Contact Information


DUMC 3156
Durham, NC 27713
Phone: 919-684-5018
Email

Bigner Lab

Bigner Lab

Darell Doty Bigner, MD, PhD

Professor of Pathology

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.

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.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brains. These include EGFRwt; EGFRvIII; and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate, which are heavily expressed in developing brains but are only re-expressed on malignant brain tumors with no expression on normal adult brains. We raised conventional monoclonal antibodies against all of these targets as well as developed single fragment chain molecules from naïve human libraries.

My personal research focuses on molecularly targeted therapies of primary and metastatic CNS tumors with monoclonal antibodies and their fragments. One study we conducted was 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 are collaborating with Dr. Ira Pastan at NIH to develop tumor-targeted therapies by fusing single fragment chain molecules from monoclonal antibodies or from naïve human libraries to the truncated fragment of Pseudomonas exotoxin A. One example of this is the pseudomonas exotoxin conjugated to a single fragment chain antibody that reacts with wild type EGFR and EGFRvIII, two overexpressed proteins on glioblastoma. The immunotoxin, called D2C7-IT, is currently being investigated in an FDA dose-escalation study, in which patients undergoing treatment of this investigational new drug are showing positive responses. My laboratory is also working with Dr. Matthias Gromeier, creator of the oncolytic poliovirus—a re-engineered poliovirus that is lethal to cancer cells but non-lethal to normal cells. The oncolytic poliovirus therapeutic approach has shown such promising results in patients with glioblastoma that it was recently featured on a special two-segment program of 60 Minutes. The next clinical step will be to combine both the virus and the immunotoxin with anti-PD1, an immune checkpoint blockade inhibitor. We believe that regional tumor-targeted cytotoxic therapies, such as the oncolytic poliovirus and the D2C7 immunotoxin, not only specifically target and destroy tumor cells, but in the process initiate immune events that promote an in situ vaccine effect, which can be amplified by human checkpoint blockades to engender a long-term systemic immune response that effectively eliminates recurrent and disseminated GBM cells. Ultimately, all three agents may be used together, providing different antigenic targets and cytotoxicity mechanisms.

Publications

Conference Papers

Journal Articles

Other Articles

  • Rasheed, BK, McLendon, RE, Friedman, HS, Friedman, AH, Fuchs, HE, Bigner, DD, and Bigner, SH. "Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25." Oncogene 10, no. 11 (June 1, 1995): 2243-2246.  Link to Item
  • Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; 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. Journal of Clinical Oncology. 2002;20:1389-1397.  Abstract