Francis Ali-Osman

Positions:

Margaret Harris and David Silverman Professor of Neuro-Oncology Research

Neurosurgery, Neuro-Oncology
School of Medicine

Professor Emeritus in Neurosurgery

Neurosurgery, Neuro-Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

D.Sc. 1982

Free University of Berlin (Germany)

Grants:

P53-dependent GSTP1 Gene Regulation and Glioma Drug Resistance

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

Protein Kinase C and GSTP1 interactions in glioma drug resistance

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

Publications:

Role of monoamine-oxidase-A-gene variation in the development of glioblastoma in males: a case control study.

BACKGROUND: The Mono-amine oxidase-A (MAO-A) enzyme is involved in the degradation and regulation of catecholamines such as serotonin, dopamine, epinephrine and nor-epinephrine. Preclinical studies suggest that this enzyme may contribute to an environment favorable for growth of malignant glioma. The MAO-A gene is located on the X-chromosome and has at least one functional genetic polymorphism. The aim of the present study was to explore possible effects of MAO-A genotype on development of glioblastoma in males. METHODS: Genotypes for 437 glioma cases and 876 population-based controls from the Swedish Glioma International Case-Control study (GICC) were compared. We analyzed the germline DNA using the Illumina Oncoarray. We selected seven single nucleotide polymorphisms (SNPs) located in the MAO-A gene, and imputed genotypes based on data from the 1000 genomes project. We used 1579 male glioblastoma cases and 1875 controls comprising the whole GICC cohort for subsequent validation of findings. RESULTS: The rs144551722 SNP was a significant predictor of development of glioblastoma in males (p-value = 0.0056) but not in females even after correction for multiple testing. We conducted haplotype analysis to confirm an association between MAO-A gene and risk of glioblastoma (p-value = 0.016). We found similar results in the validation sample. CONCLUSIONS: These results suggest the possibility of a role for the MAO-A enzyme and the MAO-A gene in the development of glioblastoma in males.
Authors
Sjöberg, RL; Wu, WY-Y; Dahlin, AM; Tsavachidis, S; Gliogene Group,; Bondy, ML; Melin, B
MLA Citation
Sjöberg, Rickard L., et al. “Role of monoamine-oxidase-A-gene variation in the development of glioblastoma in males: a case control study..” J Neurooncol, vol. 145, no. 2, Nov. 2019, pp. 287–94. Pubmed, doi:10.1007/s11060-019-03294-w.
URI
https://scholars.duke.edu/individual/pub1422306
PMID
31556016
Source
pubmed
Published In
J Neurooncol
Volume
145
Published Date
Start Page
287
End Page
294
DOI
10.1007/s11060-019-03294-w

Aspirin, NSAIDs, and Glioma Risk: Original Data from the Glioma International Case-Control Study and a Meta-analysis.

BACKGROUND: There have been few studies of sufficient size to address the relationship between glioma risk and the use of aspirin or NSAIDs, and results have been conflicting. The purpose of this study was to examine the associations between glioma and aspirin/NSAID use, and to aggregate these findings with prior published studies using meta-analysis. METHODS: The Glioma International Case-Control Study (GICC) consists of 4,533 glioma cases and 4,171 controls recruited from 2010 to 2013. Interviews were conducted using a standardized questionnaire to obtain information on aspirin/NSAID use. We examined history of regular use for ≥6 months and duration-response. Restricted maximum likelihood meta-regression models were used to aggregate site-specific estimates, and to combine GICC estimates with previously published studies. RESULTS: A history of daily aspirin use for ≥6 months was associated with a 38% lower glioma risk, compared with not having a history of daily use [adjusted meta-OR = 0.62; 95% confidence interval (CI), 0.54-0.70]. There was a significant duration-response trend (P = 1.67 × 10-17), with lower ORs for increasing duration of aspirin use. Duration-response trends were not observed for NSAID use. In the meta-analysis aggregating GICC data with five previous studies, there was a marginally significant association between use of aspirin and glioma (mOR = 0.84; 95% CI, 0.70-1.02), but no association for NSAID use. CONCLUSIONS: Our study suggests that aspirin may be associated with a reduced risk of glioma. IMPACT: These results imply that aspirin use may be associated with decreased glioma risk. Further research examining the association between aspirin use and glioma risk is warranted.
Authors
Amirian, ES; Ostrom, QT; Armstrong, GN; Lai, RK; Gu, X; Jacobs, DI; Jalali, A; Claus, EB; Barnholtz-Sloan, JS; Il'yasova, D; Schildkraut, JM; Ali-Osman, F; Sadetzki, S; Jenkins, RB; Lachance, DH; Olson, SH; Bernstein, JL; Merrell, RT; Wrensch, MR; Johansen, C; Houlston, RS; Scheurer, ME; Shete, S; Amos, CI; Melin, B; Bondy, ML
MLA Citation
Amirian, E. Susan, et al. “Aspirin, NSAIDs, and Glioma Risk: Original Data from the Glioma International Case-Control Study and a Meta-analysis..” Cancer Epidemiol Biomarkers Prev, vol. 28, no. 3, Mar. 2019, pp. 555–62. Pubmed, doi:10.1158/1055-9965.EPI-18-0702.
URI
https://scholars.duke.edu/individual/pub1359049
PMID
30482874
Source
pubmed
Published In
Cancer Epidemiol Biomarkers Prev
Volume
28
Published Date
Start Page
555
End Page
562
DOI
10.1158/1055-9965.EPI-18-0702

Endothelial colony forming cells (ECFCs) as a model for studying effects of low-dose ionizing radiation: growth inhibition by a single dose.

