CINCINNATI—The research and development of improved therapy for metastatic brain tumors and high-grade gliomas is the focus of $200,000 in pilot grants awarded by the University of Cincinnati Brain Tumor Center’s Molecular Therapeutics Program. The three scientists who will be supported are:
- El Mustapha Bahassi, PhD, research assistant professor in the Division of Hematology Oncology.
- Pankaj Desai, PhD, professor of pharmacokinetics and drug metabolism, James L. Winkle College of Pharmacy.
- Xiaoyang Qi, PhD, associate professor in the Division of Hematology Oncology.
The annual competition for pilot grants has become a hallmark of the Molecular Therapeutics Program, an ambitious research initiative that seeks to translate novel laboratory research into phase-1 and -2 clinical trials for patients. The three scientists who earned this year’s pilot awards are members of the UC Neuroscience Institute, the UC Cancer Institute and the Cincinnati Cancer Center.
"Pilot grants like these enable researchers to test promising new ideas that otherwise might not be funded,” notes Ronald Warnick, MD, medical director of the UC Brain Tumor Center and the John M. Tew, Jr., Chair in Neurosurgical Oncology.
"Competition for research grants is more competitive than ever, and unproven ideas are often at risk of being left on the table. The more new ideas we explore, the better we will understand the molecular basis of primary and metastatic brain cancers and the closer we will be to finding a cure for cancers that afflict more than 180,000 Americans each year.”
Dr. Bahassi: Exploring the resilience of circulating cancer cells
Bahassi will use his grant to wade into what is currently a hot topic in cancer research: the complex, multistep process of metastasis, in which cancer cells break away from their primary site, survive in the bloodstream and then take root in distant organs.
Although 90 percent of all cancer deaths arise from the metastatic spread of primary tumors, the process is not well understood at the molecular level, Bahassi says.
A cancer cell that breaks off from the initial tumor site can be likened to a small boat that pushes off from an island in hopes of reaching a distant mainland. In theory, the cancer cell, like the small boat, should face a harsh environment upon entering the vast bloodstream. It has lost touch with its neighboring cells, which provide protection, and it is now exposed to chemotherapeutic attack.
But for some unknown reason, cancer cells often survive this journey instead of dying off. They are able to travel successfully through the blood stream and reach their destination—the brain—where they start a new cancerous colony.
Bahassi will test whether mutations in three genes—Keap1, Nrf2 and P300—provide a survival benefit to circulating tumor cells in patients whose cancer has spread to the brain. He will begin by testing his theory in a rodent model and then study cancer cells in patients whose primary cancer originated in the lung, breast, colon or skin (e.g., melanoma).
Dr. Desai: Letrozole for the treatment of high-grade gliomas
Desai will use his grant to continue his research into the potential of letrozole to treat malignant high-grade gliomas (grades III and IV), which carry an unfavorable prognosis. Letrozole, already widely used in the treatment of breast cancer, targets an enzyme (aromatase) that triggers the conversion of androgens into estrogens.
A key characteristic of letrozole is its ability to penetrate the blood-brain barrier, a biological safety net that keeps toxins out of the healthy brain but which also prevents potentially helpful drugs from gaining access to brain tumors.
Desai plans to further test his hypothesis that letrozole can be used to treat high-grade gliomas by studying the drug’s effectiveness against glioma stem cells derived from patients. These cancer stem cells differ from normal cancer cells and, as a result, present a special challenge. As stem cells, they are able to differentiate into all cell types found within a tumor. They are also usually resistant to conventional therapy. Zombie-like, they can continue to form new tumors, causing a patient who has been treated with chemotherapy to suffer a relapse.
Beyond the problem of glioma stem cells’ resistance, glioma tumors also vary widely from one person to another. As a result, Desai wants to learn whether letrozole’s benefits extend across the broad spectrum of patient-derived glioma cancers.
Finally, Desai aims to translate his understanding of letrozole’s effectiveness to a clinical trial for patients. He hopes to calculate a safe starting dose of letrozole as well as a strategy for dose escalation in anticipation of phase 1/2 clinical trials for patients. Such a clinical trial could begin as early as September 2015.
Dr. Qi: Radiation-enhanced SapC-DOPS therapy for metastatic brain tumors
Qi will use his grant to expand his growing body of research involving the nanovesicle SapC-DOPS. Qi has recently shown that, in an animal model, SapC-DOPS can successfully target brain metastases that arise from human lung and breast tumor cells. He now seeks to test his hypothesis that combining SapC-DOPS with radiation therapy could provide an enhanced therapeutic option for patients whose cancers have spread to the brain.
Qi has gained international recognition for designing SapC-DOPS, short for saposin-C dioleoylphosphatidylserine, while working at Cincinnati Children’s Hospital Medical Center in 2002. SapC-DOPS has been shown in preclinical studies to cause several types of cancer cells—including brain cancer cells—to self-destruct, without causing harm to healthy cells or tissues. Qi explains that the nanovesicle works by selectively binding with phosphatidylserine (PS), a lipid molecule that "is abundantly present” on the outside of cancer cell membranes.
Radiation therapy, which is frequently prescribed for metastatic brain tumors, works by damaging the DNA of cancer cells. In the process it also increases the exposure of the PS lipid molecule on cancer cells’ membranes. As a result, Qi hypothesizes that radiation plus SapC-DOPS will offer a one-two punch in the treatment of brain metastases in animal models.
From local fundraising, hope and promise
The three pilot grants are the latest example of how fundraising efforts by the UC Brain Tumor Center’s Community Advisory Council have enabled the center’s cadre of elite scientists to pursue innovative ideas that could lead to future treatments.
In addition to the Molecular Therapeutics Program grants and grants from the University of Cincinnati Center for Clinical and Translational Science Training (CCTST), UC Brain Tumor Center researchers have benefited from support provided from fundraising events such as the Center’s annual Wine Tasting event and Walk Ahead for a Brain Tumor Cure, as well as from generous donations from community organizations including the Shemenski Foundation, the Mayfield Education and Research Foundation and the LCS/Sahlfeld Foundation.
When pilot grants result in extraordinary preliminary data, researchers can parlay their new knowledge into million-dollar grants from the National Institutes of Health (NIH). Atsuo Sasaki, PhD, a researcher with the UC Brain Tumor Center, successfully did that when he acquired a $1.67 million NIH grant in 2014.
"The researchers, clinicians and entire UC Brain Tumor Center team express our deepest appreciation to the Community Advisory Council, to the Shemenski Foundation, and to our supporters and donors,” Warnick says. "Without them, these exciting 2015 pilot grants would not have been possible.”