Darell Doty Bigner

Darell Doty Bigner
E. L. and Lucille F. Jones Cancer Research Professor, in the School of Medicine
Cell and Molecular Biology Program (CMB)
Campus mail: 177 Med Sci Res Bldg, Durham, NC 27710
Phone: (919) 684-5018

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.

For the last 44 years my research has involved the investigation of the causes, mechanism of 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 are 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 25 years has focused on molecularly targeted therapy of primary and metastatic CNS tumors with monoclonal antibodies and their fragments. Our most advanced study is with a molecule we discovered many years ago, the extracellular matrix molecule, Tenascin. We have treated over 150 malignant brain tumor patients with excellent results with a radiolabeled antibody we developed against Tenascin. We currently 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 is being administered by catheters and slow infusion directly around the resection cavity of malignant gliomas. The first trial is a Phase I safety, efficacy, and dose escalation trial. I have just published, in the Journal of Clinical Oncology, a promising vaccine trial for glioblastoma with intradermal injections of a peptide of EGFRvIII.

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 and chondroitin proteoglycan sulfate, 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.

I was senior author on a New England Journal of Medicine paper that was the first to show markedly increased survival in low to intermediate grade gliomas with an isocitrate dehydrogenase mutation.

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 27th 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 40th year of continuous funding. It is one of the few MERIT awards awarded three consecutive times, and it is the longest continually funded grant of the NCI Division of Cancer Diagnosis and Treatment. I am the Director of the Pediatric Brain Tumor Foundation Institute at Duke, which was established in 2003 and is supported by a $12 million grant from the Foundation for research on childhood brain tumors.

In addition to the representative publications listed, I have made national presentations and international presentations during the past year.

My laboratory has trained over 50 third year medical students, residents, Ph.D. students, and postdoctoral fellows and I have 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.

Education and Training

  • Duke University, M.D. 1965
  • Duke University, Ph.D. 1971
  • Duke University, Intern, Surgery
  • Duke University, Fellow, Neurological Surgery
  • National Institutes of Health, Clinical Associate, Medical Neurology

Selected Grants and Awards