Journal of Medicinal Chemistry and Molecular Cancer Therapeutics.