Glioblastoma is the most common and aggressive brain tumor. Despite surgery, radiation and chemotherapy, the median survival remains approximately 15 months. This project proposes fundamental and clinical goals that are intimately tied: to understand the biology of neural stem cells (NSCs) derived from embryonic stem cells, fetal stem cells, and adult bone marrow derived stem cells and to manipulate these functions for therapy.
The limitation of current therapies for glioblastoma stems from their inablility to target infiltrating tumor cells. However, the obstacles to effective therapy match the known biological properties of neural stem cells (NSCs). NSCs display a dramatic property of attraction towards tumors in the adult central nervous system.
We have demonstrated the safety and usefulness of fetal NSCs as delivery vehicles as a means of delivering agents to kill infiltrating brain tumor cells and have demonstrated a mechanism of how they are attracted to glioblastoma cells. We also described a rapid culture process whereby neural stem cells can be obtained from bone marrow cells. These findings – taken together with the desperate state-of-affairs in glioblastoma underscore the importance of research that might accelerate the translation of NSC-based adjuvant treatment strategies. This strategy has garnered attention, in part, because of the pioneering efforts and seminal reports from the investigators on this proposal who now hope to advance it rationally towards clinical translation.
More recently, our collaborators have derived NSCs from pluripotent embryonic stem cells (ESCs), termed “ESC-derived NSCs” using a human feeder layer. Culturing without an animal feeder layer enables the clinical development of these cells. The use of stable NSC lines derived from embryonic stem cells have the advantage of being well-characterized and readily available in limitless quantities for the earliest phases of a disease or insult. Starting from this point of departure, we will formulate a team of world class investigators that have been at the forefront of stem cell therapies from basic research to translational research into clinical trial development. We will collaborate to develop multi-institutional aims to prepare an IND by developing (a) a long term safety profile for the optimal hNSC with the optimal gene; (b) a protocol for its GMP scale-up; and (c) an hNSC "use" protocol that is compatible with patient standard care.
Statement of Benefit to California:
This proposal addresses the principle aspiration of CIRM: “to use stem cells to cure a variety of diseases.” Our goal and that of CIRM is to advance therapies to early stage clinical trials. This project will have an impact on five of the ten listed goals of CIRM’s Scientific Strategic Plan: Goal I, CIRM grantees will have six therapies based on stem cell research in pre-clinical development – We will advance a novel stem cell based therapy for a devastating neurological disorder, glioblastoma. Goal II: CIRM grantees will have developed new methods of making stem cell lines- We are and will continue to develop efficient means of differentiating ESCs to neural progenitor cells. Goal VII, CIRM will have increased the workforce of stem cell researchers in California-We will recruit two full time trainees to work on this grant. Goal IX and X: CIRM will have established effective partnerships in stem cell research between scientific teams in non-profit and commercial centers and between national and international collaborations in stem cell research- This grant proposal forges a strong collaboration between a large clinical and preclinical entity with investigators that have a proven track record in preclinical development and clinical research and basic embryonic stem cell research with a superb basic stem cell research institute with an investigator that has made seminal contributions in the stem cell therapy field. The development of stem cell therapies for this devastating neurological disorder would make California the leading state for stem cell therapies, attracting both scientific talent and, in the future, investment for commercialization of these therapies.