A potential new treatment for brain tumors

A research question raised by Pankaj Desai's lab led to a decade-long study, a clinical trial and massive state funding to further investigate a potential new treatment
for one of the deadliest brain tumors.

Dr.
Desai and his team at the University of Cincinnati recently received a $1.
19 million grant from the National Institutes of Health/National Institute for Neurological Disorders and Stroke to continue research into a drug called letrozole to treat glioblastoma (GBM
).

Research progress

GBMs are an aggressive brain tumor that patients usually become aware
of when symptoms develop and the tumor is severe.
Current treatments include immediate surgical safety removal of as many tumors as possible, radiation therapy and chemotherapy, but tumors often recur or become resistant to treatment
.
The average survival time of patients after diagnosis is not more than 15 months
.

In 2001, letrozole was approved by the U.
S.
Food and Drug Administration as a treatment for breast cancer in postmenopausal women
.
The drug's mechanism of action is to target an enzyme called aromatase, which is present in breast cancer cells and helps cancer cells grow
.

In the fall of 2012, Desai and his lab's doctoral student, Nimita Dave, now a senior pharmacologist at a Boston biotechnology company, posed the question: Did aromatases play a similar role in GBM tumors? If so, can letrozole be an effective treatment?

Early studies in the lab found that the enzyme was present in brain tumor cell lines, and further testing found that brain tumor samples in the UC tumor bank contained large amounts of aromatase
at both the protein and mRNA levels.
However, this does not guarantee that letrozole is as effective against brain tumors as it is
for breast cancer tumors.

Desai explained that a defense system called the blood-brain barrier only allows certain compounds to enter the brain, based on their physical and chemical properties
.

"Otherwise, any compound could enter the brain, causing damage and neurotoxicity," said Desai, a professor and chair in the Department of Pharmaceutical Sciences at the University of California's James Winkel School of Pharmacy and a member of the University of
Cincinnati Cancer Center.
"There are other compounds like letrozole, but we chose letrozole because, based on its properties, we think this compound is actually the most likely to circulate from the bloodstream into the brain
.
"

Studies of animal models showed that letrozole was effective, and Desai's team began testing the compound
in cells from human brain tumor tissue.
Current PhD student Aniruddha Karve has made key contributions during this phase of his work, and he will continue to work
with Desai as a postdoc under the new grant from the NIH.

"We saw letrozole in patient-derived cells kill tumor cells very effectively in cell culture models," Desai said
.

With funding from the Cancer Center and the University of California Center for Brain Oncology, Desai's team launched a Phase 0/1 clinical trial to test the appropriate dose
for the treatment of glioblastoma with letrozole.
The trial was led by Trisha Wise-Draper, MD, who was an expert in the Phase I oncology trial and was also involved in several other neuro-oncologists and neurosurgeons
.

The trial will be completed soon, but Desai said early results showed that the drug "unmistakably" safely reached the target of
brain tumor tissue.
Preliminary results also suggest that the dose of letrozole is higher than that required for breast cancer treatment and can be safely used in GBM patients
.

A new study

Despite the encouraging findings so far, Desai says GBMs remain a sophisticated, aggressive form of
brain cancer.
Despite the promise of letrozole, it is unlikely to be the only cure for the disease
.

"We hope this will work, but it's not necessarily rooted in reality
.
" It will be a combination of drugs," Desai said
.

With support from the NIH/NINDS new grant, Desai and his team will study the preclinical efficacy of letrozole in combination with other chemotherapy compounds
.
The three-year grant begins
on 1 August.

Desai said: "It's really exciting
to get that kind of assurance from a peer-reviewed grant application.
" "It's an exciting time
.
I think finding a cure for GBM is like finding a needle in a haystack and we hope it will really work, which is what we've been working towards
.
”

Desai said the research has been and will continue to be a collaborative effort
between colleagues at the University of California School of Pharmacy, the Cancer Center and the Center for Brain Oncology.

"It was really a wonderful collaboration and I am very grateful," Desai said
.
"This is a disease that absolutely needs an urgent breakthrough, and our team and others in the field are working to make a change
.
"

Plath said his lab has been focused on tumors that lack a tumor suppressor protein called PTEN, and new research may reveal a suitable treatment
for glioblastoma that could lead to PTEN deficiency when used in combination with letrozole with other therapies.

"This new collaboration will combine my team's experience in experimental therapeutics for glioblastoma and Dr.
Desai's experience in GBM therapy and pharmacokinetics," Plas said
.
"By studying the possible combination therapy with letrozole for GBM, this new project has the potential to be translated into clinical trials
more quickly.
" It's exciting
to be working with Desai on this new project.
”