MRP3: a molecular target for human glioblastoma multiforme immunotherapy.
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BACKGROUND: Glioblastoma multiforme (GBM) is refractory to conventional therapies. To overcome the problem of heterogeneity, more brain tumor markers are required for prognosis and targeted therapy. We have identified and validated a promising molecular therapeutic target that is expressed by GBM: human multidrug-resistance protein 3 (MRP3). METHODS: We investigated MRP3 by genetic and immunohistochemical (IHC) analysis of human gliomas to determine the incidence, distribution, and localization of MRP3 antigens in GBM and their potential correlation with survival. To determine MRP3 mRNA transcript and protein expression levels, we performed quantitative RT-PCR, raising MRP3-specific antibodies, and IHC analysis with biopsies of newly diagnosed GBM patients. We used univariate and multivariate analyses to assess the correlation of RNA expression and IHC of MRP3 with patient survival, with and without adjustment for age, extent of resection, and KPS. RESULTS: Real-time PCR results from 67 GBM biopsies indicated that 59/67 (88%) samples highly expressed MRP3 mRNA transcripts, in contrast with minimal expression in normal brain samples. Rabbit polyvalent and murine monoclonal antibodies generated against an extracellular span of MRP3 protein demonstrated reactivity with defined MRP3-expressing cell lines and GBM patient biopsies by Western blotting and FACS analyses, the latter establishing cell surface MRP3 protein expression. IHC evaluation of 46 GBM biopsy samples with anti-MRP3 IgG revealed MRP3 in a primarily membranous and cytoplasmic pattern in 42 (91%) of the 46 samples. Relative RNA expression was a strong predictor of survival for newly diagnosed GBM patients. Hazard of death for GBM patients with high levels of MRP3 RNA expression was 2.71 (95% CI: 1.54-4.80) times that of patients with low/moderate levels (p = 0.002). CONCLUSIONS: Human GBMs overexpress MRP3 at both mRNA and protein levels, and elevated MRP3 mRNA levels in GBM biopsy samples correlated with a higher risk of death. These data suggest that the tumor-associated antigen MRP3 has potential use for prognosis and as a target for malignant glioma immunotherapy.
Mice, Inbred BALB C
Multidrug Resistance-Associated Proteins
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Published Version (Please cite this version)10.1186/1471-2407-10-468
Publication InfoKuan, Chien-Tsun; Wakiya, Kenji; Herndon, James E; Lipp, Eric S; Pegram, Charles N; Riggins, Gregory J; ... Bigner, Darell D (2010). MRP3: a molecular target for human glioblastoma multiforme immunotherapy. BMC Cancer, 10. pp. 468. 10.1186/1471-2407-10-468. Retrieved from https://hdl.handle.net/10161/16100.
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E. L. and Lucille F. Jones Cancer Distinguished Research Professor, in the School of Medicine
The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS). There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to
Professor of Biostatistics and Bioinformatics
Current research interests have application to the design and analysis of cancer clinical trials. Specifically, interests include the use of time-dependent covariables within survival models, the design of phase II cancer clinical trials which minimize some of the logistical problems associated with their conduct, and the analysis of longitudinal studies with informative censoring (in particular, quality of life studies of patients with advanced cancer).
Adjunct Associate Professor in the Department of Pathology
Research Interests: Conventional therapy for malignant brain tumors is ineffective. Targeted therapy using tumor-specific antibodis (MAb) alone or MAbs armed with radionuclides or toxins is a promising alternative approach for increasing therapeutic efficacy and decreasing toxicity to normal tissue. The major factors that influence antibody-targeted therapy for cancer treatment, including glioma therapy, are specificity, affinity, tumor penetration, toxicity and immunogenicity. The
Professor of Pathology
Brain tumors are diagnosed in more than 20,000 Americans annually. The most malignant neoplasm, glioblastoma, is also the most common. Similarly, brain tumors constitute the most common solid neoplasm in children and include astrocytomas of the cerebellum, brain stem and cerebrum as well as medulloblastomas of the cerebellum. My colleagues and I have endeavored to translate the bench discoveries of genetic mutations and aberrant protein expressions found in brain tumors to better understan
Assistant Professor in Pathology
Our lab is interested in identifying the specific genetic alterations associated with the genesis and progression of glial malignancies. Studies from our and other laboratories have shown that in adult glioblastomas, approximately 80% of the cases show loss of alleles on chromosome 10, and to a lesser extent on 9p, 17p, 19q and 22q. Amplification of epidermal growth factor receptor gene is detected in about a third of glioblastomas. The high incidence of loss of chromosome 10 alleles sug
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