A research question posed in Pankaj Desai’s lab has led to a decade of research, a clinical trial and major national funding to further investigate a potential new treatment for the most deadly form of brain tumors.
Desai, PhD, and his team at the University of Cincinnati recently received a $1.19 million grant from the National Institutes of Health/National Institute of Neurological Disorders and Stroke to continue research into the use of a drug called letrozole to treat glioblastomas (GBM).
Research progression
GBMs are aggressive brain tumors that patients often are unaware of until symptoms emerge and the tumor is substantial. Current treatments include immediate surgery to safely remove as much tumor as possible, radiation and chemotherapy, but the tumor often recurs or becomes resistant to treatments. The average patient survives no more than 15 months after diagnosis.
The medication letrozole was approved by the U.S. Food and Drug Administration as a treatment for postmenopausal women with breast cancer in 2001. The drug works by targeting an enzyme called aromatase that is present in breast cancer cells and helps the cancer grow.
In the fall of 2012, Desai and a doctoral student in his lab, Nimita Dave (now a senior pharmacologist at a biotech company in Boston), asked a question: Does aromatase play a similar role in GBM tumors, and if so, will letrozole work as an effective treatment?
Early research in the lab found the enzyme was present in brain tumor cell lines, and further testing found a very high amount of aromatase at protein and mRNA levels in brain tumor samples from UC’s tumor bank. However, that did not guarantee that letrozole would be similarly effective in brain tumors like it is in breast cancer tumors.
Desai explained a defense system called the blood-brain barrier only allows certain compounds into the brain based on their physical and chemical properties.
“Otherwise any compound could come into the brain and cause havoc and neurotoxicity,” said Desai, professor and chair of the Pharmaceutical Sciences Division in UC’s James L. Winkle College of Pharmacy and a University of Cincinnati Cancer Center member. “There are other compounds similar to letrozole, but we went with letrozole because we figured that based on its properties, this compound actually has the best chance of getting through into the brain from the blood circulation.”
Studies in animal models showed that letrozole was effective, and Desai’s research group moved to test the compound in cells derived from human brain tumor tissues. In this phase of work, key contributions were made by current doctoral student Aniruddha Karve who will continue to work with Desai as a postdoctoral fellow on the new NIH grant.
“What we saw in the patient-derived cells is that letrozole is very effective in killing the tumor cells in cell culture models,” Desai said.
With funding support from the Cancer Center and the UC Brain Tumor Center, Desai’s team launched a phase 0/1 clinical trial testing what dosage of letrozole is appropriate to treat glioblastomas. This trial was led by Trisha Wise-Draper, MD, PhD, an expert in phase 1 oncology trials with contributions from several other neuro-oncologists and neurosurgeons.
The trial is set to be completed soon, but Desai said early results have shown the drug is “unequivocally” reaching its target of the brain tumor tissue safely. Preliminary results also show that doses of letrozole higher than those needed for breast cancer treatment can be safely achieved in GBM patients.
New research
While the body of research results has been encouraging so far, Desai said GBMs remain a complicated, aggressive form of brain cancer. As promising as letrozole is, it is still unlikely that the drug will be a singular cure for the disease.
“We hope that would work, but it’s not necessarily rooted in reality. It’s going to be a combination of drugs,” Desai said.
Supported by the new NIH/NINDS funding, Desai and his team will research the preclinical effectiveness of combining letrozole with other chemotherapy compounds. The three-year grant began Aug. 1.
