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Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor
Segura, Miguel F; Hanniford, Douglas; Menendez, Silvia; Reavie, Linsey; Zou, Xuanyi; Alvarez-Diaz, Silvia; Zakrzewski, Jan; Blochin, Elen; Rose, Amy; Bogunovic, Dusan; Polsky, David; Wei, Jianjun; Lee, Peng; Belitskaya-Levy, Ilana; Bhardwaj, Nina; Osman, Iman; Hernando, Eva
The highly aggressive character of melanoma makes it an excellent model for probing the mechanisms underlying metastasis, which remains one of the most difficult challenges in treating cancer. We find that miR-182, member of a miRNA cluster in a chromosomal locus (7q31-34) frequently amplified in melanoma, is commonly up-regulated in human melanoma cell lines and tissue samples; this up-regulation correlates with gene copy number in a subset of melanoma cell lines. Moreover, miR-182 ectopic expression stimulates migration of melanoma cells in vitro and their metastatic potential in vivo, whereas miR-182 down-regulation impedes invasion and triggers apoptosis. We further show that miR-182 over-expression promotes migration and survival by directly repressing microphthalmia-associated transcription factor-M and FOXO3, whereas enhanced expression of either microphthalmia-associated transcription factor-M or FOXO3 blocks miR-182's proinvasive effects. In human tissues, expression of miR-182 increases with progression from primary to metastatic melanoma and inversely correlates with FOXO3 and microphthalmia-associated transcription factor levels. Our data provide a mechanism for invasion and survival in melanoma that could prove applicable to metastasis of other cancers and suggest that miRNA silencing may be a worthwhile therapeutic strategy
PMCID:2634798
PMID: 19188590
ISSN: 1091-6490
CID: 92154
Stromal anti-apoptotic androgen receptor target gene c-FLIP in prostate cancer
Ye, Huihui; Li, Yirong; Melamed, Jonathan; Pearce, Patrice; Wei, Jianjun; Chiriboga, Luis; Wang, Zhengxin; Osman, Iman; Lee, Peng
PURPOSE: The tumor microenvironment significantly influences prostate cancer progression. Androgen receptor exerts its effect through downstream target genes to regulate prostate cancer cell proliferation. The c-FLIP gene was recently shown to be an androgen receptor target gene. c-FLIP is an inactive homologue of caspase-8 and, thus, it inhibits the death receptor mediated apoptosis pathway. c-FLIP over expression was shown to accelerate the progression of prostate cancer cells to androgen independence. We evaluated the role of c-FLIP expression in stromal cells in prostate cancer development. MATERIALS AND METHODS: We examined c-FLIP expression in 53 androgen dependent and 21 androgen independent prostate cancer stromal cells by immunohistochemical analysis. The effects of c-FLIP over expression in stromal cells on the growth and invasion of LNCaP and PC3 prostate cancer cells were determined in indirect coculture systems. RESULTS: At the androgen dependent stage the stromal c-FLIP level was increased in prostate cancer tissue. The expression level of stromal c-FLIP was associated with tumor differentiation. However, stromal c-FLIP expression was not increased in androgen independent human prostate cancer. c-FLIP over expression in stromal cells stimulated the growth and invasion of prostate cancer, including LNCaP and PC3 cells in vitro. CONCLUSIONS: These results indicate the over expression of stromal c-FLIP and its function for promoting prostate cancer growth and invasion
PMID: 19095249
ISSN: 1527-3792
CID: 92157
MDM2 Expression and Regulation in Prostate Cancer Racial Disparity
Wang, Guimin; Firoz, Elnaz F; Rose, Amy; Blochin, Elen; Christos, Paul; Pollens, Danuta; Mazumdar, Madhu; Gerald, William; Oddoux, Carole; Lee, Peng; Osman, Iman
MDM2 is a key negative regulator of tumor suppressor p53. A single nucleotide polymorphism in the MDM2 promoter, SNP309, enhances transcriptional activation of MDM2 and has been associated with early onset of several types of cancer. In this study, we attempted to determine if the MDM2 SNP309 polymorphism plays a role in the aggressive phenotype seen in African American (AA) prostate cancer by examining the association between MDM2 SNP309 and MDM2 protein levels in prostate cancer (PCa) patients of different racial backgrounds. Prospectively enrolled PCa patients (AA=51, CA=50) were evaluated for MDM2 SNP309 and MDM2 protein expression. MDM2 overexpression, defined as >10% of tumor cells in three tissue cores, was assessed using immunohistochemistry on tissue microarray. MDM2 protein expression was significantly greater in CA than AA patients (78% versus 45% respectively, p=0.0007). Germline DNA was analyzed by PCR-RFLP then confirmed by DNA sequencing. MDM2 SNP309 genotype frequencies did not differ significantly between AA and CA PCa patients (AA: TT 68.6%, TG 25.5%, GG 5.9%; CA: TT 62.0%, TG 20.0%, GG 18.0%; p=0.16), suggesting that the MDM2 SNP309 allele does not play a significant role in the observed overexpression
