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FINDING CURES TOGETHER<sup>SM</sup>

AACR-Aflac Incorporated Career Development Awards for Pediatric Cancer Research

The AACR Career Development Award for Pediatric Cancer Research is open to junior faculty in their first full-time faculty appointment. Proposed research projects may be in any discipline of basic, clinical, translational or epidemiological research with direct applicability and relevance to pediatric cancer.

2014 Grantee

Wei Li, PhDWei Li, PhD
Research Scientist, Sloan-Kettering Institute for Cancer Research, New York, NY

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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2013 Grantee

Yiping He, PhDYiping He, PhD
Assistant Professor/Pathology, Duke University, Durham, NC

Role of the MLL2-REST Link in Medulloblastoma Pathogenesis 

"Medulloblastoma is the most common malignant brain tumor in children. Despite advances in therapy, about 30 percent of children afflicted with medulloblastoma die of the disease. Children who survive often suffer from severe side effects as a result of damage done to the developing brain caused by current standard treatment. To achieve our long-term goal of developing better therapeutic strategies that are both curative and without serious side effect, it is essential that we understand the underlying oncogenic alterations and the resulting consequences for cellular processes in medulloblastoma.

"Recently, a promising development arose showing that the Mixed-lineage leukemia 2 (MLL2) pathway is a frequently mutated driver in medulloblastoma and other cancers. MLL2 is a histone methyltransferase and tumorigenesis is thought to be driven by its inactivating mutations. However, the underlying mechanisms by which inactivation of MLL2 drives pathogenesis remain unknown. Studying MLL2 has been challenging due to the large size (~600 kDa) of the protein and the lack of appropriate in vitro and in vivo cancer models. To overcome these obstacles, we have established novel human cell-based models by using gene knockout and somatic genetic editing technologies. Functional assays of MLL2 in these models reveal that MLL2 regulates a variety of signaling pathways including those essential for cell cycle progression and cell differentiation. The objective of our continuous research is to illuminate the role of signaling pathways that mediate MLL2 inactivation-driven tumorigenesis. In particular, we will use the AACR-Aflac Inc. Career Development Award for Pediatric Cancer Research to determine the role of MLL2 in medulloblastoma cell differentiation, the effect of MLL2 inactivation on REST, another regulator of cell differentiation, and to uncover other downstream mediators of MLL2’s function. Findings from these studies will contribute to our understanding of medulloblastoma and improving therapeutics. The generous support provided by the 2013 AACR-Aflac Inc. Career Development Award for Pediatric Cancer Research will, therefore, move us one step closer to our long-term goal of developing better medulloblastoma therapeutic strategies."

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2012 Grantees

Carl R. Walkley, PhD, AACR-Aflac Inc. Career Development Award 2012 GranteeCarl R. Walkley, PhD
Research Fellow, St. Vincent's Institute of Medical Research, Melbourne, Australia
New Models and Approaches in Osteosarcoma
 

"Osteosarcoma (OS) is the most common primary tumor of bone, occurring predominantly in the children and young adults. High-dose cytotoxic chemotherapy and surgical resection have improved outcomes, with long-term survival for patients with localized (non-metastatic) disease approaching 70 percent, but at the cost of considerable therapy-related illness. At presentation approximately 20 percent of patients have metastases and almost all patients with recurrent OS have metastatic disease. Cure rates for patients with metastatic or recurrent disease remain poor (<20 percent survival). Over the past 20 years, considerable progress has been made in the understanding of OS pathogenesis. This research has not yet been translated into substantial therapeutic benefit. The development of animal models that are directly reflective of the human cancer on which they are based and mirror the diversity underlying the human disease will be critical to improving the outcomes for patients with OS. This is particularly important in a cancer like OS which is relatively rare.

"We have been involved in the development of genetically engineered mouse models of human OS. We have now generated a new model of OS through the application of lineage restricted shRNA. This has led to the development of a model of well differentiated (osteoblastic) OS that has a spontaneous metastatic rate of 75 percent. This OS subtype is observed in patients but did not develop in our previous models which present with poorly/undifferentiated OS (fibroblastic). When combined with our established model, these unique OS bearing animals will allow for experiments addressing metastatic disease in a spontaneous, reproducible and validated model of human disease. We will use the support of the AACR-Aflac Inc. Career Development Award for Pediatric Cancer Research to improve our models and also to undertake a broad screen to identify possible new approaches to treat OS. The goal of these studies is to ultimately translate this research to improve outcomes for patients with OS. The generous support provided by the 2012 AACR-Aflac Inc. Career Development Award for Pediatric Cancer Research allows me to continue to develop these models and perform experiments that I could not otherwise undertake. The award will progress my transition to becoming an independent investigator and allow a more complete utilization of the models we have developed to improve patient outcomes for osteosarcoma."

Jing Crystal Zhao, PhD, AACR-Aflac Inc. Career Development Award 2012 GranteeJing Crystal Zhao, PhD
Assistant Professor, Sanford-Burnham Medical Research Institute, La Jolla, CA 
Role of Imprinted Long Non-coding RNA Gtl2 in Gene Regulation 

"Long non protein-coding RNAs (lncRNAs) are RNAs longer than 200 bp that lack open reading frames. Emerging evidence suggests that they play essential roles in normal development. For example, imprinted lncRNAs are of particular importance to fetal and postnatal growth. Unlike most genes expressed from both inherited maternal and paternal alleles, imprinted genes are expressed exclusively from one parental allele. Although only ~100 imprinted genes have been identified, their aberrant expression results in severe developmental disorders, including pediatric cancers. Imprinted genes typically form clusters and are regulated coordinately. Interestingly, at least one lncRNA has been identified in each cluster. The functions of these imprinted lncRNAs have been elusive. Recently, however, studies have suggested that they inhibit gene expression in eukaryotic cells by recruiting chromatin modifiers onto specific targets. For example, my previous work suggested that the imprinted lncRNA Gtl2 localizes Polycomb Repressive Complex 2 (PRC2), a histone H3-lysine 27 methyltransferase, to the Gtl2-Dlk1 imprinted locus and transcriptionally silences expression of the reciprocally imprinted gene, Dlk1. These novel findings raise interesting questions, such as how lncRNAs interact with proteins, how lncRNAs recognize targets, what the function of the lncRNA/protein interaction is, and how perturbing these interactions could affect disease states. In this proposal, I plan to use Gtl2 as a model to answer some of these questions.

"Gtl2 is required for normal development, since its deletion promotes embryonic lethality in mouse. Moreover, Gtl2 RNA has been identified as a transcript critical for proper generation of induced pluripotent stem cells. Significantly, many human cancers, such as pediatric neuroblastomas, show reduced Gtl2 expression. In vitro studies suggest Gtl2 can interact with p53 to inhibit cell proliferation. Given the important functions of Gtl2 in genomic imprinting, cancer progression and development, I propose to: 1) Investigate molecular mechanisms whereby the Gtl2-PRC2 complex controls Dlk1 expression; and 2) Identify additional targets of the Gtl2-PCR2 complex in mouse embryonic stem cells and cancer cells. The results of this study will not only shed light on the molecular mechanisms governing imprinting and development but could also reveal a potential role for lncRNAs and chromatin modification in pediatric cancer and determine whether they could serve as targets in drug design."

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