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

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

Publications:

Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis.

Traditional approaches to evaluating antitumor agents using human tumor xenograft models have generally used cohorts of 8 to 10 mice against a limited panel of tumor models. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models that capture greater molecular/genetic heterogeneity of the cancer type. We retrospectively analyzed 67 agents evaluated by the Pediatric Preclinical Testing Program to determine whether a single mouse, chosen randomly from each group of a study, predicted the median response for groups of mice using 83 xenograft models. The individual tumor response from a randomly chosen mouse was compared with the group median response using established response criteria. A total of 2,134 comparisons were made. The single tumor response accurately predicted the group median response in 1,604 comparisons (75.16%). The mean tumor response correct prediction rate for 1,000 single mouse random samples was 78.09%. Models had a range for correct prediction (60%-87.5%). Allowing for misprediction of ± one response category, the overall mean correct single mouse prediction rate was 95.28%, and predicted overall objective response rates for group data in 66 of 67 drug studies. For molecularly targeted agents, occasional exceptional responder models were identified and the activity of that agent confirmed in additional models with the same genotype. Assuming that large treatment effects are targeted, this alternate experimental design has similar predictive value as traditional approaches, allowing for far greater numbers of models to be used that more fully encompass the heterogeneity of disease types. Cancer Res; 76(19); 5798-809. ©2016 AACR.
Authors
Murphy, B; Yin, H; Maris, JM; Kolb, EA; Gorlick, R; Reynolds, CP; Kang, MH; Keir, ST; Kurmasheva, RT; Dvorchik, I; Wu, J; Billups, CA; Boateng, N; Smith, MA; Lock, RB; Houghton, PJ
MLA Citation
Murphy, Brendan, et al. “Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis.Cancer Res, vol. 76, no. 19, Oct. 2016, pp. 5798–809. Pubmed, doi:10.1158/0008-5472.CAN-16-0122.
URI
https://scholars.duke.edu/individual/pub1139033
PMID
27496711
Source
pubmed
Published In
Cancer Res
Volume
76
Published Date
Start Page
5798
End Page
5809
DOI
10.1158/0008-5472.CAN-16-0122

Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program.

MLN0128 is an investigational small molecule ATP-competitive inhibitor of the serine/threonine kinase mTOR. MLN0128 was tested against the in vitro panel at concentrations ranging from 0.1 nM to 1 μM and against the PPTP in vivo panels at a dose of 1 mg/kg administered orally daily × 28. In vitro the median relative IC(50) concentration was 19 nM. In vivo MLN0128 induced significant differences in EFS in 24/31 (77%) solid tumor models, but 0/7 ALL xenografts. The modest activity observed for MLN0128 against the PPTP preclinical models is similar to that previously reported for another TOR kinase inhibitor.
Authors
Kang, MH; Reynolds, CP; Maris, JM; Gorlick, R; Kolb, EA; Lock, R; Carol, H; Keir, ST; Wu, J; Lyalin, D; Kurmasheva, RT; Houghton, PJ; Smith, MA
MLA Citation
Kang, Min H., et al. “Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 61, no. 8, Aug. 2014, pp. 1486–89. Pubmed, doi:10.1002/pbc.24989.
URI
https://scholars.duke.edu/individual/pub1025086
PMID
24623675
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
61
Published Date
Start Page
1486
End Page
1489
DOI
10.1002/pbc.24989

Exomic sequencing of four rare central nervous system tumor types.

A heterogeneous population of uncommon neoplasms of the central nervous system (CNS) cause significant morbidity and mortality. To explore their genetic origins, we sequenced the exomes of 12 pleomorphic xanthoastrocytomas (PXA), 17 non-brainstem pediatric glioblastomas (PGBM), 8 intracranial ependymomas (IEP) and 8 spinal cord ependymomas (SCEP). Analysis of the mutational spectra revealed that the predominant single base pair substitution was a C:G>T:A transition in each of the four tumor types. Our data confirm the critical roles of several known driver genes within CNS neoplasms, including TP53 and ATRX in PGBM, and NF2 in SCEPs. Additionally, we show that activating BRAF mutations play a central role in both low and high grade glial tumors. Furthermore, alterations in genes coding for members of the mammalian target of rapamycin (mTOR) pathway were observed in 33% of PXA. Our study supports the hypothesis that pathologically similar tumors arising in different age groups and from different compartments may represent distinct disease processes with varied genetic composition.
Authors
Bettegowda, C; Agrawal, N; Jiao, Y; Wang, Y; Wood, LD; Rodriguez, FJ; Hruban, RH; Gallia, GL; Binder, ZA; Riggins, CJ; Salmasi, V; Riggins, GJ; Reitman, ZJ; Rasheed, A; Keir, S; Shinjo, S; Marie, S; McLendon, R; Jallo, G; Vogelstein, B; Bigner, D; Yan, H; Kinzler, KW; Papadopoulos, N
MLA Citation
Bettegowda, Chetan, et al. “Exomic sequencing of four rare central nervous system tumor types.Oncotarget, vol. 4, no. 4, Apr. 2013, pp. 572–83. Pubmed, doi:10.18632/oncotarget.964.
URI
https://scholars.duke.edu/individual/pub952544
PMID
23592488
Source
pubmed
Published In
Oncotarget
Volume
4
Published Date
Start Page
572
End Page
583
DOI
10.18632/oncotarget.964

Combination testing (Stage 2) of the Anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program.