PMCID:2615592
PMID: 19158992
ISSN: 1936-2625
CID: 92155
Developing a multidisciplinary prospective melanoma biospecimen repository to advance translational research
Wich, Lindsay G; Hamilton, Heather K; Shapiro, Richard L; Pavlick, Anna; Berman, Russell S; Polsky, David; Goldberg, Judith D; Hernando, Eva; Manga, Prashiela; Krogsgaard, Michelle; Kamino, Hideko; Darvishian, Farbod; Lee, Peng; Orlow, Seth J; Ostrer, Harry; Bhardwaj, Nina; Osman, Iman
Several challenges face the development and operation of a biospecimen bank linked to clinical information, a critical component of any effective translational research program. Melanoma adds particular complexity and difficulty to such an endeavor considering the unique characteristics of this malignancy. We describe here a review of biospecimen bank and our experience in establishing a multi-disciplinary, prospective, integrated clinicopathological-biospecimen database in melanoma. The Interdisciplinary Melanoma Cooperative Group (IMCG), a prospective clinicopathological and biospecimen database, was established at the New York University (NYU) Langone Medical Center. With patients' informed consent, biospecimens from within and outside NYU, clinicopathological data, and follow-up information are collected using developed protocols. Information pertaining to biospecimens is recorded in 35 fields, and clinicopathological information is recorded in 371 fields within 5 modules in a virtual network system. Investigators conducting research utilizing the IMCG biospecimen resource are blind to clinicopathological information, and molecular data generated using biospecimens are linked independently with clinicopathological data by biostatistics investigators. This translational research enterprise acts as a valuable resource to efficiently translate laboratory discoveries to the clinic
PMCID:2776290
PMID: 19966936
ISSN: 1943-8141
CID: 105566
Increased expression of histone deacetylaces (HDACs) and inhibition of prostate cancer growth and invasion by HDAC inhibitor SAHA
Wang, Longgui; Zou, Xuanyi; Berger, Aaron D; Twiss, Christian; Peng, Yi; Li, Yirong; Chiu, Jason; Guo, Hongfeng; Satagopan, Jaya; Wilton, Andrew; Gerald, William; Basch, Ross; Wang, Zhengxin; Osman, Iman; Lee, Peng
Histone deacetetylases (HDACs) are a group of corepressors of transcriptional activators and their levels of expression are potentially dysregulated in prostate cancer. Certain inhibitors of histone deacetylases show anti-tumor activity in prostate cancer cell lines. Here, we systemically studied the expression of HDACs in human prostate cancer and the suppression of prostate cancer growth and invasion by HDAC inhibitor SAHA. HDAC1-5 showed increased expression using a combination of DNA microarray, in-situ hybridization, and immunohistochemistry in benign and malignant human prostate tissue as well as RT-PCR and Western blot analysis on various PCa cell lines. Importantly, HDAC inhibitor SAHA suppressed, in particular, prostate cancer cell growth and invasion determined using cell proliferation and Matrigel invasion assays. The findings of this study show that the expression of HDACs and their associated corepressors are increased in prostate cancer in humans and HDAC inhibitor SAHA could serve as a potential therapeutic agent in prostate cancer in addition to anti-androgens
PMCID:2776287
PMID: 19966939
ISSN: 1943-8141
CID: 115887
Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma
Solit, David B; Osman, Iman; Polsky, David; Panageas, Katherine S; Daud, Adil; Goydos, James S; Teitcher, Jerrold; Wolchok, Jedd D; Germino, F Joseph; Krown, Susan E; Coit, Daniel; Rosen, Neal; Chapman, Paul B
PURPOSE: Activation of the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase/AKT pathway seems to be critical for melanoma proliferation. Components of these pathways are client proteins of heat-shock protein 90 (hsp90), suggesting that inhibition of hsp90 could have significant antimelanoma effects. We conducted a phase II trial using the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in melanoma patients. The primary end points were clinical responses and whether treatment inhibited MAPK pathway activity. EXPERIMENTAL DESIGN: Melanoma patients with measurable disease were stratified on the basis of whether or not their tumor harbored a V600E BRAF mutation. The hsp90 inhibitor 17-AAG was administered i.v. once