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

New insights into estrogenic regulation of O6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells: Co-degradation of ER-α and MGMT proteins by fulvestrant or O6-benzylguanine indicates fresh avenues for therapy.

Endocrine therapy using estrogen receptor-α (ER-α) antagonists for attenuating horm2one-driven cell proliferation is a major treatment modality for breast cancers. To exploit any DNA repair deficiencies associated with endocrine therapy, we investigated the functional and physical interactions of ER-α with O6-methylguanine DNA methyltransferase (MGMT), a unique DNA repair protein that confers tumor resistance to various anticancer alkylating agents. The ER-α -positive breast cancer cell lines (MCF-7, T47D) and ER- negative cell lines (MDAMB-468, MDAMB-231), and established inhibitors of ER-α and MGMT, namely, ICI-182,780 (Faslodex) and O6-benzylguanine, respectively, were used to study MGMT- ER interactions. The MGMT gene promoter was found to harbor one full and two half estrogen-responsive elements (EREs) and two antioxidant-responsive elements (AREs). MGMT expression was upregulated by estrogen, downregulated by tamoxifen in Western blot and promoter-linked reporter assays. Similarly, both transient and stable transfections of Nrf-2 (nuclear factor-erythroid 2-related factor-2) increased the levels of MGMT protein and activity 3 to 4-fold reflecting novel regulatory nodes for this drug-resistance determinant. Of the different ER-α antagonists tested, the pure anti-estrogen fulvestrant was most potent in inhibiting the MGMT activity in a dose, time and ER-α dependent manner, similar to O6-benzylguanine. Interestingly, fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O6-benzylguanine also induced a specific loss of ER-α and MGMT proteins in MCF-7 and T47D breast cancer cells with similar kinetics. Immunoprecipitation revealed a specific association of ER-α and MGMT proteins in breast cancer cells. Furthermore, silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-α proteins. The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated. Fulvestrant enhanced the cytotoxicity of MGMT-targeted alkylating agents, namely, temozolomide and BCNU by 3 to 4-fold in ER-α positive cells, but not in ER-negative cells. We conclude that MGMT and ER-α proteins exist as a complex and are co-targeted for ubiquitin-conjugation and subsequent proteasomal degradation. The findings offer a clear rationale for combining alkylating agents with endocrine therapy.
Authors
Paranjpe, A; Bailey, NI; Konduri, S; Bobustuc, GC; Ali-Osman, F; Yusuf, MA; Punganuru, SR; Madala, HR; Basak, D; Mostofa, A; Srivenugopal, KS
URI
https://scholars.duke.edu/individual/pub1157444
PMID
27845303
Source
pubmed
Published In
Journal of Biomedical Research
Volume
30
Published Date
Start Page
393
End Page
410
DOI
10.7555/JBR.30.20160040

A Phase 2 Trial of Imatinib Mesylate As Maintenance Therapy for Patients with Newly Diagnosed C-Kit Positive Acute Myeloid Leukemia (AML)

Authors
Advani, A; Cooper, B; Sowunmi, O; Elson, P; Ali-Osman, F; Park, J; Rao, A; Rizzieri, DA; Wang, ES; Cotta, C; Sekeres, MA; Kalaycio, M; Sobecks, R; Rouphail, B; Maciejewski, JP; Davis, R; Bailey, L; Foster, B; Rush, ML; Adams, D; Tse, W
MLA Citation
URI
https://scholars.duke.edu/individual/pub938437
Source
wos
Published In
Blood
Volume
120
Published Date

UNDERSTANDING AND TARGETING KINASE-INDEPENDENT ACTIVITY OF EGFR AND EGFRVIII TO OVERCOME GBM DRUG RESISTANCE

Authors
Zhu, H; Cao, X; Keir, S; Ali-Osman, F; Lo, H-W
MLA Citation
Zhu, Hu, et al. “UNDERSTANDING AND TARGETING KINASE-INDEPENDENT ACTIVITY OF EGFR AND EGFRVIII TO OVERCOME GBM DRUG RESISTANCE.” Neuro Oncology, vol. 12, OXFORD UNIV PRESS INC, 2010, pp. 8–8.
URI
https://scholars.duke.edu/individual/pub928420
Source
wos
Published In
Neuro Oncology
Volume
12
Published Date
Start Page
8
End Page
8

Serine-phosphorylation of the GSTP1 protein by PKC\#945; increase GSTP1-mediated cisplatin metabolism and descrease cisplatin-induced DNA interstrand cross link formation and cisplatin sensitivity in human glioma cells

Authors
Singh, S; Ali-Osman, F
URI
https://scholars.duke.edu/individual/pub1149154
Source
wos
Published In
Cancer Research
Volume
69
Published Date