Early Translational IV
$1 638 051
Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer. Despite recent advances in surgery, radiation, and chemotherapy, it remains a virtually incurable disease. It has been established that a drug-resistant population of cells present in GBM tumors called cancer stem cells (CSCs) are required for tumor maintenance, therapy resistance and recurrence following surgery. As such, the identification of drugs that selectively target these cells would represent a transformative advancement in the pursuit of a cure for this devastating disease. We have established conditions that allow us to culture GBM CSCs in the laboratory and, with the goal of identifying potential drugs that kill GBM CSCs selectively, have conducted screens using a large library of drug-like compounds. This led to the identification of a compound that induces cell death selectively in GBM CSCs without inhibiting the survival or function of normal cell types. The objective of this research project is to use chemical approaches to optimize the properties of this drug candidate and to then test it in a highly relevant animal model of the disease.
Statement of Benefit to California:
Glioblastoma multiforme (GBM) is a devastating disease that remains virtually incurable. The overall 5 year survival rate is less than 5% and median survival for recurrent GBM is less than 6 months. This disease has a dramatic negative impact not only on the patients, but also on the patient families, friends and co-workers of the roughly 7000 Californians diagnosed with GBM. Surgery, radiation, and chemotherapy are all used to treat GBM but invariably fail, resulting in abrupt recurrence and patient death. Clearly, alternative more effective treatment strategies are needed. Recently, it has been established that in GBM a population of cells, termed cancer cells (CSCs), are responsible for tumor maintenance, growth, brain invasion and also tumor recurrence following surgery. The goal of this research project is to take advantage of this understanding to develop an alternative treatment strategy. Specifically, we aim to identify new drug candidates that selectively target and kill GBM CSCs without damaging normal brain tissue. The identification and development of such agents would have a significant impact on the well-being of Californians and reduce the negative economic impact on the state that results from this disease.
This Development Candidate Feasibility Award application seeks to identify and obtain preclinical proof of concept for a small molecule drug targeting glioblastoma multiforme (GBM) cancer stem cells (CSC). Glioblastoma multiforme is an aggressive brain cancer with an overall five year survival rate of <5%. The applicant proposes to use medicinal chemistry to optimize the activity of a lead candidate molecule already identified in a high throughput screen (HTS) against GBM CSC. Milestones proposed are to: 1) establish the mechanism of action of the lead compound, 2) select a backup chemical scaffold from the hits already obtained in the HTS, 3) complete gene expression analysis on GBM CSC, 4) perform in vitro and in vivo tests of selectivity, metabolic stability, pharmacokinetics and toxicology with the optimized lead compound, 5) demonstrate in vivo efficacy in GBM tumor models, and 6) conduct a preliminary preclinical toxicology study. Objective and Milestones - Overall the milestones were considered reasonable with the exception of the gene expression analysis (Milestone 3) which was considered to be out-of-scope at this point in the development process. - The Target Product Profile was considered sound and clinically feasible. Rationale and Significance - Developing improved therapies for glioblastoma continues to be a great unmet medical need. - The use of a high throughput screening approach using the GBM CSC is appropriate and if successful could provide potentially novel therapeutics for this disease area. Feasibility and Design - The major deficiency in the research plan is the lack of preliminary data demonstrating that the lead candidate molecule is targeting the CSC. It was suggested that experiments treating the cells with the compound followed by assessment of remaining tumor initiating capacity should have been done. - Reviewers were not convinced that the lead compound is potent enough, nor as specific as it needs to be. - Some concern was expressed that the toxicology assays only examined astrocytes and neuroepithelial cells. It was felt that additional cell types should be examined to be convinced about how selective the lead compound is for the CSC. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI is well qualified, has been working in this field for several years and has industry drug development experience. Collaborations, Assets, Resources and Environment - Key collaborations have been established with Investigators with expertise in neurosurgical animal models and in medicinal chemistry. - A communication plan has been outlined and is appropriate for this project. Responsiveness to the RFA - The application is responsive with the high throughput screening performed on patient-derived GBM cancer stem cells.