New Faculty II
In children, cancers are the deadliest of diseases and second only to accidents as the leading cause of death. Cancers of the brain are the worst. Our current forms of therapy for these diseases can best be described as brutal: brain surgery followed by administration of very high doses of very toxic drugs and exposure to high doses of radiation. The deadliest of the brain cancers are the malignant gliomas. All children with this type of cancer die and in all cases the course of the disease and its treatment are horrific. About two-thirds of children can survive the rest of the types of brain cancers but two-thirds of these survivors go on to have a recurrence of their cancer. Even more heartbreaking is the fact that those that do survive are usually left with lifelong disabilities. It is clear that a new medical approach to brain cancers is needed. Importantly, stem cells appear to be able to provide the basis for a new approach. That is, stem cells, because of their seemingly natural ability to seek out diseased tissue, could be used to deliver therapy directly to the cancer, lessening the reliance on the harsh treatment methods that we currently use, and increasing the chance of eliminating the cancer once and for all. It is obvious that medical research on stem cells for the treatment of brain cancers is an important and necessary endeavor. The problem is that it is likely that, by doing this research in the usual fashion, it is going to take a very long time to come up with new therapies, perhaps decades. The usual fashion includes using animal models to test each therapeutic variation, each possible way of using different stem cells to treat different brain cancers. An additional and very troublesome problem is that once stem cells are introduced into the animal, they become very difficult to track as they blend in with the animal tissue, since they are not an organ and they are very small. So it becomes difficult to say, exactly, where the cells are going and what the cells are doing. Our grant proposal suggests a new concept with a much more efficient way to do this. By using 3D matrix and living slices of rat brain to create an optimal therapeutic competent stem cell population, we can introduce stem cells into to these living “brains in a dish” and watch the stem cell to target for brain tumors. Using the platform technology , we can try many variations on a theme in a relatively short period of time before actually moving into experiments in the whole animal. This allows us to much more quickly identify and abandon techniques that aren’t working and arrive at techniques that do. This also allows us to use far fewer animals for this type of research. Importantly, we believe that this approach to medical research lends itself to applications for a wide variety of other brain diseases and diseases of other organs of the body as well.
Statement of Benefit to California:
The malignant brain cancers comprise the leading cause of cancer death. Three decades of research have afforded little to allow us to change the outcome in these lethal brain cancers. For example, virtually all patients die after being diagnosed a diffuse brainstem glioma. Of the two-thirds of patients who survive at least 5 years after being diagnosed with any brain cancer, more than two-thirds go on to have a recurrence of their disease. Moreover, the treatments that these patients suffer can only be described as brutal and most of those that do survive are left with life-long mental disabilities. Overall estimates of the incidence of brain cancers in the United States show that about 20,000 will be diagnosed annually with about 2500 in California. The costs for the patient and family cannot be overestimated, given the statistics above. The economic costs are also grim: repeated use of physician, inpatient, outpatient and laboratory services as well as lost future earnings and occurrence of secondary diseases incur costs of more than 1.5 billion dollars annually in California alone. It is clear that California patients with brain cancers need a new therapeutic approach. One promising approach is to use stem cell’s natural ability to seek out cancer cells. Since part of our current therapeutic approach involves administering toxic drugs and radiation, we may be able to use stem cells to deliver these drugs directly, and only, to the cancer, thus sparing the rest of the body and brain of the damaging effects of these drugs. This not only would spare the patient from the ravaging effects of the treatment but also allow much higher effective drug concentrations at the cancer itself, resulting in a much more efficient destruction of the cancer cells. Unfortunately, there is not a comprehensive and efficient way of assessing whether or not the stem cell can adequately perform this particular function in the living animal, which types of cancers might be best suited to this approach, when, in the cancer progression, it is best to institute this type of treatment, and whether or not repeated treatments might be appropriate. The work described in this grant proposal is based on using a novel concept and “brain-in-a-dish” method to answer these questions. Given the applicant’s extensive training, the participation of established stem cell and clinical collaborators, and the demonstration of competence by way of work that has already been done, it is expected that the work will promote new clinical therapies for the brain cancers and will pave the way for using the techniques described for devising therapies for other brain diseases and injuries as well. Other long-term economic impact is for the scientists to teach students to pursue research and development career on stem cells in California.
In the present application, the Principal Investigator (PI) proposes a new therapeutic approach for malignant glioma. Conventional therapeutic strategies for this cancer are unsuccessful and new strategies are required. One emerging strategy is to use the tumor tracking capacity inherent in many stem cell (SC) populations to deliver therapeutic agents to the brain cancer cells. There are two properties of SCs that are crucial to this approach: a) the ability to detect a target (homing) and b) the ability to migrate through tissue (matrix remodeling). The objective of this applicant’s proposal is to optimize SCs as targeting vehicles for delivering drugs or therapeutic viruses to the site of tumors in patients with malignant glioma. The applicant proposes in Aim 1 to isolate sub-populations of different SCs and test 3D matrix microenvironments for maintenance of SC quiescence. In Aim 2, the applicant proposes to optimize the SC “therapeutic window” - the potential for SC homing and reaching a target tissue -using the 3D matrix model. In Aim 3, the (PI) will test these optimized SCs in vitro, ex vivo (slice model) and in vivo. Reviewers recognized the fact that malignant gliomas are, for all practical purposes, incurable and new therapeutic approaches are needed. However, reviewers felt that, in the present proposal, this strength is offset by a very weak study plan that is confusing, overly descriptive and unrealistically broad in scope with poorly defined goals and outcomes. Overall, reviewers found the experimental design very confusing. By intermixing multiple types of SC, and other tools throughout the research plan, it is often vague what SC the PI is referring. Another important point raised was the fact that it is unclear how a “therapeutic window” is defined and/or measured. It was also unclear to the review panel how many conditions were going to be tested and the plan for prioritizing testing of the conditions. The final aim (Aim 3) will make use of a slice culture system. Reviewers agreed that this was a potentially interesting assay. However, reviewers felt that again, no measurable outcomes were defined. Finally, the in vivo xenograft model proposed is not terribly relevant. The reviewers were concerned about the fact that, although the applicant may be technically eligible to respond to this RFA as a newly “independent investigator”, there is nothing in his/her lengthy track record to date that suggests a high potential for innovation or leadership in the stem cell field. The applicant’s training and career experience prior to his/her recent current appointment were not in stem cells. The reviewers did note that the applicant’s career development plan includes a career development committee consisting of a number of experts in relevant fields but expressed concern that the scientific, teaching and mentoring components of the applicant’s career will be spread across different campuses. Similarly, the reviewers also noted that the record of the institution is limited with regard to supporting the development of young PIs as future leaders in stem cell research. In terms of institutional support, the reviewers agreed that the institution has provided reasonable financial and physical resources, as well as core facilities to support the project. Overall, reviewers agreed that this proposal is based on a confusing and weak research plan by an investigator who is unlikely to meet one of the objectives of this RFA to support the future leaders in stem cell research.