Summary: Researchers are investigating letrozole — a drug approved for postmenopausal breast cancer — as a potential therapy for glioblastoma, the most aggressive form of brain tumor.
Source: University of Cincinnati
A question asked in Pankaj Desai’s laboratory has grown into more than a decade of work, a clinical trial and new national funding to further evaluate letrozole as a treatment for glioblastoma (GBM).
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 (NIH/NINDS) to advance preclinical and translational studies evaluating letrozole in GBM models.
Research progression
Glioblastomas are highly aggressive brain tumors that often remain undetected until symptoms appear and the tumor has grown significantly. Standard care includes surgical resection when possible, followed by radiation and chemotherapy, but GBMs frequently recur or develop resistance. Median survival after diagnosis remains approximately 15 months.
Letrozole was approved by the U.S. Food and Drug Administration in 2001 to treat hormone receptor–positive breast cancer in postmenopausal women. It inhibits the enzyme aromatase, which synthesizes estrogen and can support tumor growth in hormone-driven cancers.
In 2012, Desai and a doctoral student in his lab, Nimita Dave (now a senior pharmacologist in Boston), asked whether aromatase plays a similar role in GBM and whether letrozole might be effective against these brain tumors.
Initial laboratory studies found aromatase expressed in GBM cell lines, and analyses of tumor specimens from UC’s tissue bank revealed high aromatase protein and mRNA levels. Presence of the enzyme alone, however, did not guarantee therapeutic benefit; the drug also needed the ability to reach tumor tissue inside the brain.
Desai noted that the blood-brain barrier restricts entry to many compounds, so choosing a drug with properties favorable for brain penetration was critical.
“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. “We selected letrozole because its physical and chemical properties make it a promising candidate to cross from the bloodstream into brain tissue.”
Animal studies supported the idea that letrozole can act on brain tumors, and subsequent experiments in patient-derived GBM cells — with important contributions from doctoral student Aniruddha Karve — demonstrated potent anti-tumor activity in cell culture models.
“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 support from the UC Cancer Center and the UC Brain Tumor Center, Desai’s team initiated a phase 0/1 clinical trial to determine safe and effective dosing of letrozole in GBM patients. That trial, led by Trisha Wise-Draper, MD, PhD, an experienced investigator in early-phase oncology studies, includes contributions from neuro-oncologists and neurosurgeons across UC.
The trial is nearing completion. Early findings indicate letrozole reaches tumor tissue in the brain at concentrations that are safe, and doses higher than those typically used for breast cancer can be achieved in GBM patients without unacceptable toxicity.
New research
Despite encouraging signals, GBM remains complex and highly aggressive. Desai emphasizes that single drugs rarely cure GBM; combination strategies will likely be required.
Supported by the new NIH/NINDS grant, the research team will study preclinical combinations of letrozole with other chemotherapy agents and targeted therapies. The three-year IGNITE grant (R61/R33) began on Aug. 1 and will test combinations that may enhance efficacy, overcome resistance, and inform future clinical trials.
“It’s really exciting to get this sort of reassurance from a peer reviewed grant application,” Desai said. “Finding a cure for a disease like GBM is extremely challenging, but this funding allows us to expand our efforts and explore combinations that could translate more rapidly to patients.”
The project is highly collaborative across UC schools and centers. David Plas, PhD, professor and the Anna and Harold W. Huffman endowed chair in glioblastoma experimental therapeutics in the Department of Cancer Biology, is joining the effort to contribute expertise in tumor biology and experimental therapeutics.
Plas’ lab focuses on tumors lacking the tumor suppressor PTEN. The team will explore whether letrozole combined with other therapies produces meaningful responses in PTEN-deficient GBM models and whether such combinations can be advanced toward clinical testing.
“This collaboration will combine my group’s experience in glioblastoma experimental therapeutics with Dr. Desai’s expertise in GBM pharmacology and drug delivery,” Plas said. “Investigating combinations with letrozole could speed the path from lab findings to clinical trials.”
Additional collaborators include Gary Gudelsky, PhD, and Tim Phoenix, PhD, from the UC College of Pharmacy, as well as Soma Sengupta, MD, PhD, and Mario Zuccarello, MD, from the UC Brain Tumor Center.
Funding: The grant (Project No. 1R61NS128232-01) was awarded through the NIH/NINDS Innovation Grants to Nurture Initial Translational Efforts (IGNITE) program (R61/R33).
About this brain cancer research news
Author: Tim Tedeschi
Source: University of Cincinnati
Contact: Tim Tedeschi – University of Cincinnati
Image: The image is in the public domain