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 at Chapel Hill

DrPH 2004

University of North Carolina at Chapel Hill

Grants:

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

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

Assessment of ST101 in Glioblastoma

Administered By
Neurosurgery, Neuro-Oncology
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

Publications:

Correction: Reversing the Warburg effect as a treatment for glioblastoma.

Authors
Poteet, E; Choudhury, GR; Winters, A; Li, W; Ryou, M-G; Liu, R; Tang, L; Ghorpade, A; Wen, Y; Yuan, F; Keir, ST; Yan, H; Bigner, DD; Simpkins, JW; Yang, S-H
MLA Citation
Poteet, Ethan, et al. “Correction: Reversing the Warburg effect as a treatment for glioblastoma..” J Biol Chem, vol. 293, no. 39, Sept. 2018. Pubmed, doi:10.1074/jbc.AAC118.005625.
URI
https://scholars.duke.edu/individual/pub1353406
PMID
30266879
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
293
Published Date
Start Page
14973
DOI
10.1074/jbc.AAC118.005625

Dynamic treatment effect (DTE) curves reveal the mode of action for standard and experimental cancer therapies.

We present a method for estimating the empirical dynamic treatment effect (DTE) curves from tumor growth delay (TGD) studies. This improves on current common methods of TGD analysis, such as T/C ratio and doubling times, by providing a more detailed treatment effect and overcomes their lack of reproducibility. The methodology doesn't presuppose any prior form for the treatment effect dynamics and is shown to give consistent estimates with missing data. The method is illustrated by application to real data from TGD studies involving three types of therapy. Firstly, we demonstrate that radiotherapy induces a sharp peak in inhibition in a FaDu model. The height, duration and timing of the peak increase linearly with radiation dose. Second, we demonstrate that a combination of temozolomide and an experimental therapy in a glioma PDX model yields an effect, similar to an additive version of the DTE curves for the mono-therapies, except that there is a 30 day delay in peak inhibition. In the third study, we consider the DTE of anti-angiogenic therapy in glioma. We show that resulting DTE curves are flat. We discuss how features of the DTE curves should be interpreted and potentially used to improve therapy.
Authors
Choudhury, KR; Keir, ST; Ashcraft, KA; Boss, M-K; Dewhirst, MW
MLA Citation
Choudhury, Kingshuk Roy, et al. “Dynamic treatment effect (DTE) curves reveal the mode of action for standard and experimental cancer therapies..” Oncotarget, vol. 6, no. 16, June 2015, pp. 14656–68. Pubmed, doi:10.18632/oncotarget.4141.
URI
https://scholars.duke.edu/individual/pub1072663
PMID
25986925
Source
pubmed
Published In
Oncotarget
Volume
6
Published Date
Start Page
14656
End Page
14668
DOI
10.18632/oncotarget.4141

The integrated landscape of driver genomic alterations in glioblastoma.

Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.
Authors
Frattini, V; Trifonov, V; Chan, JM; Castano, A; Lia, M; Abate, F; Keir, ST; Ji, AX; Zoppoli, P; Niola, F; Danussi, C; Dolgalev, I; Porrati, P; Pellegatta, S; Heguy, A; Gupta, G; Pisapia, DJ; Canoll, P; Bruce, JN; McLendon, RE; Yan, H; Aldape, K; Finocchiaro, G; Mikkelsen, T; Privé, GG; Bigner, DD; Lasorella, A; Rabadan, R; Iavarone, A
MLA Citation
Frattini, Veronique, et al. “The integrated landscape of driver genomic alterations in glioblastoma..” Nat Genet, vol. 45, no. 10, Oct. 2013, pp. 1141–49. Pubmed, doi:10.1038/ng.2734.
URI
https://scholars.duke.edu/individual/pub960323
PMID
23917401
Source
pubmed
Published In
Nat Genet
Volume
45
Published Date
Start Page
1141
End Page
1149
DOI
10.1038/ng.2734

Malcolm A. Smith, John M. Maris, Richard Gorlick, E. Anders Kolb, Richard Lock, Hernan Carol, Stephen T. Keir, C. Patrick Reynolds, Min H. Kang, Christopher L. Morton, Jianrong Wu, Peter G. Smith, Jie Yu and Peter J. Houghton. Initial testing of the inves

Authors
Smith, MA; Maris, JM; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Keir, ST; Reynolds, CP; Kang, MH; Morton, CL; Wu, J; Smith, PG; Yu, J; Houghton, PJ
URI
https://scholars.duke.edu/individual/pub752053
Source
scopus
Published In
Pediatric Blood & Cancer
Volume
59
Published Date
Start Page
772
End Page
772
DOI
10.1002/pbc.24291

Initial testing of lenalidomide by the pediatric preclinical testing program.

BACKGROUND: Lenalidomide, a novel immunomodulatory agent, is reported to modulate stem cell differentiation, and have direct antiproliferative activity as well as inhibit inflammation and hyperalgesia. On the basis of this varied pharmacological profile, lenalidomide is under investigation as a treatment for a range of oncologic indications. PROCEDURES: Lenalidomide was evaluated against the PPTP in vitro panel using 96-hr exposure at concentrations ranging from 1 nM to 10 µM. It was tested against the PPTP in vivo panels at a dose of 30 mg/kg administered orally (PO) once daily for a planned for 6 weeks. RESULTS: In vitro activity was not observed at concentrations up to 10 µM. Lenalidomide was well tolerated, and induced significant differences in EFS distribution compared to control in 7 of 37 (18.9%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. The best response in the solid tumor panel was PD2 [progressive disease with growth delay (EFS T/C > 1.5)], observed in 4 of 37 (10.8%) solid tumor xenografts. A single ALL xenograft showed a PD2 response. CONCLUSIONS: Direct antiproliferative effects of lenalidomide were not observed in vitro. In vivo lenalidomide demonstrated low activity against tumors in immune-deficient mice. Our results suggest that lenalidomide's utility in the pediatric clinical setting may depend upon its ability to induce antitumor activity through effects on host immune and stromal cells rather than through direct effects on tumor cells.
Authors
Reynolds, CP; Kang, MH; Keir, ST; Gorlick, R; Kolb, EA; Lock, R; Maris, JM; Carol, H; Morton, CL; Billups, CA; Smith, MA; Houghton, PJ
MLA Citation
Reynolds, C. Patrick, et al. “Initial testing of lenalidomide by the pediatric preclinical testing program..” Pediatr Blood Cancer, vol. 57, no. 4, Oct. 2011, pp. 606–11. Pubmed, doi:10.1002/pbc.22877.
URI
https://scholars.duke.edu/individual/pub780284
PMID
21360651
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
57
Published Date
Start Page
606
End Page
611
DOI
10.1002/pbc.22877