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.
Claudia Benavente, PhD
University of California, Irvine
Role of UHRF1 in osteosarcoma
Scientific Statement of Research
Genetic alterations at the RB1 gene are associated with poor prognosis in osteosarcoma. However, the precise mechanism through which this occurs is unknown. Dr. Benavente identified UHRF1 as a protein overexpressed in osteosarcoma. UHRF1 is a multifunctional protein involved in epigenetic regulation that directly interacts with RB1. Further, the RB/E2F pathway directly regulates UHRF1 expression. Their data shows that targeting UHRF1 overexpression dramatically increases survival of mice bearing osteosarcoma tumors and reduces the rate and number of metastases. This project aims to determine the mechanism(s) through which UHRF1 contributes to tumor progression to help design novel therapeutic interventions for osteosarcoma treatment. For this, they will define the role of UHRF1 in osteosarcoma pathogenesis and progression and define the role of the UHRF1 domains associated with migration and invasion in osteosarcoma. They will test the hypothesis that gene expression alterations driven by UHRF1 underlie tumor progression and poor survival in osteosarcoma.
Dr. Claudia Benavente received her BS/MS in Molecular Biotechnology Engineering at Universidad de Chile where her interest in pursuing cancer research first started. She then pursued her PhD in Cancer Biology at The University of Arizona as a Fulbright Scholar. As a postdoctoral fellow in Dr. Michael Dyer’s laboratory at St Jude Children’s Research Hospital she began studying the role of the RB pathway epigenetic regulation. Dr. Benavente is currently an assistant professor at the Departments of Pharmaceutical Sciences and Developmental and Cell Biology at UCI, where she continues to conduct basic and translational research in childhood solid tumors.
Acknowledgement of Support
The AACR-Aflac Career Development Award will offer the support necessary to ensure this project reaches publication. At the same time, it provides the resources to strengthen the project foundations that are necessary for securing long-term funding and establish my independent career in the field of pediatric cancer research.
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Amit J. Sabnis, MD
Adjunct Assistant Professor
University of California, San Francisco
San Francisco, California
PAX3-FOXO1 requires activation of mTOR by GATOR2 in rhabdomyosarcoma
Scientific Statement of Research
The PAX3-FOXO1 fusion marks an aggressive subset of rhabdomyosarcoma (RMS) with poor cure rates, and is not amenable to pharmacologic inhibition. We conducted a CRISPRi screen to find precision therapies for fusion-positive RMS, and found that loss of either MIOS or WDR24 is deleterious to PAX3-FOXO1 expressing cells, but tolerated by isogenic, oncogene-depleted cells. MIOS and WDR24 are part of GATOR2, a nutrient-responsive activator of mTORC1, leading us to hypothesize of a synthetic lethal interaction between GATOR2 and PAX3-FOXO1. To test this, we will identify the consequences of GATOR2 loss in multiple RMS models and confirm the sufficiency of PAX3-FOXO1 to create GATOR2 dependence. Next, using genetic manipulation and ribosome profiling, we will determine the output of GATOR2-mTOR that enables the growth and survival of PAX3-FOXO1 positive cells. Our work will identify the molecular mechanism behind an oncogene-directed therapy in RMS and define the PAX3-FOXO1 translatome to motivate future discovery.
Dr. Sabnis completed a joint BS/MS degree in biological sciences at Stanford University before joining the University of California, San Francisco, as a medical student, pediatrics resident, and pediatric hematology-oncology fellow. Through early work with Dr. Kevin Shannon and postdoctoral studies with Dr. Trever Bivona, he has developed an emerging research program focused on therapeutic opportunities in the protein homeostatic networks of pediatric sarcomas. He is currently an assistant professor in the Division of Pediatric Hematology-Oncology at UCSF, where he carries out his basic and translational research in parallel to caring for childhood cancer patients and survivors.
Acknowledgement of Support
The AACR-Aflac Pediatric Cancer Award comes at a critical time as my postdoctoral funding concludes, permitting me to advance a foundational project to publication. Simultaneously, the prestige and protection of this grant will help me secure long-term support for an independent translational research program taking aim at pediatric sarcomas.
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Birgit Knoechel, MD,
Dana-Farber Cancer Institute
Mechanisms of enhancer rewiring in drug resistant T-ALL
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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