AACR-Aflac Incorporated Career Development Award for Pediatric Cancer Research
The AACR-Aflac, Inc. Career Development Award
for Pediatric Cancer Research represents a joint effort to encourage and
support junior faculty, who have completed their most recent doctoral degree or
medical residency within the past 11 years, to conduct pediatric cancer
research and establish successful career paths in this field. The research
proposed for funding may be basic, translational, clinical, or epidemiological
in nature and must have direct applicability and relevance to pediatric cancer.
Branden S. Moriarity, PhD
University of Minnesota
Validation and testing of novel therapeutic targets to treat osteosarcoma
Osteosarcoma is the most common primary bone cancer and third most common cancer in children and adolescents. Despite advances in our knowledge of osteosarcoma biology, treatment options have not changed over the last three decades and rely on tumor resection and non-specific combination chemotherapy, which results in a five-year survival rate of 0-29 percent if clinically apparent metastases are present. Further, osteosarcomas are among the most disordered cancers in terms of whole chromosome and gene copy number changes, making it difficult to identify specific driver genes. While many genes have been proposed as drivers of osteosarcoma, only TP53, RB1, CDKN2A and MYC have been implicated with certainty. Studies attempting to identify driver genes using copy number variation (CNV), mRNA expression, and methylation data from human tumors have identified a limited number of candidate genes with low to no overlap among studies, likely due to the heterogeneity across tumors. To overcome these problems, Dr. Moriarity performed a forward genetic screen utilizing the conditional Sleeping Beauty (SB) transposon mutagenesis system in mice to identify the drivers of osteosarcoma. For first time, the genes promoting osteosarcoma development and metastasis were directly identifiable by use of transposon insertion mapping. His screen identified 232 candidate genes implicated in osteosarcoma development and 44 promoting metastasis. Utilizing a comparative genomics approach of his candidate genes using mRNA expression, CNV, and methylation data from human osteosarcomas he found candidate oncogenes SEMA4D, SEMA6D, and CSF1R are highly expressed in tumors compared to normal osteoblasts. Dr. Moriarity went on to validate SEMA4D and SEMA6D as newly identified osteosarcoma oncogenes, that when genetically inhibited reduced the transformed properties of human osteosarcoma cells (Moriarity et al., Nature Genetics). Thus, Dr. Moriarity's work suggests SEMA4D, SEMA6D, and CSF1R may be therapeutically relevant, actionable targets to treat osteosarcoma. Since there have been no breakthrough targeted therapies for osteosarcoma, despite many trials, these novel targets have the potential to be the first successful targeted treatments for osteosarcoma patients. He will use the support from the AACR-Aflac Inc. Career Development Awards for Pediatric Cancer Research to assess the therapeutic potential of candidate oncogenes SEMA4D, SEMA6D, and CSF1R and further validate candidate metastasis genes.
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Wei Li, PhD
The Pennsylvania State University College of Medicine
The pro-oncogenic role of EZH2 and CRL4(DCAF1) in NF2 mutant gliomas
Brain tumors are a major class of pediatric cancers. These tumors arise in the cranium or central spinal canal. Because of the limited space of the intracranial cavity, brain tumors are usually inherently serious and life-threatening. Despite major advances in neuroimaging and neurosurgical techniques over the past decades, the neurosurgical management of brain tumor patients remains challenging. In order to radically alter the clinical course of these brain tumors, it is important to develop targeted therapies based on identified oncogenic mutations and signaling pathways that drive their development and sustain their maintenance. Inactivating mutations in the NF2 tumor suppressor gene have been linked to gliomas and some other pediatric brain tumors. The NF2 gene encodes the FERM domain protein Merlin. The mechanisms by which Merlin suppresses tumorigenesis have long remained unclear, therefore, hampering the progress in the development of targeted therapies for NF2 mutant tumors. Dr. Li has recently discovered that the active form of Merlin accumulates in the nucleus and inhibits an E3 Ubiquitin ligase CRL4DCAF1. Genetic epistasis experiments and analysis of several Merlin missense mutations from patients support the hypothesis that the dephosphorylated form of Merlin suppresses tumorigenesis by inhibiting CRL4DCAF1. Following this study, he identified the Lats kinases in the Hippo tumor suppressor pathway as substrates of CRL4DCAF1. By ubiquitylating and inhibiting Lats, CRL4DCAF1 activates the oncogenic transcription coactivators YAP. These findings identify the oncogenic elements of this newly discovered pathway, CRL4DCAF1 and YAP, as therapeutic targets in NF2 mutant tumors. He will use the support from the AACR-Aflac Inc. Career Development Awards for Pediatric Cancer Research to further study the inhibitory regulation of Lats by CRL4DCAF1. This study will focus on examining the role of a Polycomb-group methyltransferase EZH2 in facilitating the inhibitory regulation, and exploring the therapeutic efficacy when CRL4DCAF1 and EZH2 are inhibited in NF2 mutant glioma cells. If these studies determine that NF2 mutant glioma cells are sensitive to these inhibitions, it will provide scientific rationale to test if this method can be translated into novel clinical trials for patients with NF2 mutant gliomas.
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