Stephen Keir

Overview:

Brain Tumors, Preclinical Testing, Translational Research

Positions:

Professor in Neurosurgery

Neurosurgery, Neuro-Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.P.H. 2001

University of North Carolina - Chapel Hill

DrPH 2004

University of North Carolina - Chapel Hill

M.M.C.i. 2019

Duke University

Grants:

Evaluation of Panobinostat in Patient Derived Adult IDH1 Mutated Brain Tumor Xenografts

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
Midatech Pharma Plc
Role
Principal Investigator
Start Date
End Date

Assessment of ST101 in Glioblastoma

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
Sapience Therapeutics Inc.
Role
Principal Investigator
Start Date
End Date

Truncated GLI1 In Glioblastoma

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

Oncolytic Viral Therapy in Brain Tumor Setting

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
ImmVira Pharma Co., Ltd.
Role
Principal Investigator
Start Date
End Date

Evaluation of Cannabinoid Therapeutics in Brain Tumor Xenografts

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

Publications:

A Therapeutic Antibody for Cancer, Derived from Single Human B Cells.

Some patients with cancer never develop metastasis, and their host response might provide cues for innovative treatment strategies. We previously reported an association between autoantibodies against complement factor H (CFH) and early-stage lung cancer. CFH prevents complement-mediated cytotoxicity (CDC) by inhibiting formation of cell-lytic membrane attack complexes on self-surfaces. In an effort to translate these findings into a biologic therapy for cancer, we isolated and expressed DNA sequences encoding high-affinity human CFH antibodies directly from single, sorted B cells obtained from patients with the antibody. The co-crystal structure of a CFH antibody-target complex shows a conformational change in the target relative to the native structure. This recombinant CFH antibody causes complement activation and release of anaphylatoxins, promotes CDC of tumor cell lines, and inhibits tumor growth in vivo. The isolation of anti-tumor antibodies derived from single human B cells represents an alternative paradigm in antibody drug discovery.
Authors
Bushey, RT; Moody, MA; Nicely, NL; Haynes, BF; Alam, SM; Keir, ST; Bentley, RC; Roy Choudhury, K; Gottlin, EB; Campa, MJ; Liao, H-X; Patz, EF
MLA Citation
Bushey, Ryan T., et al. “A Therapeutic Antibody for Cancer, Derived from Single Human B Cells.Cell Rep, vol. 15, no. 7, May 2016, pp. 1505–13. Pubmed, doi:10.1016/j.celrep.2016.04.038.
URI
https://scholars.duke.edu/individual/pub1132020
PMID
27160908
Source
pubmed
Published In
Cell Reports
Volume
15
Published Date
Start Page
1505
End Page
1513
DOI
10.1016/j.celrep.2016.04.038

Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas.

Frequent mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and the promoter of telomerase reverse transcriptase (TERT) represent two significant discoveries in glioma genomics. Understanding the degree to which these two mutations co-occur or occur exclusively of one another in glioma subtypes presents a unique opportunity to guide glioma classification and prognosis. We analyzed the relationship between overall survival (OS) and the presence of IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas. We hypothesized and show that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. Analyzing gliomas based on their genetic signatures allows for the stratification of these patients into distinct cohorts, with unique prognosis and survival.
Authors
Killela, PJ; Pirozzi, CJ; Healy, P; Reitman, ZJ; Lipp, E; Rasheed, BA; Yang, R; Diplas, BH; Wang, Z; Greer, PK; Zhu, H; Wang, CY; Carpenter, AB; Friedman, H; Friedman, AH; Keir, ST; He, J; He, Y; McLendon, RE; Herndon, JE; Yan, H; Bigner, DD
MLA Citation
Killela, Patrick J., et al. “Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas.Oncotarget, vol. 5, no. 6, Mar. 2014, pp. 1515–25. Pubmed, doi:10.18632/oncotarget.1765.
URI
https://scholars.duke.edu/individual/pub1027276
PMID
24722048
Source
pubmed
Published In
Oncotarget
Volume
5
Published Date
Start Page
1515
End Page
1525
DOI
10.18632/oncotarget.1765

Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model.

Glioblastoma multiforme (GBM) is a devastating disease with a dismal prognosis and a very limited response to treatment. The current standard of care for GBM usually consists of surgery, radiation and chemotherapy with the alkylating agent temozolomide, although resistance to this drug is common. The predominant mechanism of action of temozolomide is methylation of guanine residues although this can be reversed by methylguanine methyltransferase (MGMT) as well as other DNA repair systems. The presence of methylguanine causes abortive DNA synthesis with subsequent apoptosis. This suggests that the closer a particular cell is to S phase when it is exposed to temozolomide the more likely it is to die since repair enzymes will have had less time to reverse the damage. T type calcium channel inhibitors can stop the entry of extracellular calcium that is necessary for transit past the G1/S boundary. As a result, T type calcium channel blockers can slow the growth of cancer cells, but do not generally kill them. Though slowing the growth of cancer cells is important in its own right, it also provides a therapeutic strategy in which a T type channel blocker is administered then withdrawn followed by the administration of temozolomide. We show here that imposing this cell cycle restriction increases the efficacy of subsequently administered temozolomide in immunodeficient mice bearing various human GBM xenograft lines. We also present data that MGMT expressing GBM tumors, which are temozolomide resistant, may be rendered more sensitive by this strategy.
Authors
Keir, ST; Friedman, HS; Reardon, DA; Bigner, DD; Gray, LA
MLA Citation
Keir, Stephen T., et al. “Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model.J Neurooncol, vol. 111, no. 2, Jan. 2013, pp. 97–102. Pubmed, doi:10.1007/s11060-012-0995-0.
URI
https://scholars.duke.edu/individual/pub760899
PMID
23086436
Source
pubmed
Published In
J Neurooncol
Volume
111
Published Date
Start Page
97
End Page
102
DOI
10.1007/s11060-012-0995-0

