Funded Projects

Immunosignature Strategy for Development of Clinical Biomarkers and Identification of New Drug Target Candidates for Pediatric Brain Cancer

Antibody-based profiling shows promise as a general approach to diagnosis and as an indicator/biomarker of response to treatment. Researchers have developed a novel technology platform to detect patterns of tumor-recognizing antibodies, or immunosignatures, that differ by tumor type and disease state. Using this platform, researchers will assay human tumor and blood samples to define signatures that correlate with each of the four molecular subtypes of medulloblastoma. Simple blood tests analyzing these immunosignatures patterns have already been shown by Dr. Johnston’s lab to recognize different types of adult brain cancer. In specialized laboratory models of medulloblastoma, researchers will test the utility of the immunosignatures as dynamic biomarkers for early detection of tumor growth/relapse and of tumor responsiveness to drugs. The tumor-associated proteins that elicit the immunosignatures will also be identified, thereby uncovering candidate targets for novel therapies for medulloblastoma.

Award $234,000
Principal Investigators Bob Carter, MD, PhD, University of California, San Diego; Stephen Albert Johnston, PhD, Arizona State University; and Robert Wechsler-Reya, PhD, Sanford Burnham Prebys Medical Discovery Institute
Funding Partner ABC2 (Accelerate Brain Cancer Cure)

Project:EveryChild (The Children’s Oncology Group)

The Children’s Oncology Group (COG) unites more than 9,000 experts in childhood cancer at more than 200 leading children’s hospitals, universities and cancer centers across North America and other continents in the fight against childhood cancer. The COG’s Project:EveryChild is an initiative that will create a fundamental platform for translational research. The initiative involves taking extra tissue available from children who must undergo a diagnostic procedure and then storing samples in COG’s state-of-the-art biorepository which serves as a worldwide resource. Laboratories studying these tumor tissue samples can then link clinical data from each child, such as the treatment the child received and how effective it was, as their research moves forward. Project:EveryChild will result in a well annotated childhood cancer biobank to enable robust discovery research and a platform for personalized medicine. The study is open to all children diagnosed with cancer. Funding from the PBTF specifically supports the acquisition of follow-up clinical information and central nervous system (CNS) tumor biospecimens. The costs of obtaining the biospecimens and corresponding clinical follow-up data obtained at diagnosis or relapse from children with brain tumors are often not covered by grants from the National Cancer Institute.

Award $100,000
Principal Investigators Peter Adamson, MD, Chair, Children’s Oncology Group, Alan R. Cohen Endowed Chair in Pediatrics at the Children’s Hospital of Philadelphia

BRD4 as a Therapeutic Target for Medulloblastoma

In approximately 25 percent of medulloblastoma cases, tumor growth is driven by the amplification of a gene called MYC. The majority of children with MYC-amplified medulloblastoma die of their disease. Other pediatric cancers that harbor amplifications of MYC family members, notably neuroblastoma, are also similarly associated with devastating outcomes. Novel therapeutic strategies are desperately needed in the clinic for children with these cancers. Experience with novel agents, however, has shown that cancers frequently evolve to become resistant. A promising therapeutic approach is to develop combination treatments that include drugs to overcome or circumvent the development of resistance. In laboratory studies, Dr. Beroukhim has shown that MYC- amplified medulloblastomas are sensitive to a class of chromatin modifiers called BET-bromodomain inhibitors. The specific aims of his proposal are to fully elucidate the mechanism of action of this family of inhibitors and thereby gain insight into the genes and proteins that confer resistance. His results will guide strategies to optimize the efficacy of BET-bromodomain inhibitors for children with MYC-amplified medulloblastoma and provide a framework to study cancer’s evolution in response to this novel class of cancer drugs.

Award $150,000
Principal Investigator Rameen Beroukhim, MD, PhD, Dana-Farber Cancer Institute
Funding Partner Christopher Brandle Joy of Life Foundation

Epigenetic Alterations Define Lethal CMP-positive Ependymomas of Infancy

The principal investigators started a worldwide consortium, GENE (Global Ependymoma Network of Excellence) consisting of scientists, pathologists and clinicians from more than 30 centers around the world. Cumulatively, the members have contributed more than 400 PF-ependymomas with matched clinical data to the tumor bank in Toronto. With funding from the PBTF, the PIs will continue to grow the tumor bank and develop biomarkers to discern PFA (poor prognosis) from PFB (better prognosis) ependymoma in a CLIA-certified manner. They will also develop additional human PFA xenograft models to study epigenetic agents for therapy and to study biology and response to novel agents in the relapse setting.

