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.
2010 GRANTEE
Zhe Li, Ph.D.Associate Geneticist, Brigham and Women's Hospital, Boston, MA
MicroRNA 125b-2 in Down Syndrome Megakaryocytic Leukemia
"Down syndrome (DS) children carry an extra copy of chromosome 21 (trisomy 21). At least 10 percent of DS babies develop a transient form of leukemia (DS-TL) that usually resolves on its own. However, about 20-30 percent of these babies progress to a more serious form of leukemia known as Down syndrome acute megakaryoblastic leukemia (DS-AMKL). In addition to trisomy 21, another key feature of these leukemias is the presence of acquired mutations in the gene encoding for a blood cell-specific nuclear regulatory protein called GATA1 in almost all cases, leading to the production of a truncated variant of GATA1 known as GATA1s. However, in both human and mouse cells without the extra copy of chromosome 21 (or its equivalent), GATA1s mutant protein alone is not sufficient to drive leukemia, suggesting trisomy 21 is absolutely required to cooperate with GATA1s for the development of this disease. Recently, we found a gene regulator on chromosome 21 called miR-125b-2 plays a key role in DS-TL and DS-AMKL. miR-125b-2 encodes for a microRNA, miR-125b, which silences expression of selective genes by reducing the production of their corresponding protein products. Expression of miR-125b is dramatically elevated in human DS-TL and DS-AMKL cells. In the mouse system, overexpression of this microRNA can cooperate with GATA1s mutation to drive abnormal proliferation of fetal blood progenitor cells, the presumed cells of origin of this disease.
"Based on these preliminary data, we hypothesize that miR-125b-2 may be one of the key genes on chromosome 21 to link trisomy 21 to GATA1s mutation for the development of DS-TL and DS-AMKL. In this project, we will further test this hypothesis by investigating whether transgenic overexpression of miR-125b-2 in mouse fetal blood progenitor cells engineered to express the GATA1s mutant protein (instead of the full-length GATA1 protein) is sufficient to drive a pre-cancerous phenotype in mice, similar to the transient leukemia found in DS babies. In DS cells, the gene dosage of miR-125-b2 is only increased from two copies to three copies, yet its gene product, the microRNA miR-125b, is much more overexpressed. We hypothesize that there may be a regulatory loop in DS cells to further elevate expression of this microRNA by increasing transcription of its gene to primary microRNA. Thus, in our second aim, we will explore the potential mechanism for this upregulation.
"Since DS-TL and DS-AMKL are strictly restricted to the pediatric population, understanding how miR-125b-2 contributes to this unique class of leukemia would not only reveal novel therapeutic targets, but also enhance our understanding of how microRNAs contribute to pediatric cancers in general. This AACR Career Development Award will provide me with the key support during the initial phase when I establish my full independence."
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2009 GRANTEE
Theodore Nicolaides, M.D.
Clinical Instructor, University of California, San Francisco, San Francisco, CA
Optimizing EGFR Targeted Therapy in Pediatric Malignant Glioma
"Malignant glioma is a particularly aggressive form of brain tumor found in children and adults. Children with diffuse brainstem glioma, for example, live an average of ten months. The Epidermal Growth Factor Receptor (EGFR) is an overactive protein in a large number of these tumors and is associated with decreased survival. Drugs that block the function of EGFR have been developed but are only marginally effective in patients. My preliminary data suggest two explanations for this lack of efficacy: 1) While inhibitors of EGFR are effective in blocking the function of this protein, the function of an additional protein, MAP kinase, is able to rescue the cancer cells. 2) Current EGFR blocking drugs are not potent enough to inhibit EGFR sufficiently in malignant gliomas - a new class of EGFR-blocking drugs called irreversible inhibitors appear to have increased potency. To address these problems, we show that we can increase the effectiveness of EGFR inhibitors in malignant glioma cells grown in petri dishes by combining these drugs with a second agent that blocks the MAP kinase protein or through the use of irreversible EGFR inhibitors. In studies proposed, we will expand our testing of combination therapy, using an EGFR-blocking drug in combination with a MAP kinase inhibitor in human brainstem glioma tumors transplanted into mice. In the second part of my proposal, I will use the newly developed irreversible inhibitors to EGFR to assess their effectiveness against pediatric glioma tumors transplanted into mice. If, as expected, we see a benefit using these agents in mice, this could pave the way for clinical trials using these drugs in the treatment of childhood malignant gliomas. The generous support provided by the 2009 AACR-Aflac, Inc. Career Development Award for Pediatric Cancer Research will allow me to continue to pursue this line of investigation and assist me in the transition to becoming an independent investigator, while also continuing to care for children with brain tumors."
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