Darell Bigner

Overview:

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 16,000 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 80,000 cases of primary brain tumors were expected to be diagnosed last year. Of that number, approximately 4,600 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 the founding Director of the Preston Robert Tisch Brain Tumor Center, I help coordinate the research activities of all 37 faculty members in the Brain Tumor Center. 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 brain. These include EGFRwt, EGFRvIII, and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We raised conventional and fully human monoclonal antibodies against most of these targets as well as having 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. Our 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 Matthias Gromeier, creator of the oncolytic poliovirus - a re-engineered poliovirus that is lethal to cancer cells, but not 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 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 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. That immune response can be amplified by human checkpoint blockade 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.

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. 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.

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.

Positions:

E. L. and Lucille F. Jones Cancer Distinguished Research Professor, in the School of Medicine

Neurosurgery
School of Medicine

Professor of Neurosurgery

Neurosurgery
School of Medicine

Chief, Division of Experimental Pathology

Pathology
School of Medicine

Professor of Surgery

Surgery
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1965

Duke University

Ph.D. 1971

Duke University

Intern, Surgery

Duke University

Fellow, Neurological Surgery

Duke University

Clinical Associate, Medical Neurology

National Institutes of Health

Grants:

NCI Howard Temin Award (K01) Transition

Administered By
Surgery, Surgical Sciences
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Anti-tumor efficacy of EGFR-targeting immunotoxin in combination with CCNU or PD-L1 blockade in glioma mouse models

Administered By
Neurosurgery, Neuro-Oncology
Role
Principal Investigator
Start Date
End Date

Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Oncolytic PVSRIPO Expressing Tumor Antigens as a Cancer Vaccine

Administered By
Neurosurgery
Role
Significant Contributor
Start Date
End Date

Oncolytic Poliovirus Immunotherapy of Malignant Glioma

Administered By
Pathology
Role
Principal Investigator
Start Date
End Date

Publications:

Oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG): Experience with retreatment of survivors from the phase I trial.

Authors
Desjardins, A; Gromeier, M; Herndon, JE; Randazzo, D; Threatt, S; Lipp, ES; Miller, ES; Jackman, J; Bolognesi, DP; Friedman, AH; Friedman, HS; McSherry, F; Peters, KB; Johnson, MO; Sampson, JH; Ashley, DM; Bigner, DD
MLA Citation
Desjardins, Annick, et al. “Oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG): Experience with retreatment of survivors from the phase I trial..” Journal of Clinical Oncology, vol. 37, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2019, pp. 2060–2060. Crossref, doi:10.1200/jco.2019.37.15_suppl.2060.
URI
https://scholars.duke.edu/individual/pub1415615
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
37
Published Date
Start Page
2060
End Page
2060
DOI
10.1200/jco.2019.37.15_suppl.2060

DOSE ESCALATION TRIAL OF D2C7 IMMUNOTOXIN (D2C7-IT) ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMA (MG)

Authors
Desjardins, A; Randazzo, D; Chandramohan, V; Peters, K; Johnson, M; Thomas, L; Threatt, S; Bullock, C; Herndon, J; Boulton, S; Healy, P; Lipp, E; Sampson, J; Friedman, A; Friedman, H; Ashley, D; Bigner, D
MLA Citation
URI
https://scholars.duke.edu/individual/pub1375566
Source
wos
Published In
Neuro Oncology
Volume
20
Published Date
Start Page
9
End Page
9

PHASE 1B STUDY POLIO VACCINE SABIN-RHINOVIRUS POLIOVIRUS (PVSRIPO) FOR RECURRENT MALIGNANT GLIOMA IN CHILDREN

Authors
Ashley, DM; Thompson, EM; Landi, D; Desjardins, A; Friedman, AH; Threatt, S; Herndon, JE; Boulton, S; McSherry, F; Lipp, ES; Sampson, JH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Ashley, David M., et al. “PHASE 1B STUDY POLIO VACCINE SABIN-RHINOVIRUS POLIOVIRUS (PVSRIPO) FOR RECURRENT MALIGNANT GLIOMA IN CHILDREN.” Neuro Oncology, vol. 20, OXFORD UNIV PRESS INC, 2018, pp. 93–93.
URI
https://scholars.duke.edu/individual/pub1335932
Source
wos
Published In
Neuro Oncology
Volume
20
Published Date
Start Page
93
End Page
93

Patient-derived DIPG cells preserve stem-like characteristics and generate orthotopic tumors.

Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor, with a median survival of less than one year. Due to enormous difficulties in the acquisition of DIPG specimens and the sophisticated technique required to perform brainstem orthotopic injection, only a handful of DIPG pre-clinical models are available. In this study, we successfully established eight patient-derived DIPG cell lines, mostly derived from treatment-naïve surgery or biopsy specimens. These patient-derived cell lines can be stably passaged in serum-free neural stem cell media and displayed distinct morphologies, growth rates and chromosome abnormalities. In addition, these cells retained genomic hallmarks identical to original human DIPG tumors. Notably, expression of several neural stem cell lineage markers was observed in DIPG cell lines. Moreover, three out of eight cell lines can form orthotopic tumors in mouse brainstem by stereotactic injection and these tumors faithfully represented the characteristics of human DIPG by magnetic resonance imaging (MRI) and histopathological staining. Taken together, we established DIPG pre-clinical models resembling human DIPG and they provided a valuable resource for future biological and therapeutic studies.
Authors
Xu, C; Liu, X; Geng, Y; Bai, Q; Pan, C; Sun, Y; Chen, X; Yu, H; Wu, Y; Zhang, P; Wu, W; Wang, Y; Wu, Z; Zhang, J; Wang, Z; Yang, R; Lewis, J; Bigner, D; Zhao, F; He, Y; Yan, H; Shen, Q; Zhang, L
MLA Citation
Xu, Cheng, et al. “Patient-derived DIPG cells preserve stem-like characteristics and generate orthotopic tumors..” Oncotarget, vol. 8, no. 44, Sept. 2017, pp. 76644–55. Pubmed, doi:10.18632/oncotarget.19656.
URI
https://scholars.duke.edu/individual/pub1284336
PMID
29100338
Source
pubmed
Published In
Oncotarget
Volume
8
Published Date
Start Page
76644
End Page
76655
DOI
10.18632/oncotarget.19656

Development and validation of a cell-based fluorescent method for measuring antibody affinity.

Monoclonal antibodies have become essential tools for diagnostic and therapeutic purposes. Antibody affinity is one of the critical factors influencing the therapeutic success of tumor-targeting antibodies. Therefore, developing an accurate and reliable method for determining antibody affinity is crucial. In this study, we describe a fluorescent cell-based immunosorbent assay that can accurately measure antibody affinity (KD) in the nanomolar range. This method involves the addition of fluorescently labeled antibodies to antigen-positive and antigen-negative cell lines fixed on 96-well plates. The fluorescent signals from nonspecific binding to negative control cell lines is subtracted from the specific binding to the antigen-positive cell lines. The KD values obtained by this method were comparable with values obtained by the flow cytometry and radioactive (I125) scatchard assay. Our results demonstrate that this modified cell-based fluorescent method allows for a convenient and efficient identification of therapeutically relevant leads.
Authors
Yu, X; Pegram, CN; Bigner, DD; Chandramohan, V
MLA Citation
Yu, Xin, et al. “Development and validation of a cell-based fluorescent method for measuring antibody affinity..” J Immunol Methods, vol. 442, Mar. 2017, pp. 49–53. Pubmed, doi:10.1016/j.jim.2016.12.004.
URI
https://scholars.duke.edu/individual/pub1163156
PMID
28024998
Source
pubmed
Published In
J Immunol Methods
Volume
442
Published Date
Start Page
49
End Page
53
DOI
10.1016/j.jim.2016.12.004