Three projects from University of Colorado Cancer Center researchers have received grants from the Denver-based Michele Plachy-Rubin Fund for Pilot Grants in Brain Cancer Research. Receiving $40,000 each to fund their work around brain cancer are Sujatha Venkataraman, PhD; and the teams of Philip Reigan, PhD, and Michael Graner, PhD; and Natalie Serkova, PhD, and Nicholas Foreman, MD, MBChB.
New treatments for ependymoma
Venkataraman will use her grant to research new treatments for ependymoma, a childhood brain tumor that is incurable in a high percentage of cases.
“These brain tumor cells have high levels of a gene called EZHIP, which makes the tumor cells grow very fast,” Venkataraman says. “There is no drug to target this gene, so we looked for other genes that work with EZHIP to give growth advantage to ependymoma tumor cells.”
Venkataraman and her team used a highly sensitive technology to examine individual cells within ependymoma tumors and identified a small number of previously unidentified cells that potentially cause tumors to regrow after failure to respond to standard treatment. They found that a gene called BMI1 can convert normal cells to tumor cells and protect tumor cells from all treatments.
“We propose that EZHIP interacts with BMI1 in making ependymoma tumor cells grow aggressively,” Venkataraman says. “If we can stop this interaction, it will lead to tumor cell death. We intend to test a drug that has the potential to selectively destroy those resistant tumor cells, with the hope of curing all children with ependymoma. These studies will generate critical pre-clinical data for the design of trials for this potentially more effective and less toxic treatment.”
An alternative to brain biopsies for pediatric patients
Serkova and Foreman’s grant also will investigate ependymomas, in particular one form, PFA1, which is the most aggressive. Inflammation in the brain plays a critical role in these tumors, which means they don’t respond as well to therapies and tend to have a poor overall outcome.
“As of today, the only way to determine the inflammatory status of a child with an ependymoma is invasive biopsies,” Serkova says. “Our multi-expert team will develop advanced non-invasive imaging strategies for ependymoma inflammation in mouse patient-derived ependymoma models. The proposed magnetic resonance imaging of inflammation (iMRI) will first be developed pre-clinically, with the long-term goal of translating iMRI into clinical pediatric trials to improve the care and survival of children with ependymomas without the need of debilitating brain biopsies.”
Reigan and Graner will use their Michele Plachy-Rubin Fund grant to examine the role of a protein called thymidine phosphorylase (TP) in glioblastoma, the most common brain tumor in adults.
“Interestingly, TP is present at high levels in the tumor, but is not detectable in normal brain tissue,” Reigan says. “This presents an opportunity to target a unique characteristic of the tumor, with reduced risk of damage to normal tissue.”
Reigan and Graner plan to evaluate the effect of small molecule TP inhibitors, including the known inhibitor TPI, on glioblastoma growth. They believe that disrupting TP activity could sensitize tumor cells to improve the effectiveness of temozolomide, a chemotherapy drug that is part of first-line therapy for patients with glioblastoma.
“We are very grateful for the Michele Plachy-Rubin award, as these funds will allow us to extend our studies and accumulate crucial data to support targeting TP in glioblastoma.” Reigan says. “These studies are critically important for patients with brain cancers, as their therapeutic options are limited and survival rates are poor.”