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New insights into estrogenic regulation of O^6-methylguanine DNA-methyltransferase (MGMT) in human breast cancer cells： Co-degradation of ER-α and MGMT proteins by fulvestrant or O^6-benzylguanine indicates fresh avenues for therapy

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The Journal of Biomedical Research 2016年第5期30卷 393-410页

作者： Ameya Paranjpe Nathan I. Bailes Santhi Konduri George C. Bobustuc Francis Ali-Osman Mohd. A. Yusuf Surendra R. Punganuru Hanumantha Rao Madal Debasish Basak AGM Mostofa Kalkunte S. Srivenugopa Department of Biomedical Sciences and Cancer Biology center School of Pharmacy Texas Tech University Health Sciences Center Amarillo TX 79106 USA Neuro-Oncology Section Aurora Advanced Cancer Care Milwaukee WI 53215 USA Department of Surgery The Preston Robert Tisch Brain Tumor Center Duke University Durham NC 27710 USA

Endocrine therapy using estrogen receptor-u （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 O^6-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 O^6- 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 dragresistance 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 O^6-benzylguanine. Interestingly, fulvestrant exposure led to a degradation of both ER-α and MGMT proteins and O^6-benzylguanine also induced a specific loss of ER-a and MGMT proteins in MCF-7 and T47D breast cancer cells with similar kinetics. Immunoprecipitation revealed a specific association of ER-a and MGMT proteins in breast cancer cells. Furthermore, silencing of MGMT gene expression triggered a decrease in the levels of both MGMT and ER-a proteins. The involvement of proteasome in the drug-induced degradation of both proteins was also demonstrated. Fulvestrant enhanced th

关键词： estrogen signaling MGMT DNA repair ubiquitin-proteasome pathway breast cancer anti-estrogens

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Immunotherapy for pediatric brain tumors

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Neuroimmunology and Neuroinflammation 2018年第7期5卷 20-35页

作者： Daniel B.Landi Eric M.Thompson David M.Ashley preston robert tisch brain tumor center DurhamNC27710USA Department of Pediatrics Duke University Medical CenterDurhamNC27710USA Department of Neurosurgery Duke University Medical CenterDurhamNC27710USA

Immunotherapy, while effective against lymphoid cancers and some solid tumors, has shown less benefit against pediatric brain tumors. tumor heterogeneity, a suppressive immune microenvironment, and the blood-brain barrier have the potential to diminish any immune-based approach and limit efficacy. More importantly, most pediatric brain tumors are immunologically quiescent, stemming from a low mutational burden. This review focuses on innate vs. adaptive immunotherapeutic approaches and describes how the immunologic context of pediatric brain tumors can help identify well-suited immunotherapies for our patients. In this framework, we will discuss past and current approaches using virotherapy, immunoconjugates, monoclonal antibodies, active immunization, and adoptive cel-lular therapy, and share our thoughts on how immunotherapy can cure children with brain tumors.

关键词： Immunotherapy brain tumor pediatrics virotherapy active immunization adoptive cellular therapy

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New treatment strategies for malignant gliomas

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中国神经肿瘤杂志 2006年第2期4卷 92-92页

作者： Sathornsumetee S Rich JN The preston robert tisch brain tumor center Division of Neurosurgery/Neuro-Oncology Duke UniversityMedical Center DUMC 3624 Durham NC 27710 USA.

Malignant gliomas are the most prevalent type of primary brain tumor in adults。Despite progress in brain tumor therapy, the prognosis of malignant glioma patients remains dismal。The median survival of patients with glioblastoma muhiforme, the most common grade of malignant glioma, is 10-12 months。Conventional therapy of surgery, radiation and chemotherapy is largely palliative。Essentially, tumor recurrence is inevitable。Salvage treatments upon recurrence are palliative at best and rarely provide significant survival benefit。Therapies targeting the underlying molecular pathogenesis of brain tumors are urgently required。Common genetic abnormalities in malignant glioma specimens are associated with aberrant activation or suppression of cellular signal transduction pathways and resistance to radiation and chemotherapy。

关键词：神经胶质瘤治疗方法临床病理机制

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Lack of Efficacy of Bevacizumab Plus Irinotecan in Children with Recurrent Malignant Glioma and Diffuse brainstem Glioma:A Pediatric brain tumor Consortium Study

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中国神经肿瘤杂志 2010年第2期8卷 81-81页

作者： Gururangan S Chi SN Young Poussaint T Onar-Thomas A Gilbertson RJ Vajapeyam S Friedman HS Packer RJ Rood BN Boyett JM Kun LE preston robert tisch brain tumor center Duke University Medical center Dana-Farber Cancer Institute Children's Hospital Boston St Jude Children's Research Hospital Operations and Biostatistics center for the Pediatric brain tumor Consortium the Children's National Medical center

PURPOSE:A phase Ⅱ study of bevacizumab(BVZ) plus irinotecan(CPT-11) was conducted in children with recurrent malignant glioma(MG) and intrinsic brainstem glioma(BSG).PATIENTS AND METHODS:Eligible patients received tw... 详细信息

关键词：肿瘤临床 BSG BVZ 治疗

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