Darell Doty Bigner, M.D., Ph.D.

Chief, Division of Experimental Pathology

Edwin L. Jones, Jr. and Lucille Finch Jones Cancer Research Professor of Pathology

Department:
Pathology

Division:
Pathology Research

Email:
bigne001mcdukeedu

Mailing Address:
Box 3156, DUMC
Durham, NC 27710

Telephone:
919-684-5018

Training:
M.D., Duke University School of MedicinePh.D., Duke University

Last Updated:
October 26, 2006

Research Interests:
The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS).

There are over 100,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma.  An estimated 43,800 cases of primary brain tumors were expected to be diagnosed last year.  Of that number, approximately 3,410 diagnosed will be children less than 19 years of age.  During the last 20 years, however, there has been a significant increase in survival rates for those with primary malignant brain tumors.  In 2000, approximately 359,000 people in the United States were living after the diagnosis of a primary brain tumor.  

For the last 35 years my research has involved the investigation of the causes, mechanismof transformation and altered growth control, and development of new methods of therapy for primary brain tumors and those metastasizing to the CNS and its coverings.  In collaboration with my colleagues in the Preston Robert Tisch Brain Tumor Center, new drugs and those not previously thought to be active against CNS tumors have been identified.  Overcoming mechanisms of drug resistance in primary brain tumors is also being pursued.

As Director of the Preston Robert Tisch Brain Tumor Center and the Pediatric Brain Tumor Foundation Institute at Duke and Leader of the Neuro-Oncology Program of the Duke Comprehensive Cancer Center, I coordinate the research activities of all 37 faculty members in the Brain Tumor Center and Neuro-Oncology Program.  These faculty members have projects ranging from very basic research into molecular etiology, molecular epidemiology, signal transduction; translational research performing pre-clinical evaluation of new therapies, and many clinical investigative efforts.  I can describe any of the Brain Tumor Center faculty member’s research to third year students and then direct them to specific faculty members with whom the students would like a discussion.  

My personal research over the last 20 years has focused on molecularly targeted therapy of primary and metastatic CNS tumors with monoclonal antibodies and their fragments.  Our most advanced study is now in Phase III randomized trial with a molecule we discovered many years ago, the extracellular matrix molecule, Tenascin.  A randomized multi-institutional Phase III trial with 131I-radiolabeled anti-tenascin monoclonal antibody 81C6 will begin April 1st with Duke being the lead institution in those trials.  In January 2007, we expect to have a Food and Drug Administration Investigational New Drug Permit for an immunotoxin composed of a single fragment chain antibody fragment genetically conjugated to pseudomonas toxin.  The targeted molecule is a constitutively active mutant of the wild type epidermal growth factor receptor that we call EGFRvIII, which has a tumor-specific epitope.  This immunotoxin will be administered by catheters and slow infusion directly around the resection cavity of malignant gliomas.  The first trial will be a Phase I safety efficacy and dose escalation trial.  

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain.  These include glycoprotein non-metastatic B (GPNMB), a molecule shared with malignant melanoma; MRP3, a member of the multidrug resistant family; and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1, which are heavily expressed in developing brain but are only re-expressed on malignant brain tumors with no expression on normal adult brain.  We are raising conventional monoclonal antibodies against all of these targets as well as developing single fragment chain molecules from naïve human libraries.  When necessary, affinity maturation in vitro is carried out and the antibodies and fragments are armed either with radioactive iodine, radioactive lutetium, or radioactive Astatine-211.  Other constructs are evaluated for unarmed activity and some are armed with pseudomonas exotoxin.  After development of the constructs, they are evaluated in human malignant glioma xenograft systems and then all studies necessary for Investigational New Drug Permits from the Food and Drug Administration are carried out prior to actual clinical trial.  

The first fully funded Specialized Research Center on Primary and Metastatic Tumors to the CNS funded by the National Institutes of Health, of which I am Principal Investigator, is currently in its 26th year of continuous funding.  My NCI MERIT Award, which ranked in the upper 1.2 percentile of all NIH grants at the time of its last review, is currently in its 36th year of continuous funding.  I am also Principal Investigator of one of only four SPORE (Specialized Program of Research Excellence) grants in brain cancer, currently in its third year of funding from the National Cancer Institute.  I am the Director of the Pediatric Brain Tumor Foundation Institute at Duke, which was established in 2003 and supported by the $6 million grant from the Foundation for research on childhood brain tumors.  In addition to the representative publications listed, I have made 5 national presentations and 6 international presentations during the past year.

My laboratory has trained over 50 third year medical students, residents, Ph.D. students, and postdoctoral fellows and has a great deal of experience in career development with some students having advanced all the way from fellowship status to endowed professorships.  A major goal with third year medical students is to perform work that can be presented in abstract form at national or international meetings and to obtain publication in major peer-reviewed journals.

Publications:
2002 -- Pubmed # 11870184 -- Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, Herndon JE 2nd, Cokgor I, McLendon RE, Pegram CN, Provenzale JM, Quinn JA, Rich JN, Regalado LV, Sampson JH, Shafman TD, Wikstrand CJ, Wong TZ, Zhao XG, Zalutsky MR, Bigner DD. Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol. 2002 Mar 1;20(5):1389-97.

2000 -- Sampson, J.H., Crotty, L.E., Lee, S., Archer, G.E., Ashley, D.M., Wikstrand, C.J., Hale, L.P., Small, C., Dranoff, G., Friedman, A.H., Friedman, H.S., and Bigner, D.D.: Unarmed, tumor-specific, monoclonal antibody effectively treats brain tumors. Proc. Natl. Acad. Sci. USA 97(13): 7503-7508, 2000.

1998 -- Bigner DD, McLendon R, and Bruner J, eds.: Russell and Rubinstein's Pathology of Tumors of the Nervous System, sixth edition. Arnold, London, 1998.

1998 -- Bigner, D.D., Brown, M.T., Friedman, A.H., Coleman, R.E., Akabani, G., Friedman, H.S., Thorstad, W.L., McLendon, R.E., Bigner, S.H., Zhao, X.-G., Pegram, C.N., Wikstrand, C.J., Herndon, II J.D., Vick, N.A., Paleologos, N., Cokgor, I., Provenzale, J.M., and Zalutsky, M.R.: Iodine-131-labeled anti-tenascin in monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: Phase I trial results. J. Clin. Oncol. 16: 2202-2212, 1998.

1995 -- Wikstrand, C.J., Hale, L.P., Batra, S.K., Hill, M.L., Humphrey, P.A., Kurpad, S.N., McLendon, R.E., Moscatello, D., Pegram, C.N., Reist, C.J., Traweek, S.T., Wong, A.J., Zalutsky, M.R., and Bigner, D.D.: Monoclonal antibodiesagainst EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas. Cancer Res. 55: 3140-3148, 1995.