April 6, 2011

NYU Cancer Institute Experts Present At The AACR 102nd Annual Meeting 2011

Experts from The Cancer Institute at NYU Langone Medical Center presented new research findings at the American Association for Cancer Research 102nd Annual Meeting 2011 held April 2-6, 2011 in Orlando, Florida. NYU Cancer Institute researchers discussed various breakthroughs such as a novel test for early-stage asbestos-related pulmonary cancer, a promising treatment strategy for glioblastomas, genome-wide mapping of nickel-related cancer and greater understanding of melanoma and bladder cancer.

Detection of Mesothelioma in Asbestos Exposed Individuals with Aptamer Proteomic Technology
Author: Harvey I. Pass, MD, professor, Cardiothoracic Surgery and Surgery

Malignant pleural mesothelioma is an aggressive, asbestos-related pulmonary cancer that develops in the lining of the lungs. Researchers investigated a novel protein test to detect early-stage, asbestos-related pulmonary cancer. The new test can accurately identify proteins secreted from cancerous tumors caused by asbestos exposure. In a blinded test researchers detected 15 of 19 cases of stage 1 or stage 2 malignant pleural mesothelioma. The goal of the new diagnostic test is to find the cancer early enough to effectively treat it. The test called "Multiplex SOMAmer Assay" by SomaLogic, Inc. uses SOMAmers, chemically modified single-stranded DNA molecules to bind specifically to target proteins and quantify biomarkers. The test successfully measures 19 protein biomarkers for malignant pleural mesothelioma and quantifies the small amount of proteins secreted by tumor cells.

Abstract 2812: Monday, April 4, 2011, 8:30 AM
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Effects of Nickel Treatment on H3K4 Trimethylation and Gene Expression
Authors: Kam-Meng Tchou-Wong, PhD, associate professor and Max Costa, PhD, professor and chair, Environmental Medicine

In the past, occupational exposure to nickel (Ni) has been associated with lung cancer. Researchers have previously shown exposure of the human lung carcinoma A549 cells to nickel for 24 hours can significantly increase trimethylated H3K4 (H3K4me3), a transcriptional activating mark that maps to the promoters of transcribed genes. To further understand epigenetic mechanisms underlying nickel carcinogenesis, researchers performed genome-wide mapping of H3K4me3. The study shows the effects of nickel treatment on H3K4me3 on a set of genes highly induced by nickel in A549 cells and human peripheral blood mononuclear cells. This is the first genome-wide mapping of trimethylated H3K4 in the promoter regions of genes induced by nickel exposure. The study provides insights into epigenetic mechanisms underlying nickel carcinogenesis.

Abstract 1992: Monday, April 4, 2011, 1:00 PM
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Dimethylbenzanthracene (DMBA) and DMBA Dihydrodiol Mutagenicity in Rat Epithelial and Fibroblast Cell Lines, and its Inhibition by Combinations of Nutraceuticals
Authors: Peter G. Sacks, PhD, professor, Basic Science; Joseph B. Guttenplan, PhD, research associate professor, Environmental Medicine and Basic Science

7,12-Dimethylbenzanthracene (DMBA) is a potent mammary carcinogen in rats. In the study combinations of non-toxic nutraceuticals, dietary components providing health benefits, were administered at or near physiological levels. These agents were investigated for their abilities to inhibit the mutagenicity of DMBA or DMBA-dihydrodiol (DMBAD, a primary metabolite and proximate mutagen of DMBA) in rat mammary epithelial and fibroblast cells. DMBA in epithelial cells were not significantly mutagenic but DMBAD was significantly mutagenic at ten-fold lower concentrations. These results indicate the epithelial cells can bioactivate the intermediate, DMBAD, but cannot effect the complete biotransformation of DMBA to its ultimate mutagenic metabolite, DMBA-dihydrodiolepoxide. In contrast, the fibroblast cell line DMBA was mutagenic at low concentrations and DMBAD was even more potent than DMBA. Several combinations of nutraceuticals were tested for their abilities to inhibit mutagenesis in these cell lines at 1x concentrations. These results indicate these combinations can inhibit mutagenesis and suggests a role for fibroblast cells in the bioactivation of carcinogens.

Abstract 3701: Tuesday, April 5, 2011, 8:00 AM
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Radiosensitization and Decreased Neurosphere-Forming Capacity with TGFÃŽ² Inhibition in Glioma Cells
Authors: Matthew E. Hardee, house staff, Radiation Oncology; Ariel E. Marciscano, medical student, Radiation Oncology; Mine Esencay, graduate student, Pathology; David Zagzag, MD, PhD, professor, Pathology; Mary Helen Barcellos-Hoff, PhD, professor, Radiation Oncology

Glioblastoma tumors produce abundant transforming growth factor- ÃŽ² (TGFÃŽ²), a pleotropic cytokine in the tumor microenvironment can promote malignant behaviors, including invasion and motility, at late stages of tumorigenesis. Glioblastomas are routinely treated with radiation and have a poor prognosis with a median survival of only 14.6 months with standard treatments. In the study researchers investigated whether TGFÃŽ² inhibition could radiosensitize glioblastoma cells. Researchers used the murine glioblastoma cell line, GL261, to test the effects of TGFÃŽ² inhibition by LY364947, a small molecule inhibitor of the TGFÃŽ² type I receptor kinase on proliferation, radiosensitivity, and neurosphere-forming capacity. Study results suggest that inhibition of TGFÃŽ² in combination with radiation represents a promising therapeutic strategy in glioblastoma to improve patient outcomes.