Award $1,000,000 over three years
Principal investigators James T. Rutka, MD, PhD, FRCSC and Michael D. Taylor, MD, PhD, The Hospital for Sick Children, Toronto, Canada
Funding partner Meagan’s Walk Foundation

Development of a Peptide Vaccine for DIPG

Immunotherapy promises an exquisitely precise approach to treatment. However, it is limited in this role due to a lack of consistently expressed and tumor-specific antigens. Recently, a point mutation was discovered that provides a highly conserved and tumor-specific mutation, H3.3K27M, in 60 percent of DIPGs. Research objectives are to maximize immunogenicity of an H3.3K27M-containing peptide, to optimize vaccination timing in combination with radiation therapy in a murine model of H3.3K27M positive DIPG, and to perform IND-enabling studies.

Award $400,000 over three years
Principal investigators John Sampson, MD, PhD, MBA, Oren Becher, MD and Kendra Congdon, PhD, Duke University

A Novel Peptide Vaccine Targeting CMV Antigens in Recurrent Medulloblastoma

Recent findings have shown that cytomegalovirus (CMV) antigens are expressed in 92% of medulloblastoma cases. Targeting CMV antigens through peptide vaccination is therefore a candidate treatment strategy for this type of brain tumor. This novel strategy will be tested in a pilot clinical trial of a rationally-designed vaccine formulation containing multiple CMV peptides. The trial will enroll children with recurrent medulloblastoma and the primary goals are to determine safety and immunogenicity.

Award $200,000 over two years
Principal investigators Eric Thompson, MD, Duke University
Funding Partner Catching up with Jack

The Oligodendrocyte Developmental Methylome to Characterize Progenitors for Pediatric Glioma

To better understand pediatric glioma origins, it is important to determine the precise stages of oligodendrocyte progenitor cell (OPC) development targeted by oncogenic mutations. The broad objective of this proposal is to use the methylome as a new index of oligodendrocyte developmental character and use this data to interrogate OPC-like character across different subtypes of human pediatric gliomas from brain stem and forebrain.

Award $300,000 over three years
Principal investigators  Arturo Alvarez-Buylla, PhD and David Rowitch, MD, PhD, University of California, San Francisco

Personalized Treatment Strategies for DIPG

Mutations in the gene encoding for histone H3.3 (K27M and G34V/R) have been reported as molecular drivers in pediatric HGGs. Moreover, the presence of K27M mutation correlates with worse clinical outcome. PIs will perform whole exome sequencing and gene expression profiling of tumor tissue from children newly diagnosed with DIPG to explore the genomic heterogeneity and to identify key alterations associated with treatment resistance and progression. This clinical feasibility study is being conducted through the Pacific Pediatric Neuro-Oncology Consortium.

Award $300,000 over three years
Principal investigators Sabine Mueller, MD, PhD, Nalin Gupta, MD, PhD and Joseph Costello, PhD, University of California, San Francisco

Targeting Tumor-associated Inflammatory Cells to Ameliorate Radiation-induced Cognitive Changes

Radiotherapy can cause late effects including progressive cognitive dysfunction. The activation of inflammatory pathways that occur along with tumor recurrence and after cranial irradiation produce many adverse effects, and no treatment is effective. The experiments proposed in this project will help provide a detailed understanding of macrophage accumulation in a rodent brain tumor model, and how modulating this response may affect cognitive performance.

Award $150,000 over three years
Principal investigators Nalin Gupta, MD, PhD and Susanna Rosi, PhD

Targeting Wnt-driven Angiogenesis in Pediatric Glioma

The Rowitch laboratory has shown that oligodendrocytes maintain a Wnt-activated program of angiogenesis at postnatal stages (Yuen et al., 2014, Cell in press). Moreover, many laboratories have shown conservation of oligodendrocyte-like features in human glioma. Therefore, PIs will test the hypothesis that gliomas have co-opted a mechanism for angiogenesis that is normally required during CNS development. This study may identify a novel target for anti-angiogenic therapy.

Award $150,000 over three years
Principal investigators David Rowitch, MD, PhD and William Weiss, MD, PhD, University of California, San Francisco
Funding partner Bryan’s Dream Foundation

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