Frederic G. Barr, MD, PhD

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Adjunct Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
10 Center Drive, Room 3B55, MSC1500
Bethesda, MD 20892
Office: (301) 594-3780
Fax: (301) 480-0853
B.A. (Chemistry)
Williams College, 1980.
Ph.D. (Molecular Biology)
Washington University, 1987.
Washington University, St. Louis, 1987.
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Description of Research Expertise

The major focal points of my current research program are chromosomal alterations and the pediatric soft tissue malignancy rhabdomyosarcoma. These issues were initially unified by a major research focus on the 2;13 and 1;13 chromosomal translocations in the alveolar subtype of rhabdomyosarcoma (ARMS). My laboratory's initial studies identified that these translocations fuse either PAX3 or PAX7, which encode members of the paired box transcription factor family, to FKHR (FOXO1), which encodes a novel member of the fork head transcription factor family. These fusion events generates PAX3-FKHR and PAX7-FKHR chimeric genes that encode fusion proteins containing the PAX3/PAX7 DNA binding domain and FKHR transcriptional activation domain. Our studies also revealed that these gene fusion events result in alterations at the level of protein function, gene expression, and subcellular localization, to produce oncogenic effects.

Our more recent studies are analyzing the downstream effects of these fusion transcription factors. For these studies, we developed a human myoblast cell culture system, which is converted to a tumorigenic state by the combination of PAX3-FKHR and additional oncogenic events. Using both constitutive and inducible forms of PAX3-FKHR in a xenograft model of ARMS, we are exploring the relationship between downstream target genes and phenotypic consequences of this fusion protein. Furthermore, we are assessing how these target genes and phenotypic effects vary with changes in fusion protein expression. Finally, we are investigating the hypothesis that PAX3-FKHR by itself is toxic, and that collaborating events provide tolerance to the toxic effects of PAX3-FKHR.

In a second set of recent studies, we are analyzing the genomic amplification events that occur in ARMS and are candidates for collaborating with the gene fusions in the molecular pathogenesis of ARMS. Using genome-wide screens for copy-number changes, we identified five chromosomal regions frequently amplified in ARMS (1p36, 2p24, 12q13-q14, 13q14, and 13q31). Following determination of the minimal common region of amplification, the involved genes in these regions were identified from the corresponding human genome sequence). The expression of these genes was assessed to determine which genes are commonly overexpressed, and are candidate target genes of these amplification events. Our future studies will assess the interactions of these genes with PAX3-FKHR or PAX7-FKHR and the phenotypic consequences of overexpression of these genes in ARMS.

To investigate the utility of these chromosomal alterations in the diagnosis and management of rhabdomyosarcoma, I have also established a translational research program focusing on molecular approaches for detection and monitoring of these genetic alterations in clinical material. To simplify detection of typical and variant fusions, my laboratory developed real-time PCR-based protocols in which both fusions can be detected and differentiated in a single protocol. As part of collaborations, we helped to established in situ hybridization-based assays for the various amplicons in rhabdomyosarcoma. Our initial studies with the gene fusions in ARMS and other pediatric sarcomas indicated that the genetic categories correspond closely to the standard histopathologic categories, and thus the molecular assays are sensitive, specific, and efficient tools for differential diagnosis. Our subsequent comparison of the clinical characteristics of ARMS cases with different fusion subtypes revealed significant differences, and thus indicated the importance of these molecular assays in the identification of clinically distinct subgroups. In current studies, we are examining the clinical significance of the amplification events and have recently found that the 12q13-q14 amplicon is associated with a poor outcome set of PAX3-FKHR-positive ARMS tumors. In contrast, the 13q14 amplicon, which is associated with amplification of PAX7-FKHR and less commonly PAX3-FKHR is predictive of a good outcome set of fusion-positive tumors. Larger studies are now being planned to better integrate the gene fusions and amplicons into the risk stratification model for management of ARMS patients. Finally, we have shown that high sensitivity PCR assays are capable of identifying submicroscopic metastatic disease in sites such as the bone marrow. To evaluate the clinical significance of detection of such submicroscopic disease in rhabdomyosarcoma patients, we are also working with the Children’s Oncology Group to collect bone marrow and peripheral blood samples from rhabdomyosarcoma patients to conduct a large study of the predictive value of minimal disease in patients with clinically localized disease.

Selected Publications

Zhang, P.J. Goldblum, J.R., Pawel, B.R., Pasha, T., Fisher, C., Barr, F.G.: PDGF-A, PDGF-Rb, TGFb3 and bone morphogenic protein-4 in desmoplastic small round cell tumors with EWS-WT1 gene fusion product and their role in stromal desmoplasia:an immunohistochemical study. Modern Path. 18: 382-7, 2005.

Du, S., Lawrence, E.J., Strzelecki, D., Rajput, P., Xia, S.J., Gottesman, D.M., Barr, F.G. : Co-expression of alternatively spliced forms of PAX3, PAX7, PAX3-FKHR, and PAX7-FKHR with distinct DNA binding and transactivation properties in rhabdomyosarcoma. Int. J. Cancer 115: 85-92, 2005.

Blandford, M., Barr, F.G., Lynch, J.C., Randall, R.L., Capecchi, M.R., Keller, C.: Rhabdomyosarcomas utilize developmental myogenic growth factors for disease advantage. Ped. Blood Cancer 46: 329-38, 2006.

Mercado, G.E., Barr, F.G.: : Looking downstream of sarcoma-associated chimeric transcription factors - When is a target really a target? Cancer Biol. Ther. 4: 456-458, 2005.

Xia, S.J., Barr F.G.: Oncogenic transcription factors resulting from chromosome translocations in sarcomas. Eur. J. Cancer 41: 2513-2527, 2005.

Zhang, P.J., Pawel, B., Pasha, T., Barr, F.G. : D2-40 is a useful marker for subtyping rhabdomyosarcoma. Modern Pathol. 18: 23A, 2005.

Lae, M., Edgar, M., Chuai, S., Olshen, A.B., Pawel, B.R., Barr, F.G., Ladanyi, M.: Global gene expression profiling of alveolar and embryonal rhabdomyosarcoma. Modern Pathol. 18: 305A, 2005.

Nishio, J., Althof, P., Bailey, J., Zhou, M,. Neff, J.R., Barr, F., Parham, D., Qualman, S., Bridge, J.A. : Use of FISH on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma (ARMS). Modern Pathol. 18: 305A-306A, 2005.

Mercado, G.E., Barr, F.G., Zhang, P.J.L., Pawel, B.R.: Identification of downstream targets of the PAX3-FKHR fusion oncoprotein that are differentially expressed between alveolar and embryonal rhabdomyosarcoma. Proc. Am. Assoc. Cancer Res. 46: 456, 2005.

Xia, S.J., Barr, F.G.: The paired-box domain of the fusion oncoprotein PAX3-FKHR suppressed oncogenic activity. Proc. Am. Assoc. Cancer Res. 46:: 1439-1440, 2005.

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Last updated: 07/06/2011
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