Disease Team Planning
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. What we suggest in this grant proposal is that by assembly of a team we can develop a new and much more efficient way to translate the stem cell research to clinical therapy. By using living slices of rat brain that we can keep alive in the laboratory for many weeks, we can introduce stem cells into to these living "brains in a dish" and then watch the cells' every move. In this way, 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 consequences of the disease and its treatment, including disturbances in mental abilities, movement, and hormonal balance, which prevent them from re-entering the work force or, in the case of children, from ever entering the work force. 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 and should be clear, 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 cells’ natural ability to seek out diseased cells, such as cancer cells. Since part of our current therapeutic approach involves administering very large amounts of very 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, at present, 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 "brain-in-a-dish" method to answer these very 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.
Executive Summary The goal of this proposal is to use tumor-tracking capacity inherent in many stem cell (SC) populations to identify, track and potentially affect brain tumor microenvironment. Malignant tumors such as high grade gliomas migrate within the brain early in the disease course, disseminating to distant regions of the central nervous system. The authors hypothesize that there is a “therapeutic window” during which SCs are most capable of tumor tracking and that this must be identified prior to successful application of SC therapy directed to brain tumors. The authors propose to expand on their “therapeutic window” hypothesis as a tool to treat pediatric brain tumors. Childhood brain tumors are the second most frequent malignancy of childhood and represent the leading cause of cancer death in children under age 15 in California. The outcome for children with primary brain tumors has not changed over three decades of research, although progress has been made in the treatment of some forms of childhood cancer such as acute lymphatic leukemia. Reviewers agreed that new strategies are needed to circumvent the limitations of conventional brain tumor treatments. In this application, the principal investigator (PI) proposes to use several poorly-described systems to define the mechanisms by which SCs home to cancer cells. While reviewers were supportive of the idea of targeting brain tumors with SCs, they commented that it is not clear from the application what the research objectives are and how they will be achieved. They judged that this application does not appear to contain a research plan that would result in a clinical trial within 5 years. The PI is a basic scientist with a strong background in signaling science but little to no experience with clinical trials or neuro-oncology. S/he is not a recognized leader in neuro-oncology or SC science. It is not clear that s/he has the leadership experience that would equip him/her to lead a large and diverse collaborative effort. Reviewers judged the planning proposal to be poorly constructed, based largely on the single PI’s hypothesis. Furthermore, it is not clear what the planning objectives are, what the composition of the team would be, and whether the objectives of the grant will be furthered by the kind of collaborative effort that CIRM seeks to fund. The members of the team, other than participating in suggested periodic by-weekly conferences held at a single medical center, don’t appear to have well-defined roles. In addition, there is a lack of clear, well-defined input from multiple experts in various fields that would help advance the proposed concept. In summary, the panel determined that the application does not meet the standards put forth in the present CIRM RFA. There was strong agreement within the review panel that compared to other applications for this disease oriented program, this application was superficial in detail and showed insufficient experience with designing and planning a multidisciplinary approach. Reviewer One Comments This is a poorly constructed proposal, based largely on the single author’s hypothesis of a therapeutic window and limited in-vitro and in-vivo biology. The concept is not clear, and the rationale is without evidence beyond the author’s single theory. The author proposed to put together a team, but does little to define the team, the members of the team other than to suggest periodic bi-weekly conferences held at a single medical center with no clear well defined input from multiple experts in various fields that would help advance this concept. Some steps are outlined including identification of milestones and a program report; but compared to other applicants for this disease oriented program this one seems quite superficial, quite investigator centric, and shows little experience with designing and planning these multi-disciplinary approaches. There is little about this proposal that provides confidence that the investigator can truly carry out any disease or any program towards development of stem cell therapeutics for brain tumors. It’s highly likely that this proposal would not lead to any well defined goals or outcomes, or in any way advance the needs of central hypothesis of developing tools for better brain tumors in pediatrics. Reviewer Two Comments Concept: In this grant the PI proposes to use several poorly described systems to define the mechanisms by which stem cells home to cancer cells. He hypothesizes that there is a “therapeutic window” during stem cells are most capable for tumor tracking and that this must be identified prior to successful application of stem cell therapy to brain tumors. While targeting brain tumors with stem cells is plausible and supported, this grant does not appear to contain a research plan that would result in a clinical trial within 5 years. It is not clear what the research objectives are and how they will be achieved. Principal Investigator: The PI is a basic scientist with a strong background in signaling science but little to no experience with clinical trials or neuro-oncology. He is not a recognized leader in neuro-oncology or stem cell science. It is not clear that he has leadership experience that would equip him to lead a large and diverse collaborative effort. Planning Approach: The proposal does not meet the standards put forth in the CIRM RFA. It is not clear what the objectives are, who the team is and whether the objectives of the grant will be furthered by the kind of collaborative effort CIRM seeks to fund. This planning process is not likely to prepare the team for a subsequent Disease Team Award application, as it is not clear that this work will result in a clinical trial application.