Evaluating the Therapeutic Potential of Cardiac Glycosides Against Medulloblastoma
Abstract
Scientific Objective and Rationale: Medulloblastoma is one of the most common brain tumors in children, with around 500 cases diagnosed in the United States each year, approximately 1 in 5 tumors. With current treatments, approximately three-fourths of children diagnosed with medulloblastoma survive their tumor. However, survivors face major long-term side effects, life-long learning disability, and poor quality-of-life. These side effects are often related to learning and memory and significantly impair a patient’s ability to complete school or hold a job. Furthermore, there are no effective alternative therapies currently available for those patients who fail to respond to initial therapies or who suffer a relapse in their disease. For these reasons, the development of new therapies for medulloblastoma remains of the utmost importance. Much of ongoing cancer research focuses on the development of new medicines. However, the re-purposing of older medications provides another promising potential avenue for creating therapies for pediatric cancer patients. Repurposed medicines have the advantage, compared to new medicines, of having known toxicity and safety information. This means these medicines may require less testing and can potentially reach the patients faster. Using bioinformatics techniques to analyze how genes are turned on and off in medulloblastoma cells in response to over 1,300 medicines, we have identified a group of medicines (including proscillaridin A), typically used to treat heart failure, as a potential new treatment for patients with medulloblastoma. We were also able to show that these medications suppress the growth of medulloblastoma cells grown in cell culture. The Brain Tumor Center at Cincinnati Children’s Hospital Medical Center has multiple mouse models of medulloblastoma in which cells from patient tumors grow and cause brain tumors in the mice. These mouse models provide a way to test the potential effectiveness of new treatments for pediatric brain tumors. In collaboration with pediatric cancer doctors in the Brain Tumor Center, we have begun testing whether proscillaridin A and its combination with other drugs or radiation therapy can prolong survival in our model system. Further work using multiple mouse models of medulloblastoma to validate these findings is needed. However, these initial results suggest proscillaridin A may be a promising potential therapeutic for medulloblastoma. In addition, by combining the expertise of our labs in bioinformatics and pre-clinical testing, we are laying the foundation for the identification and evaluation of additional promising therapies for medulloblastoma in the future. Career Goals: As an Assistant Professor in the Brain Tumor Center of Cincinnati Children’s Hospital Medical Center, the Principal Investigator (PI) is committed to advancing the translation of brain tumor therapies. As short-term goals, my laboratory is analyzing the multiple genomic data of brain tumors to identify driver genes and regulatory networks and then discover optimized new drugs and drug combinations. Specifically, we have identified digoxin and proscillaridin A as a novel therapy for Group 3 and 4 medulloblastomas. We have also tested these drugs on other high-grade gliomas, such as ependymoma and diffuse intrinsic pontine glioma (DIPG), in which digoxin demonstrated significant cell-killing results. My long-term goals involve dissecting the molecular mechanism of tumorigenesis, tumor/immune cell interactions of pediatric brain tumors, and an attempt to identify novel targets and thus, developing combination treatments for pediatric brain tumors. In addition to regular interactions with my mentors, training in leadership and management, team and translational science, genomics, and pharmacology, I anticipate that the studies proposed in this grant will provide a key cornerstone by which I can build a long career as an independent researcher. Ultimate Applicati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010870
Entities
People
- Lei Frank Huang
Organizations
- United States Army