BTFC Collaborative Grant Award Recipients

Date Posted: March 13, 2006

Project Title: Tumor Stem Cell-Based Drug Discovery for Adult and Pediatric Glioma
Sponsoring Institution: Kennedy- Krieger Institute, Baltimore, Maryland
Project Manager: Dr. John Laterra

Pre-clinical models of malignant brain tumors remain important in the identification of anti-cancer compounds. Unfortunately, the cell culture and animal models currently used for drug discovery have deficiencies that limit their ability to predict therapeutic responses in patients. A potentially critical explanation for this deficiency is that past models inadequately address possibility that a small subpopulation of glioma cancer cells with stem cell-like properties (i.e. glioma cancer stem cells) may generate the bulk of cancer cells within each tumor. This emerging concept predicts that therapies will fail if they do not specifically target the cancer stem cells and stem cell-driven tumor recurrence. The hypothesis of this 3-year research program is that stem cell-like cancer cells in glioma are a necessary and specific primary target for therapeutic intervention. We propose to pursue this hypothesis, looking at both adult and pediatric gliomas, with a new collaborative network of scientists and clinicians from four academic institutions within the United States and Italy who are experts in the fields of basic stem cell biology, cancer biology, molecular genetics, neuropathology, neuro-oncology, neurosurgery, neuroradiology, experimental therapeutics, and clinical trial design.

Project Title: Molecularly Guided Clinical Trials for Glioma
Sponsoring Institution: David Geffen School of Medicine at UCLA
Program Manager: Dr. Paul Mischel

Malignant glioma is a disease with great genetic complexity. The traditional research approach of analyzing individual genes or proteins in isolation has yielded few breakthroughs; a paradigm shift is needed. Diverse types of high dimensional molecular (and clinical) data must be integrated to identify effective combinations of therapeutic agents and novel drug targets. We hypothesize that a systems level integration will facilitate the development and testing of new glioma treatments. The recent finding of the critical role for molecular interactions in determining response to EGFR kinase inhibitors highlights this point. Efficient translation using dynamic models and the design of prospective “smart” clinical trials will require a new type of team. The assembled team, with complementary expertise, diverse perspectives, a range of clinical populations (both adult and pediatric gliomas) and a history of successful collaboration should facilitate the development of innovative new treatments for malignant glioma patients. The focus will be on using an integrated systems approach to accelerate discovery, biologic modeling, and clinical application of novel molecular therapeutic targets in malignant glioma.

Project title: Identifying and Overcoming Resistance Mechanisms in Glioblastomas: A Joint EORTC-RTOG Effort
Sponsoring Institution: Radiation Therapy Oncology Group
Project Manager: Dr. Minesh Mehta

Currently available treatments for glioblastoma can prolong survival in some patients, but are rarely curative. Fundamentally new approaches are required to uncover biological mechanisms of resistance from which novel therapeutic strategies can be developed. As glioblastomas are relatively uncommon tumors, there is only a limited ability of single institutions to conduct studies with adequate power to address these issues. Accordingly, the Radiation Therapy Oncology Group (RTOG) and European Organization for Research and Treatment of Cancer (EORTC) have joined forces in initiating the largest clinical study to date for newly-diagnosed glioblastomas. The required submission of tissue specimens within this carefully managed clinical trial system will create unparalleled translational research resources with enormous potential to uncover mechanisms of therapeutic resistance in glioblastomas. The BTFC is supporting the research component, a valuable leveraging of the unprecedented clinical trial infrastructure. The working hypothesis of the team is that designing more effective therapeutic strategies for glioblastoma patients will be optimized via a pharmacogenomic/pharmacoproteomic approach. Mechanisms of resistance identified through molecular and genetic profiling of large numbers of prospectively-collected clinical specimens will be hopefully lead to the development of targeted therapy strategies to overcome observed mechanisms of glioma resistance.