Stem cell based therapies for ameliorating radiation-induced cognitive dysfunction in a pediatric model of medulloblastoma
Early Translational IV
$3 608 750
Radiotherapy is a front line treatment used for the treatment of medulloblastoma, a common CNS tumor in children. Cranial irradiation remains the only treatment capable of successfully forestalling the growth of this brain tumor, and is largely responsible for the long-term survival of children so afflicted. While cranial radiotherapy is an effective treatment for CNS cancer, it is frequently associated with debilitating and progressive cognitive impairment. Depending on the extent of the initial disease, patient age, and radiation dose, marked reductions in IQ (i.e. up to 10-20 points) are routinely observed that adversely impact quality of life. Radiation-induced cognitive dysfunction is a growing problem, in part, due to increasing cancer survival rates and because there are no satisfactory long-term solutions to this unmet medical need. To address this serious clinical problem, we propose to test 2 development candidates for their capability to ameliorate radiation-induced cognitive dysfunction. Rodents subjected to head-only irradiation will be cranially transplanted with our selected stem cell derivative disease candidates and tested for improved cognitive performance 1 and 4 months later. Our past findings showing that stem cell transplants into the brain can reverse the adverse effects of irradiation on cognitive performance suggest that such an approach may one day help cancer survivors suffering from their deteriorating mental health.
Statement of Benefit to California:
Radiotherapy is a front line treatment used throughout the world and in California for the treatment of a variety of CNS malignancies. It remains the only treatment capable of successfully forestalling the growth of brain tumors, and is largely responsible for the long-term survival of children afflicted with medulloblastoma. While cranial radiotherapy is an effective treatment for CNS cancer, it is frequently associated with debilitating and progressive cognitive impairment. Cognitive dysfunction is a growing problem, in part, due to increasing survival rates among all cancer patients, including pediatric cases, but also since there are no satisfactory long-term solutions to this unmet medical need. Therefore, successful development of a stem cell based treatment for the reversal of radiation-induced cognitive dysfunction would benefit California in several major ways. First, academic and private sector personnel employed in California involved in the preclinical studies necessary to demonstrate efficacy and safety of the stem cell treatments would provide direct economic stimulus. Second, the state of California would be well positioned to attract cancer patients throughout the United States, and possibly the world, thereby benefiting from the increased economic activity associated with a rise in clinical trials. Lastly, success of CIRM funded research may stimulate philanthropic efforts aimed at promoting stem cell based research in California.
The objective of this Development Candidate Award proposal is to develop human embryonic stem cell-derived neural progenitor cells (NPC) as a potential therapy for cognitive deficits resulting from radiation therapy for pediatric medulloblastoma, a common form of brain cancer. The applicant will first characterize the extent of cognitive and behavioral deficits in a preclinical model of radiation-induced cognitive dysfunction, which will then be utilized to evaluate two differently staged NPC populations for their ability to reverse those declines following intracranial transplantation. After conducting additional studies to elucidate mechanism of action, the applicant plans to select the better development candidate, verify its therapeutic activity and optimize the dosing and treatment regimen in the preclinical model. Objective and Milestones - If successful, this research would provide sufficient basis for further development, including a pre-Investigational New Drug (IND) meeting with the Food and Drug Administration (FDA). - Project milestones represent incremental, achievable steps in a logical development process. Rationale and Significance - Of significant concern, the proposal does not take into account the effects of standard post-irradiation chemotherapy in the treatment of medulloblastoma, which may block engraftment and/or differentiation of the transplanted cells. Without consideration of this issue, it is unclear whether the described approach could be translated into medulloblastoma care. - Reviewers were uncertain of the extent to which transplantation of cells into the hippocampus would address cognitive deficits from radiation damage to other parts of the brain, including white matter. They also noted that cognitive defects resulting from chemotherapy in the clinical setting might obfuscate results. - The proposed therapeutic would address an important unmet medical need. Damage to the developing central nervous system represents a serious problem in the treatment of cancer in children, leading to poor quality of life and increased societal and economic burden. There are currently no approaches for treating such damage in the growing numbers of pediatric cancer survivors. Feasibility and Design - Reviewers found the preliminary data interesting but thought it could have been strengthened by comparative studies with anti-inflammatory agents, which others have shown can ameliorate the effects of radiation on neurogenesis in the hippocampus. Given the complexity of the proposed approach, it would be important to demonstrate its advantages over such alternatives. - The standard use of multi-agent chemotherapy after radiation in medulloblastoma patients raises serious questions about whether the proposed approach adequately models the clinical scenario. While it would be possible to modify the research plan to evaluate the effects of chemotherapy on transplanted cells, reviewers suggested that testing the potential of NPC implantation long after irradiation to improve cognition might offer a greater and more immediate impact on the current cancer survivor population. - The behavioral tests proposed will quantify hippocampal and amygdala dysfunction in the preclinical model, but not some of the more commonly observed deficits associated with medulloblastoma treatment, such as attention, working memory and processing speed. Inclusion of additional tests, such as 5-choice serial reaction time and the Morris water maze, should be considered for evaluating cognitive defects related to frontal lobe connectivity/function. - The radiation delivery method described for the preclinical experiments differs from the clinical situation, which would be better approximated by administering a larger number of smaller fractions. - Some reviewers questioned whether the proposed experiments would be sufficiently powered to detect meaningful differences between the compared NPC populations. - The research plan lacks important controls. For Aim 2, inclusion of a non-neuronal cell type and anti-inflammatory agent such as dexamethasone would prove valuable for comparison. For Aim 3, reviewers recommended that all preclinical subjects should be assessed by the same stereology in a blinded fashion in order to determine whether any of the proposed measurements correlates with outcome. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI, who contributed most of the preliminary data, has 20 years of experience in the stem cell field. The Co-PI has industry experience including significant contributions to an IND submission. Both investigators have records of success in relevant areas of research. - The large, multi-disciplinary team has an established relationship and a successful history of working together. While they encompass a wide range of expertise, reviewers felt the proposal could have been improved with greater input from its neuro-oncologists and animal behaviorist. Collaborations, Assets, Resources and Environment - The proposed collaborations are necessary and appropriate for this project. Relevant assets appear to be in place. - The research environment and institutional support are excellent. Responsiveness to the RFA - The proposal is fully responsive to the RFA. - The proposed approach is novel and not represented in CIRM’s existing translational portfolio.