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

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:

Cold Plasma Discharge Tube Enhances Antitumoral Efficacy of Temozolomide.

Glioblastoma (GBM) is a fatal human brain tumor with a low survival rate. Temozolomide (TMZ) has been widely used in GBM therapy with noticeable side effects. Cold plasma is an ionized gas that is generated near room temperature. Here, we demonstrated the enhancement therapeutic efficacy of TMZ via using a cold plasma source based on nonequilibrium plasma in a sealed glass tube, named a radial cold plasma discharge tube (PDT). The PDT affected glioblastoma cells' function just by its electromagnetic (EM) emission rather than any chemical factors in the plasma. The PDT selectively increased the cytotoxicity of TMZ on two typical glioblastoma cell lines, U87MG and A172, compared with normal astrocyte cell line hTERT/E6/E7 to some extent. Furthermore, on the basis of a patient-derived xenograft model, our preliminary in vivo studies demonstrated the drastically improved mean survival days of the tumor-barrier mice by more than 100% compared to control. The PDT is not only independent of continuous helium supply but is also capable of resisting the interference of environmental changes. Thus, the PDT was a stable and low-cost cold atmospheric plasma source. In short, this study is the first to demonstrate the promising application of PDTs in GBM therapy as a noninvasive and portable modality.
Authors
Yao, X; Yan, D; Lin, L; Sherman, JH; Peters, KB; Keir, ST; Keidar, M
MLA Citation
Yao, Xiaoliang, et al. “Cold Plasma Discharge Tube Enhances Antitumoral Efficacy of Temozolomide.Acs Appl Bio Mater, vol. 5, no. 4, Apr. 2022, pp. 1610–23. Pubmed, doi:10.1021/acsabm.2c00018.
URI
https://scholars.duke.edu/individual/pub1513625
PMID
35324138
Source
pubmed
Published In
Acs Applied Bio Materials
Volume
5
Published Date
Start Page
1610
End Page
1623
DOI
10.1021/acsabm.2c00018

Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas.

PURPOSE: To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of Gamitrinib in gliomas. EXPERIMENTAL DESIGN: A broad panel of primary and temozolomide (TMZ)-resistant human glioma cell lines were screened by cell viability assays, flow cytometry, and crystal violet assays to investigate the therapeutic efficacy of Gamitrinib. Seahorse assays were used to measure the mitochondrial respiration of glioma cells. Integrated analyses of RNA sequencing (RNAseq) and reverse phase protein array (RPPA) data were performed to reveal the potential antitumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDO), cell line-derived xenografts (CDX), and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib. RESULTS: Gamitrinib inhibited cell proliferation and induced cell apoptosis and death in 17 primary glioma cell lines, 6 TMZ-resistant glioma cell lines, 4 neurospheres, and 3 PDOs. Importantly, Gamitrinib significantly delayed the tumor growth and improved survival of mice in both CDX and PDX models in which tumors were either subcutaneously or intracranially implanted. Integrated computational analyses of RNAseq and RPPA data revealed that Gamitrinib exhibited its antitumor activity via (i) suppressing mitochondrial biogenesis, OXPHOS, and cell-cycle progression and (ii) activating the energy-sensing AMP-activated kinase, DNA damage, and stress response. CONCLUSIONS: These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary antitumor mechanisms in gliomas.
Authors
Wei, S; Yin, D; Yu, S; Lin, X; Savani, MR; Du, K; Ku, Y; Wu, D; Li, S; Liu, H; Tian, M; Chen, Y; Bowie, M; Hariharan, S; Waitkus, M; Keir, ST; Sugarman, ET; Deek, RA; Labrie, M; Khasraw, M; Lu, Y; Mills, GB; Herlyn, M; Wu, K; Liu, L; Wei, Z; Flaherty, KT; Abdullah, K; Zhang, G; Ashley, DM
MLA Citation
Wei, Shiyou, et al. “Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas.Clin Cancer Res, vol. 28, no. 10, May 2022, pp. 2180–95. Pubmed, doi:10.1158/1078-0432.CCR-21-0833.
URI
https://scholars.duke.edu/individual/pub1511921
PMID
35247901
Source
pubmed
Published In
Clinical Cancer Research
Volume
28
Published Date
Start Page
2180
End Page
2195
DOI
10.1158/1078-0432.CCR-21-0833

A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.

<h4>Purpose</h4>To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2'-deoxyguanosine (THIO) in gliomas both <i>in vitro</i> and <i>in vivo</i>.<h4>Experimental design</h4>A panel of human and mouse glioma cell lines was used to test therapeutic efficacy of THIO using cell viability assays, flow cytometric analyses, and immunofluorescence. Integrated analyses of RNA sequencing and reverse-phase protein array data revealed the potential antitumor mechanisms of THIO. Four patient-derived xenografts (PDX), two patient-derived organoids (PDO), and two xenografts of human glioma cell lines were used to further investigate the therapeutic efficacy of THIO.<h4>Results</h4>THIO was effective in the majority of human and mouse glioma cell lines with no obvious toxicity against normal astrocytes. THIO as a monotherapy demonstrated efficacy in three glioma cell lines that had acquired resistance to temozolomide. In addition, THIO showed efficacy in four human glioma cell lines grown as neurospheres by inducing apoptotic cell death. Mechanistically, THIO induced telomeric DNA damage not only in glioma cell lines but also in PDX tumor specimens. Integrated computational analyses of transcriptomic and proteomic data indicated that THIO significantly inhibited cell invasion, stem cell, and proliferation pathways while triggering DNA damage and apoptosis. Importantly, THIO significantly decreased tumor proliferation in two PDO models and reduced the tumor size of a glioblastoma xenograft and a PDX model.<h4>Conclusions</h4>The current study established the therapeutic role of THIO in primary and recurrent gliomas and revealed the acute induction of telomeric DNA damage as a primary antitumor mechanism of THIO in gliomas.
Authors
Yu, S; Wei, S; Savani, M; Lin, X; Du, K; Mender, I; Siteni, S; Vasilopoulos, T; Reitman, ZJ; Ku, Y; Wu, D; Liu, H; Tian, M; Chen, Y; Labrie, M; Charbonneau, CM; Sugarman, E; Bowie, M; Hariharan, S; Waitkus, M; Jiang, W; McLendon, RE; Pan, E; Khasraw, M; Walsh, KM; Lu, Y; Herlyn, M; Mills, G; Herbig, U; Wei, Z; Keir, ST; Flaherty, K; Liu, L; Wu, K; Shay, JW; Abdullah, K; Zhang, G; Ashley, DM
MLA Citation
Yu, Shengnan, et al. “A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, vol. 27, no. 24, Dec. 2021, pp. 6800–14. Epmc, doi:10.1158/1078-0432.ccr-21-0374.
URI
https://scholars.duke.edu/individual/pub1497999
PMID
34593527
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
27
Published Date
Start Page
6800
End Page
6814
DOI
10.1158/1078-0432.ccr-21-0374

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