Abstract LB-361: Tuesday, April 5, 2011, 1:00 PM
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p85alpha Mediates p53 K370 Acetylation by p300 and Regulates its Promoter-Specific Transactivity in the Cellular UVB Response
Authors: Lun Song, Environmental Medicine; Jingxia Li, associate research scientist, Environmental Medicine; Chuanshu Huang, MD, PhD, professor, Environmental Medicine

The factors for regulating p53 acetylation remain largely unknown. The study shows that p85ÃŽ±, the regulatory subunit of PI-3K, plays a critical role in mediating p53 acetylation and promoter-specific transactivation in the cellular Ultraviolet B (UVB) response. Depletion of p85ÃŽ± in mouse embryonic fibroblasts significantly impairs UVB-induced apoptosis as well as p53 transactivation and acetylation at Lys370 (Lys373 of human p53). However, the accumulation, nuclear translocation and phosphorylation of p53 are not affected. Interestingly, p85ÃŽ± binds to p300, promotes the p300-p53 interaction and the subsequent recruitment of the p53/p300 complex to the promoter region of the specific p53 target gene in response to UVB irradiation. Moreover, ablation of p53 acetylation at Lys370 by site-directed mutagenesis dramatically suppresses UVB-induced expression of the specific p53-responsive gene as well as cell apoptosis. Researchers conclude that p85ÃŽ± is a novel regulator of p53-mediated response under certain stress conditions. The study shows that argeting the p85ÃŽ±-dependent p53 pathway may be promising for cancer therapy.

Abstract 4211: Tuesday, April 5, 2011, 1:00 PM
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Organ, Species and Sex Differences in Mutagenesis Induced by butyl-hydroxybutyl-N-nitrosamine in Big Blue Transgenic Rodents as the Basis for the Strict Organ Specificity of this Environmental Carcinogen Metabolite
Authors: Xue-Ru Wu, MD, professor, Urology and Pathology; Joseph B. Guttenplan, PhD, research associate professor, Environmental Medicine and Basic Science

Butyl-hydroxybutyl-N-nitrosamine (BBN) is a powerful carcinogen that specifically causes bladder cancer in rodents, the reason for such a high degree of organ specificity is unclear. BBN is a primary metabolite of the environmental carcinogen, dibutylnitrosamine and hence a potential human carcinogen. Mutagenesis induced by BBN in a chromosomally incorporated mutagenesis reporter gene was measured in bladder urothelial cells and smooth muscle cells of mice or rats and compared with mutagenesis in liver, kidney, ureter and forestomach. Since mutagenesis in the reporter gene is a surrogate for mutagenesis in general, researchers hypothesized mutations also induced in critical growth control genes would contribute to the tumor formation induced by BBN. Researchers found mutagenesis correlated with the organ specificity for cancer induction by BBN. The study results provide molecular explanations to the puzzling organ and species specificity of BBN, and indicate that BBN-induced mutagenesis in the urinary bladder represents a model for initiation of bladder cancer, and combined with other models can help explain distinct steps in bladder carcinogenesis.

Abstract 1325: Monday, April 4, 2011, 8:00 AM
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Role of Orai1 and STIM1 in Store-Operated Ca2+ Entry and Cell Migration in Melanoma
Author: Stefan Feske, MD, assistant professor, Pathology

Melanoma, the deadliest form of skin cancer, has a poor prognosis because of its strong metastatic ability controlled by its cell migration. Store-operated Ca2+ entry (SOCE), which is defined as Ca2+ entry from extracellular space triggered with depletion of Ca2+ store in the endoplasmic reticulum (ER), largely regulates Ca2+ homeostasis in non-excitable cells. However, little is known about the role of SOCE in melanoma. In the study researchers report that expressions of SOCE modulators, such as ORAI calcium release-activated calcium modulator (Orai), which is the plasma membrane Ca2+ channel, and stromal interaction molecule (STIM), an activator of Orai in the ER, in cultured melanoma cells and human melanoma tissues. Researchers examined the effect of these modulators on SOCE and cell migration in melanoma cells. The study suggests that Orai1 and STIM1 are involved in SOCE in melanoma cells. Orai1 and/or STIM1 are involved in basal cell migration in melanoma. SOCE, which is regulated by Orai1 and STIM1 in melanoma cells, plays a major role in Ca2+ homeostasis, and cell migration in melanoma, and thus potentially metastasis.

Abstract 5259: Wednesday, April 6, 2011, 8:00 AM
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