Identification of measurable nontransient responses to low-dose radiation in human primary cell cultures remains a problem. To this end, circulating endothelial colony-forming (progenitor) cells (ECFCs) were examined as an experimental model. ECFCs were isolated from three cord blood donors. Cells were positive for endothelial cell markers and remained highly proliferative after long-term cryopreservation. A single dose of X-ray radiation (0.06-0.38 Gy) inhibited ECFC culture growth. This effect was evident at 48 hours and persisted up to 72 hr postirradiation. Such protracted cytostatic response of ECFCs to low-dose radiation suggests that ECFC primary cultures can be used to study low-dose radiation effects.
Authors
Kinev, AV; Levering, V; Young, K; Ali-Osman, F; Truskey, GA; Dewhirst, MW; Il'yasova, D
MLA Citation
Kinev, Alexander V., et al. “Endothelial colony forming cells (ECFCs) as a model for studying effects of low-dose ionizing radiation: growth inhibition by a single dose..” Cancer Invest, vol. 31, no. 5, June 2013, pp. 359–64. Pubmed, doi:10.3109/07357907.2013.789903.
URI
https://scholars.duke.edu/individual/pub941157
PMID
23621632
Source
pubmed
Published In
Cancer Invest
Volume
31
Published Date
Start Page
359
End Page
364
DOI
10.3109/07357907.2013.789903

EGFR and EGFRvIII undergo stress- and EGFR kinase inhibitor-induced mitochondrial translocalization: a potential mechanism of EGFR-driven antagonism of apoptosis.

BACKGROUND: Epidermal growth factor receptor (EGFR) plays an essential role in normal development, tumorigenesis and malignant biology of human cancers, and is known to undergo intracellular trafficking to subcellular organelles. Although several studies have shown that EGFR translocates into the mitochondria in cancer cells, it remains unclear whether mitochondrially localized EGFR has an impact on the cells and whether EGFRvIII, a constitutively activated variant of EGFR, undergoes mitochondrial transport similar to EGFR. RESULTS: We report that both receptors translocate into the mitochondria of human glioblastoma and breast cancer cells, following treatments with the apoptosis inducers, staurosporine and anisomycin, and with an EGFR kinase inhibitor. Using mutant EGFR/EGFRvIII receptors engineered to undergo enriched intracellular trafficking into the mitochondria, we showed that glioblastoma cells expressing the mitochondrially enriched EGFRvIII were more resistant to staurosporine- and anisomycin-induced growth suppression and apoptosis and were highly resistant to EGFR kinase inhibitor-mediated growth inhibition. CONCLUSIONS: These findings indicate that apoptosis inducers and EGFR-targeted inhibitors enhance mitochondrial translocalization of both EGFR and EGFRvIII and that mitochondrial accumulation of these receptors contributes to tumor drug resistance. The findings also provide evidence for a potential link between the mitochondrial EGFR pathway and apoptosis.
Authors
Cao, X; Zhu, H; Ali-Osman, F; Lo, H-W
MLA Citation
URI
https://scholars.duke.edu/individual/pub737890
PMID
21388543
Source
pubmed
Published In
Molecular Cancer
Volume
10
Published Date
Start Page
26
DOI
10.1186/1476-4598-10-26

Tyrosine phosphorylation of the human glutathione S-transferase P1 by epidermal growth factor receptor.

Epidermal growth factor receptor (EGFR) gene amplification, mutations, and/or aberrant activation are frequent abnormalities in malignant gliomas and other human cancers and have been associated with an aggressive clinical course and a poor therapeutic outcome. Elevated glutathione S-transferase P1 (GSTP1), a major drug-metabolizing and stress response signaling protein, is also associated with drug resistance and poor clinical outcome in gliomas and other cancers. Here, we provide evidence that GSTP1 is a downstream EGFR target and that EGFR binds to and phosphorylates tyrosine residues in the GSTP1 protein in vitro and in vivo. Mass spectrometry and mutagenesis analyses in a cell-free system and in gliomas cells identified Tyr-7 and Tyr-198 as major EGFR-specific phospho-acceptor residues in the GSTP1 protein. The phosphorylation increased GSTP1 enzymatic activity significantly, and computer-based modeling showed a corresponding increase in electronegativity of the GSTP1 active site. In human glioma and breast cancer cells, epidermal growth factor stimulation rapidly increased GSTP1 tyrosine phosphorylation and decreased cisplatin sensitivity. Lapatinib, a clinically active EGFR inhibitor, significantly reversed the epidermal growth factor-induced cisplatin resistance. These data define phosphorylation and activation of GSTP1 by EGFR as a novel, heretofore unrecognized component of the EGFR signaling network and a novel mechanism of tumor drug resistance, particularly in tumors with elevated GSTP1 and/or activated EGFR.
Authors
Okamura, T; Singh, S; Buolamwini, J; Haystead, T; Friedman, H; Bigner, D; Ali-Osman, F
MLA Citation
Okamura, Tatsunori, et al. “Tyrosine phosphorylation of the human glutathione S-transferase P1 by epidermal growth factor receptor..” J Biol Chem, vol. 284, no. 25, June 2009, pp. 16979–89. Pubmed, doi:10.1074/jbc.M808153200.
URI
https://scholars.duke.edu/individual/pub757359
PMID
19254954
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
284
Published Date
Start Page
16979
End Page
16989
DOI
10.1074/jbc.M808153200