The research and development of improved therapies for the most common childhood brain cancer and for metastasis of the most common adult kidney cancer to the brain are the focus of $100,000 in pilot grants awarded by the UC Brain Tumor Center’s Molecular Therapeutics Program for 2016. The two scientists who will be supported are:
- Richard Lu, PhD, professor in the Brain and Spinal Tumor Program at the Cancer and Blood Diseases Institute at Cincinnati Children’s Hospital Medical Center.
- Atsuo Sasaki, PhD, assistant professor in the Division of Hematology Oncology at the UC College of Medicine and a member of the UC Cancer Institute.
Lu was awarded a one-year $50,000 grant to pursue a better understanding of medulloblastoma, the most common malignant brain tumor in children, and to continue his work toward the development of improved therapies. The need for new therapies is significant because current treatments (surgery, radiation and chemotherapy) are aggressive and can leave children with permanent, severe side-effects. In addition, medulloblastoma tumors often recur and become resistant to chemotherapeutic agents.
Sasaki was awarded a one-year $50,000 grant to help fill a void in translational research of renal cell carcinoma metastasis. Renal cell cancer, the fourth most common cancer to metastasize to the brain, makes up 90 to 95 of all kidney cancers in adults and accounts for 7 to 10 percent of all brain metastases. At this time, no nationally funded research into renal cell metastasis exists.
"The UC Brain Tumor Center’s Molecular Therapeutics Program is proud to award these pilot grants to two exceptional researchers,” says Ronald Warnick, MD, medical director of the UC Brain Tumor Center and the John M. Tew, Jr., MD, Chair in Neurosurgical Oncology. "Drs. Lu and Sasaki have long demonstrated their ingenuity in confronting the complex molecular matrix of brain cancer, which afflicts more than 180,000 Americans each year.”
Enlisting a Novel Model to Combat Medulloblastoma
Medulloblastoma develops from immature cells in the cerebellum, the lower, rear portion of the brain. The tumor accounts for 18 percent of all pediatric brain tumors, according to the American Brain Tumor Association.
Prior research by Lu has determined that a specific gene, called GNAS, encodes an enzyme (Gαs) that inhibits tumor growth in one of the four medulloblastoma sub-types. Specifically, the GNAS gene suppresses medulloblastoma tumors whose growth is driven by what is known as the "Sonic Hedgehog” pathway, a primary regulator of embryonic development. About 30 percent of medulloblastomas are of this sub-type.
Lu and his lab recently developed an animal model of medulloblastoma that will enable them to screen and test new therapies, and their preliminary research already is pointing to potential tumor suppressors.
"We have not seen significant improvement in therapies for children with this fast-growing tumor in three decades,” Lu says. "Our studies should help us gain a better understanding of the molecular basis of medulloblastoma tumor formation, and the resulting data could lead to a Phase I clinical trial for the young patients who develop this tumor.”
The pilot grant also will enable Lu to use whole-genome and RNA sequencing to analyze tumors that arise from mutations in the GNAS (tumor-suppression) gene. "The study should identify previously unrecognized signaling pathways that contribute to the formation of medulloblastoma,” Lu says.
Seeking a Molecular Therapeutic Strategy for Kidney Cancer Metastasis
Preliminary research in Sasaki’s lab has found that renal cancer cells alter the metabolism of GTP, a source of energy. Sasaki’s lab has also previously found that a drug already approved by the U.S. Food and Drug Association appears to reduce the renal cancer cells’ motility—their ability to move around freely—and their ability to proliferate.
With his pilot grant, Sasaki seeks 1) to define the role of GTP metabolism in the ability of renal cells to move about and metastasize to the brain and other parts of the body and 2) to use the FDA-approved drug to suppress the cells’ metastatic potential. Using five renal cancer cell lines, he will study how altered GTP metabolism affects the cells’ ability to grow and move around. He also will study the mechanism that alters GTP’s metabolism—the "GTP metabolic switch”—in both a cell culture system and patient specimens.
"Finding a therapy for renal cell cancer metastasis to the brain is an unmet needs in brain cancer,” Sasaki says. "This cancer, once it has metastasized, is particularly threatening because of its aggressive nature and the accompanying risk of hemorrhage in the brain.”
"We want to determine whether targeting the GTP metabolic switch in renal cell carcinoma diminishes the ability of renal cell cancer to metastasize,” Sasaki says. "This project will be the first molecular study aimed at controlling renal cell metastasis to the brain.”
Local Fundraising, Hope and Promise
The 2016 pilot grants are the latest example of how fundraising efforts by the UC Brain Tumor Center’s Community Advisory Council, chaired by Kathy Beechem, have enabled the center’s cadre of elite scientists to pursue innovative ideas that could lead to future treatments.
In addition to grants from the Molecular Therapeutics Program and UC’s Center for Clinical and Translational Science Training, UC Brain Tumor Center researchers have benefited from support provided from the center’s annual Wine Tasting event and Walk Ahead for a Brain Tumor Cure, as well as from generous donations from 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). Dr. Sasaki 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, the awards to Drs. Lu and Sasaki would not have been possible.”