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:

Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program.

VS-4718, a novel inhibitor of focal adhesion kinase (FAK), was tested against the Pediatric Preclinical Testing Program's (PPTP's) in vitro cell line panel and showed a median relative IC50 of 1.22 μM. VS-4718 was tested in vivo against the PPTP xenograft models using a dose of 50 mg/kg administered by the oral route twice daily for 21 days. VS-4718 induced significant differences in an event-free survival distribution compared with control in 18 of 36 of the evaluable solid tumor xenografts and in 0 of 8 acute lymphoblastic leukemia (ALL) xenografts, but no xenograft lines showed tumor regression. Future plans include further evaluation of the role of FAK inhibition in combination with ABL kinase inhibitors for Ph+ ALL.
Authors
Kurmasheva, RT; Gorlick, R; Kolb, EA; Keir, ST; Maris, JM; Lock, RB; Carol, H; Kang, M; Reynolds, CP; Wu, J; Houghton, PJ; Smith, MA
MLA Citation
Kurmasheva, Raushan T., et al. “Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program.Pediatr Blood Cancer, vol. 64, no. 4, Apr. 2017. Pubmed, doi:10.1002/pbc.26304.
URI
https://scholars.duke.edu/individual/pub1150088
PMID
27786412
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
64
Published Date
DOI
10.1002/pbc.26304

Erratum

MLA Citation
Erratum.” Pediatric Blood & Cancer, vol. 61, no. 9, Wiley, Sept. 2014, pp. 1716–1716. Crossref, doi:10.1002/pbc.25186.
URI
https://scholars.duke.edu/individual/pub1044197
Source
crossref
Published In
Pediatric Blood & Cancer
Volume
61
Published Date
Start Page
1716
End Page
1716
DOI
10.1002/pbc.25186

Initial testing of the MDM2 inhibitor RG7112 by the Pediatric Preclinical Testing Program.

BACKGROUND: RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. PROCEDURES: RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hours exposure (1 nM to 10 µM). It was tested against the PPTP in vivo panel focusing on p53 wild-type (WT) xenografts at a dose of 100 mg/kg daily for 14 days followed by 4 weeks of observation. Response outcomes were related to MDM2 and p53 expression datasets (http://pptp.nchresearch.org/data.html). RESULTS: RG7112 demonstrated cytotoxic activity with a lower median IC(50) for p53 WT versus p53 mutant cell lines (approximately 0.4 µM vs. >10 µM, respectively). RG7112 induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C > 2) in 10 of 26 (38%) solid tumor xenografts. Objective responses included medulloblastoma, alveolar rhabdomyosarcoma, Wilms, rhabdoid and Ewing sarcoma xenografts. For the ALL panel, there was one partial response, five complete responses and one maintained complete response. The ALL xenografts expressed the highest levels of p53 among the PPTP panels. CONCLUSIONS: RG7112 induced tumor regressions in solid tumors from different histotype panels, and exhibited consistent high-level activity against ALL xenografts. This high level of activity supports prioritization of RG7112 for further evaluation.
Authors
Carol, H; Reynolds, CP; Kang, MH; Keir, ST; Maris, JM; Gorlick, R; Kolb, EA; Billups, CA; Geier, B; Kurmasheva, RT; Houghton, PJ; Smith, MA; Lock, RB
MLA Citation
Carol, Hernan, et al. “Initial testing of the MDM2 inhibitor RG7112 by the Pediatric Preclinical Testing Program.Pediatr Blood Cancer, vol. 60, no. 4, Apr. 2013, pp. 633–41. Pubmed, doi:10.1002/pbc.24235.
URI
https://scholars.duke.edu/individual/pub823351
PMID
22753001
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
60
Published Date
Start Page
633
End Page
641
DOI
10.1002/pbc.24235

Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a γ-secretase inhibitor targeting notch signaling.

RO4929097 is a potent and selective inhibitor of γ-secretase and as a result is able to inhibit Notch pathway signaling. The activity of RO4929097 was evaluated against the in vivo panels of the Pediatric Preclinical Testing Program (PPTP). RO4929097 induced significant differences in event-free survival (EFS) distribution compared to control in 6 of 26 (23%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. The most consistent tumor growth delay effects were noted in the osteosarcoma panel. RO4929097 at the dose and schedule evaluated demonstrated little antitumor activity against childhood cancer xenografts.
Authors
Kolb, EA; Gorlick, R; Keir, ST; Maris, JM; Lock, R; Carol, H; Kurmasheva, RT; Reynolds, CP; Kang, MH; Wu, J; Houghton, PJ; Smith, MA
MLA Citation
Kolb, E. Anders, et al. “Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a γ-secretase inhibitor targeting notch signaling.Pediatr Blood Cancer, vol. 58, no. 5, May 2012, pp. 815–18. Pubmed, doi:10.1002/pbc.23290.
URI
https://scholars.duke.edu/individual/pub780276
PMID
22052798
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
58
Published Date
Start Page
815
End Page
818
DOI
10.1002/pbc.23290

Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program.

BACKGROUND: GSK690693 is a small molecule ATP-competitive inhibitor of the pro-survival kinase Akt. Since Akt regulates multiple downstream targets including transcription factors, glycogen synthase 3, the pro-apoptotic protein Bad, as well as MDM2 and mTORC1, it was tested against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). PROCEDURES: GSK690693 was tested in vitro at concentrations from 1 nM to 10 µM, and against the in vivo panel of xenografts at a dose of 30 mg/kg daily × 5 for 6 consecutive weeks. Three measures of in vivo antitumor activity were used: (1) an objective response measure modeled after the clinical setting; (2) a treated to control (T/C) tumor volume measure; and (3) a time to event measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. RESULTS: GSK690693 inhibited cell growth in vitro with IC(50) values between 6.5 nM and >10 µM. In vivo, GSK690693 significantly increased EFS in 11 of 34 (32%) solid tumor xenografts, most notably in all 6 osteosarcoma models, but not in any of the 8 ALL xenografts tested. No objective responses were observed and only one solid tumor met EFS T/C criteria for intermediate activity. CONCLUSIONS: GSK690693 demonstrated broad activity in vitro, however our results against both the solid tumor and ALL PPTP in vivo panels demonstrate that, as single agent at the dose and schedule used, GSK690693 has only modest antitumor activity.
Authors
Carol, H; Morton, CL; Gorlick, R; Kolb, EA; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Billups, C; Smith, MA; Houghton, PJ; Lock, RB
MLA Citation
Carol, Hernan, et al. “Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 55, no. 7, Dec. 2010, pp. 1329–37. Pubmed, doi:10.1002/pbc.22710.
URI
https://scholars.duke.edu/individual/pub780290
PMID
20740623
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
55
Published Date
Start Page
1329
End Page
1337
DOI
10.1002/pbc.22710