Initial testing (stage 1) of LCL161, a SMAC mimetic, by the Pediatric Preclinical Testing Program.

LCL161, a SMAC mimetic, was tested against the PPTP in vitro panel (1.0 nM to 10.0 µM) and the PPTP in vivo panels (30 or 75 mg/kg [solid tumors] or 100 mg/kg [ALL]) administered orally twice in a week. LCL161 showed a median relative IC(50) value of >10 µM, being more potent against several leukemia and lymphoma lines. In vivo LCL161 induced significant differences in EFS distribution in approximately one-third of solid tumor xenografts (osteosarcoma and glioblastoma), but not in ALL xenografts. No objective tumor responses were observed. In vivo LCL161 demonstrated limited single agent activity against the pediatric preclinical models studied.
Authors
Houghton, PJ; Kang, MH; Reynolds, CP; Morton, CL; Kolb, EA; Gorlick, R; Keir, ST; Carol, H; Lock, R; Maris, JM; Billups, CA; Smith, MA
MLA Citation
Houghton, Peter J., et al. “Initial testing (stage 1) of LCL161, a SMAC mimetic, by the Pediatric Preclinical Testing Program.Pediatr Blood Cancer, vol. 58, no. 4, Apr. 2012, pp. 636–39. Pubmed, doi:10.1002/pbc.23167.
URI
https://scholars.duke.edu/individual/pub780279
PMID
21681929
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
58
Published Date
Start Page
636
End Page
639
DOI
10.1002/pbc.23167

Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas.

INTRODUCTION: Podoplanin/aggrus is a mucin-like sialoglycoprotein that is highly expressed in malignant gliomas. Podoplanin has been reported to be a novel marker to enrich tumor-initiating cells, which are thought to resist conventional therapies and to be responsible for cancer relapse. The purpose of this study was to determine whether an anti-podoplanin antibody is suitable to target radionuclides to malignant gliomas. METHODS: The binding affinity of an anti-podoplanin antibody, NZ-1 (rat IgG(2a)), was determined by surface plasmon resonance and Scatchard analysis. NZ-1 was radioiodinated with (125)I using Iodogen [(125)I-NZ-1(Iodogen)] or N-succinimidyl 4-guanidinomethyl 3-[(131)I]iodobenzoate ([(131)I]SGMIB-NZ-1), and paired-label internalization assays of NZ-1 were performed. The tissue distribution of (125)I-NZ-1(Iodogen) and that of [(131)I]SGMIB-NZ-1 were then compared in athymic mice bearing glioblastoma xenografts. RESULTS: The dissociation constant (K(D)) of NZ-1 was determined to be 1.2 × 10(-10) M by surface plasmon resonance and 9.8 × 10(-10) M for D397MG glioblastoma cells by Scatchard analysis. Paired-label internalization assays in LN319 glioblastoma cells indicated that [(131)I]SGMIB-NZ-1 resulted in higher intracellular retention of radioactivity (26.3 ± 0.8% of initially bound radioactivity at 8 h) compared to that from the (125)I-NZ-1(Iodogen) (10.0 ± 0.1% of initially bound radioactivity at 8 h). Likewise, tumor uptake of [(131)I]SGMIB-NZ-1 (39.9 ± 8.8 %ID/g at 24 h) in athymic mice bearing D2159MG xenografts in vivo was significantly higher than that of (125)I-NZ-1(Iodogen) (29.7 ± 6.1 %ID/g at 24 h). CONCLUSIONS: The overall results suggest that an anti-podoplanin antibody NZ-1 warrants further evaluation for antibody-based therapy against glioblastoma.
Authors
Kato, Y; Vaidyanathan, G; Kaneko, MK; Mishima, K; Srivastava, N; Chandramohan, V; Pegram, C; Keir, ST; Kuan, C-T; Bigner, DD; Zalutsky, MR
MLA Citation
Kato, Yukinari, et al. “Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas.Nucl Med Biol, vol. 37, no. 7, Oct. 2010, pp. 785–94. Pubmed, doi:10.1016/j.nucmedbio.2010.03.010.
URI
https://scholars.duke.edu/individual/pub736708
PMID
20870153
Source
pubmed
Published In
Nucl Med Biol
Volume
37
Published Date
Start Page
785
End Page
794
DOI
10.1016/j.nucmedbio.2010.03.010