BACKGROUND: IMC-A12, a fully human antibody that blocks ligand binding to the Type 1 insulin-like growth factor receptor, and rapamycin, a selective inhibitor of mTORC1 signaling, have both demonstrated significant antitumor activity against PPTP solid tumor models. Here we have evaluated antitumor activity of each agent individually and in combination against nine tumor models. PROCEDURES: IMC-A12 was administered twice weekly and rapamycin was administered daily for 5 days per week for a planned 4 weeks. The impact of combining IMC-A12 with rapamycin was evaluated using two measures: (1) the "therapeutic enhancement" measure, and (2) a linear regression model for time-to-event to formally evaluate for sub- and supra-additivity for the combination compared to the agents used alone. RESULTS: Two osteosarcomas, and one Ewing sarcoma of the nine xenografts tested showed therapeutic enhancement. The combination effect was most dramatic for EW-5 for which PD2 responses of short duration were observed for both single agents and a prolonged PR response was observed for the combination. Both OS-2 and OS-9 showed significantly longer times to progression with the combination compared to either of the single agents, although objective response criteria were not met. CONCLUSIONS: The combination of IMC-A12 with rapamycin was well tolerated, and induced tumor responses that were superior to either single agent alone in several models. These studies confirm reports using other antibodies that inhibit IGF-1 receptor-mediated signaling that indicate enhanced therapeutic effect for this combination, and extend the range of histotypes to encompass additional tumors expressing IGF-1R where this approach may be effective.
Authors
Kolb, EA; Gorlick, R; Maris, JM; Keir, ST; Morton, CL; Wu, J; Wozniak, AW; Smith, MA; Houghton, PJ
MLA Citation
Kolb, E. Anders, et al. “Combination testing (Stage 2) of the Anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 58, no. 5, May 2012, pp. 729–35. Pubmed, doi:10.1002/pbc.23157.
URI
https://scholars.duke.edu/individual/pub780278
PMID
21630428
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
58
Published Date
Start Page
729
End Page
735
DOI
10.1002/pbc.23157

Initial testing (stage 1) of the multi-targeted kinase inhibitor sorafenib by the pediatric preclinical testing program.

BACKGROUND: Sorafenib is an inhibitor of multiple kinases (e.g., VEGF receptors, PDGFR, FLT3, RET, BRAF, KIT) and is approved by FDA for treatment of two adult cancers. The activity of sorafenib was evaluated against the PPTP's in vitro and in vivo panels. PROCEDURES: Sorafenib was evaluated against the PPTP in vitro panel using 96-hr exposure at concentrations ranging from 1.0 nM to 10.0 µM. It was tested against the PPTP in vivo panels at a dose of 60 mg/kg administered by oral gavage daily for 5 days per week, repeated for 6 weeks. RESULTS: In vitro sorafenib demonstrated cytotoxic activity, with a median IC(50) value of 4.3 µM. Twenty of 23 cell lines had IC(50) values between 1.0 and 10.0 µM. A single cell line (Kasumi-1) with an activating KIT mutation had an IC(50) value < 1.0 µM (IC(50) = 0.02 µM). In vivo sorafenib induced significant differences in event-free survival (EFS) distribution compared to control in 27 of 36 (75%) of the evaluable solid tumor xenografts and in 1 of 8 (12.5%) of the evaluable ALL xenografts. Sorafenib induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C) in 15 of 34 (44%) evaluable solid tumor xenografts. No xenografts achieved an objective response. CONCLUSIONS: The primary in vitro activity of sorafenib was noted at concentrations above 1 µM, with the exception of a more sensitive cell line with an activating KIT mutation. The primary in vivo effect for sorafenib was tumor growth inhibition, which was observed across multiple histotypes.
Authors
Keir, ST; Maris, JM; Lock, R; Kolb, EA; Gorlick, R; Carol, H; Morton, CL; Reynolds, CP; Kang, MH; Watkins, A; Houghton, PJ; Smith, MA
MLA Citation
Keir, Stephen T., et al. “Initial testing (stage 1) of the multi-targeted kinase inhibitor sorafenib by the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 55, no. 6, Dec. 2010, pp. 1126–33. Pubmed, doi:10.1002/pbc.22712.
URI
https://scholars.duke.edu/individual/pub780292
PMID
20672370
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
55
Published Date
Start Page
1126
End Page
1133
DOI
10.1002/pbc.22712