Early Translational III
Medulloblastoma (MB) is the most common malignant brain tumor in children. Even with an aggressive regimen of surgery, radiation and chemotherapy, one-third of medulloblastoma patients still die from their disease. Moreover, those who survive suffer devastating side effects from the treatment, including cognitive deficits, endocrine disorders and an increased incidence of secondary cancers later in life. Novel approaches to therapy are desperately needed, and these are likely to come from a deeper understanding of the cells that drive tumor formation – the cancer stem cells. The goal of our research is to identify a potent new drug that targets the medulloblastoma cancer stem cell in preparation for the development of a cancer stem cell-dependent targeted therapeutic agent, termed a Disease Candidate, for a future Phase I clinical trial for recurrent medulloblastoma. We will also perform genomic experiments on CSCs which will identify those MB patients most likely to respond to this new drug.
Statement of Benefit to California:
It should be noted that Cancer is the leading cause of death in children in the industrialized countries between the ages of 2 and 14 years of age. As stated above, brain tumors are the most frequently diagnosed solid tumor in children and medulloblastoma is the most frequent malignant brain tumors diagnosed in children. Taken together these epidemiologic results suggest that the treatment of childhood cancer represents a huge unmet medical need in the state of California and throughout the USA. If we can develop a stem cell based targeted therapeutic approach to this form of embryonal cancer in children we should be able to do so for other embryonal tumors in children. This stem cell targeted therapy is likely to be less toxic to our pediatric patients compared to high dose chemotherapy and radiation which has significant long term morbidity. As a result, the severe neurocognitive sequelae associated with high-dose radiotherapy can be avoided and these children will be able to lead more normal lives.
The goals of this proposal are to identify a Development Candidate (DC) for the treatment of medulloblastoma (MB), the most common malignant brain tumor in children and to identify the responsiveness of the MB subtypes to a proposed DC. The investigators propose to assess the therapeutic potential of several small molecule inhibitors of a key signaling molecule implicated in maintenance of medulloblastoma cancer stem cells (MB CSCs). All but one of the compounds to be tested are currently in Phase I or II clinical trials for other cancer indications. These compounds are expected to eliminate MB CSCs from patient's tumors thereby affording longer lasting remissions. Objective and Milestones - Reviewers differed in their opinions on the likelihood of the milestones being achievable in the project period with some believing that the five milestones are very challenging and would be difficult to accomplish in 3 years. - The target product profile is scientifically reasonable. - Development of cancer therapies consistently demonstrates that particular drugs end up being used in a combinatorial fashion. Thus, the ability of agents that inhibit this signaling molecule to increase toxicity of other therapeutic modalities is of great concern. Rationale and Significance - MB is the most common malignant brain tumor in children, thus the identification of a specific signaling inhibitor that specifically targets subgroup(s) of MB with a poorer outcome would represent a significant advancement in potential treatment for patients. - If new therapies targeting MB CSCs are identified, then this would not only be of clear benefit to MB patients, but it would also provide proof-of-principle that such agents might prove efficacious to treat all malignancies characterized by a CSC tumor cell subpopulation. - If successful, the DC will address a significant unmet medical need for the treatment of MB where the standard treatment of care offers only a 60% cure rate. Research Project Feasibility and Design - Most of the preliminary data is correlative in nature and does not directly address whether the MB CSCs require the targeted signaling pathway for their survival or activity. - Reviewers were of mixed opinions as to whether CSC was in fact being targeted. Some reviewers were not convinced by the data presented that a single marker can accurately distinguish the CSC fraction from the non-tumorigenic fraction in every MB tumor and that any effect of the inhibitor specifically affects the MB CSC frequency in medulloblastomas that arise in the mouse models. - Overall this proposal is very difficult to follow primarily because it is not well organized, moreover, neither the preliminary data nor the research plan addresses the objective of the proposal, which is to identify an inhibitor that specifically target MB CSCs among four compounds that were selected for studies. - A correlation in genetic signatures between human tumor-propagating MB CSCs and tumors from transgenic mouse MB models would have provided more confidence that the mouse models are predictive of human MB tumorigenesis and represent valid pre-clinical models to assess in vivo potency relevant to MB pathology. - While there was an effort to study cerebellar toxicity, some reviewers were concerned about the potential toxicity associated with the progenitor and stem cell populations of other regions of the CNS. Qualification of the PI (Co-PI, and Partner PI) and Research Team - The principal investigator, co-principal investigator and partner PI have an excellent track record and the requisite qualifications and expertise to carry out the research plan. - Some reviewers were of the opinion that the budget proposed by the PI was excessive. Collaborations, Assets, Resources and Environment - The environment is excellent and no issues with assets were raised. Responsiveness to the RFA - The proposal is responsive to the RFA primarily because it seeks to identify candidate drugs that eradicate human cancer stem cells.
- This application scored below the initial scientific merit funding line, no programmatic reason to fund the application was proposed, and the GWG voted to place the application in Tier 3, Not Recommended for Funding.
- Josh Rubin