Selective small molecule inhibitors of glioblastoma cancer stem cells
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.
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.