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.
Birgit Knoechel, MD,
Dana-Farber Cancer Institute
Mechanisms of enhancer rewiring in drug resistant T-ALL2015 Grantee
Resistance to therapy presents a major clinical challenge in cancer medicine today, and novel approaches to identify and overcome resistance are desperately needed for improving outcome. Over the past years epigenetic dysregulation in cancer has gained more and more attention. Chromatin regulators are aberrantly expressed in a wide variety of tumors, and cancer genome sequencing studies have identified frequent somatic alterations in many chromatin-regulating enzymes. Despite these efforts, we are far from understanding the biological and therapeutic significance of these epigenetic alterations and from exploiting these dependencies for targeted therapies. Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy in children and young adults that frequently relapses or becomes refractory. T-ALL frequently harbor activating mutations in NOTCH1, which confer sensitivity to Notch inhibitors such as gamma secretase inhibitors (GSI). Yet, the rapid development of resistance has limited their clinical success. Dr. Knoechel has recently shown that resistance to Notch inhibition in T-ALL is mediated through epigenetic state transitions. Rare GSI-tolerant "persister" cells are already present in the naïve T-ALL population – existing in dynamic equilibrium with GSI-sensitive cells – and give rise to the GSI-resistant population after prolonged Notch inhibition. Persisters exhibit an altered epigenetic state consistent with global chromatin compaction and local changes at enhancers of genes that are critically important for cell survival and lineage defining genes. To test whether the altered chromatin state in persisters confers new susceptibilities to emerging epigenetic therapies, Dr. Knoechel performed a short-hairpin knockdown screen targeting more than 300 known chromatin regulators. This approach identified several chromatin regulators that are essential for persister cell survival, including the BET-family protein BRD4. Further studies revealed that combination therapy targeting NOTCH1 and BRD4 is highly effective against primary human T-ALL in vivo, thus identifying a promising new therapeutic approach for T-ALL. Dr. Knoechel will use the support from the AACR-Aflac Inc. Career Development Award for Pediatric Cancer Research to define the underlying molecular mechanisms and functional relevance of enhancer rewiring events associated with drug resistance in T-ALL. These studies will provide a platform for future therapeutic targeting of dynamic enhancer states associated with drug resistance.
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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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