MOLECULAR MECHANISMS OF CELL MOTILITY IN HUMAN NEURAL STEM CELLS
Gliomas are the most common, and most fatal, primary brain tumors. Every year, about 24,000 new cases of glioma are diagnosed in the US, and about 18,000 of those people die within a year. The poor prognosis is because these cancers grow by invading the surrounding brain, rendering complete surgical removal possible only in few patients. As such, the development of a successful treatment requires devising means of eliminating every remaining invasive tumor cell left behind after surgery, at the same time protecting the functioning surrounding brain.
Our proposal addresses this great unmet medical need, and seeds a long-term goal, which is to discover novel therapeutics to treat the invasive brain cancer cell. This application is based on previous exciting studies by us and others, which has demonstrated that in animal models, neural stem cells (NSCs) move specifically towards invasive brain cancer cells and track down pockets of tumors within the brain. Importantly, NSCs can be used to deliver therapeutic agents directly to tumor cells, with significant therapeutic benefit in animals. Here, our goal is to advance the field of brain cancer stem cell therapy by establishing novel approaches to examine the mechanisms how NSCs move, or migrate, toward glioma. We expect this knowledge to translate into refinement of the processes used to generate tumor-tropic stem cells (=stem cells that specifically track tumor cells), so that this can be accomplished in a clinically practicable fashion. Specifically, the proposed studies will contribute to the development of stem cell therapy in two ways. First, we will establish rigorous "motility assays", which are laboratory tests that will facilitate an important comparison of the migratory capabilities of NSCs derived by two well-publicized but heretofore never compared routes: NSCs derived from human embryonic stem cells (hESCs) vs. NSCs isolated directly from the central nervous system. Thus, although NSC migration is an absolute requirement for the use and further development of NSCs in stem cell therapy, migratory capabilities of different NSCs are currently unknown. Second, rigorous motility tests are needed for the analysis of the detailed mechanisms (the inner workings) how NSCs move towards glioma. We will subsequently utilize various genetic, molecular and cell biological means to study these mechanisms in detail. Our goal is to identify and characterize the genes and proteins that regulate the process of NSC movement towards gliomas. We expect our knowledge on the molecular mechanisms how stem cells track infiltrating tumor cells to allow further refinement of this therapeutic modality, because specific stem cell populations could be purified or genetically engineered on the basis of enhanced motility characteristics, thereby improving the efficiency of this treatment strategy for glioma.
Each year more than 200,000 people in the United States are diagnosed with a primary or metastatic brain tumor; primary brain tumors comprise approximately 40,0000 of these diagnoses. Brain tumors are the leading cause of solid tumor cancer death in children under the age of 20, and they are the second leading cause of cancer death in male adults ages 20-29. In California alone, 1,500 people die of brain cancers annually. Due to the high mortality rate, malignant brain cancer remains the single most costly and morbid cancer per capita in the United States, and unfortunately, the overall prognosis of brain cancer patients has remained virtually unchanged over the past 20 years. Thus, there is a great unmet medical need to provide novel and more effective treatment strategies to the people affected by this disease.
Based on animal studies, human ES cell-derived neural stem cells represent an important step forward that may prove critical in the ultimate clinical implementation of a new treatment for glioma, the most common form of brain cancer. Our proposed studies in this application, once completed, are expected to greatly accelerate the path towards the generation and engineering of clinically useful stem cell therapies for this disease. If we are successful in this goal, our studies are anticipated to significantly reduce the human and economic costs of brain cancer in California and elsewhere, and also make adjuvant brain cancer therapy more readily available to the underserved population. In parallel, we expect that a successful completion of these studies will greatly invigorate stem cell therapy studies for other cancers, as well. This could open up unprecedented new opportunities for future oncology applications, and attract scientists from other states to California, all this having a positive effect on our State. Finally, the expansion of biotechnology industry (jobs, capital investments) that translates the scientific discoveries made under the auspices of CIRM to practical applications is also expected to have a significant positive economic impact on California.