weekly x 6 weeks at 450 mg/m2. Tumor biopsies were obtained pretreatment and 18 to 50 hours after the first dose of 17-AAG, and were snap-frozen. RESULTS: Fifteen evaluable patients were treated; nine had BRAF mutations and six were wild-type. No objective responses were observed. Western blot analysis of tumor biopsies showed an increase in hsp70 and a decrease in cyclin D1 expression in the posttreatment biopsies but no significant effect on RAF kinases or phospho-extracellular signal-regulated kinase expression. Plasma analyzed by mutant-specific PCR for V600E BRAF showed 86% sensitivity and 67% specificity in predicting tumor DNA sequencing results. CONCLUSIONS: At this dose and schedule of 17-AAG, the effects of 17-AAG on RAF kinase expression were short-lived, and no objective antimelanoma responses were seen. Future trials in melanoma should focus on a more potent hsp90 inhibitor or a formulation that can be administered chronically for a more prolonged suppression of the MAPK pathway
PMCID:2629404
PMID: 19088048
ISSN: 1078-0432
CID: 92158
Changes in the presentation of nodular and superficial spreading melanomas over 35 years
Warycha, Melanie A; Christos, Paul J; Mazumdar, Madhu; Darvishian, Farbod; Shapiro, Richard L; Berman, Russell S; Pavlick, Anna C; Kopf, Alfred W; Polsky, David; Osman, Iman
BACKGROUND: Nodular melanoma (NM) may be biologically aggressive compared with the more common superficial spreading melanoma (SSM), with recent data suggesting underlying genetic differences between these 2 subtypes. To better define the clinical behavior of NMs, the authors compared their clinical and histopathologic features to those of SSMs at their institution, a tertiary referral center, over 3 decades. METHODS: A total of 1,684 patients diagnosed with 1,734 melanomas were prospectively enrolled. Of these, 1,143 patients (69% SSM, 11% NM, 20% other) were diagnosed between 1972 and 1982; 541 patients (54% SSM, 23% NM, 23% other) were diagnosed between 2002 and the present. Differences between the features of NM and SSM within each time period as well as changes over time were analyzed. RESULTS: The authors found that SSMs are now diagnosed as thinner lesions (P < .0001) with a low incidence of histologic ulceration (P < .0001), whereas there was no significant change in the median tumor thickness or ulceration status of NMs over time (P = .10, P = .30, respectively). The median age at diagnosis of NM, however, did significantly increase over time (51 years to 63 years, P < .01). The median duration of NMs was reported to be only 5 months compared with 9 months in SSM patients. CONCLUSIONS: The authors' data suggest that improvements have been made in the early detection of SSM but not NM. Modifications of current screening practices, including increased surveillance of high-risk patients with an emphasis on the 'E' for 'evolution' criterion of the ABCDE acronym used for early detection of melanoma, are thus warranted
PMCID:3624077
PMID: 18988292
ISSN: 0008-543x
CID: 91976
Assessing the clinical utility of measuring Insulin-like Growth Factor Binding Proteins in tissues and sera of melanoma patients
Yu, Jessie Z; Warycha, Melanie A; Christos, Paul J; Darvishian, Farbod; Yee, Herman; Kaminio, Hideko; Berman, Russell S; Shapiro, Richard L; Buckley, Michael T; Liebes, Leonard F; Pavlick, Anna C; Polsky, David; Brooks, Peter C; Osman, Iman
BACKGROUND: Different Insulin-like Growth Factor Binding Proteins (IGFBPs) have been investigated as potential biomarkers in several types of tumors. In this study, we examined both IGFBP-3 and -4 levels in tissues and sera of melanoma patients representing different stages of melanoma progression. METHODS: The study cohort consisted of 132 melanoma patients (primary, n = 72; metastatic, n = 60; 64 Male, 68 Female; Median Age = 56) prospectively enrolled in the New York University School of Medicine Interdisciplinary Melanoma Cooperative Group (NYU IMCG) between August 2002 and December 2006. We assessed tumor-expression and circulating sera levels of IGFBP-3 and -4 using immunohistochemistry and ELISA assays. Correlations with clinicopathologic parameters were examined using Wilcoxon rank-sum tests and Spearman-rank correlation coefficients. RESULTS: Median IGFBP-4 tumor expression was significantly greater in primary versus metastatic patients (70% versus 10%, p = 0.01) A trend for greater median IGFBP-3 sera concentration was observed in metastatic versus primary patients (4.9 microg/ml vs. 3.4 microg/ml, respectively, p = 0.09). However, sera levels fell within a normal range for IGFBP-3. Neither IGFBP-3 nor -4 correlated with survival in this subset of patients. CONCLUSION: Decreased IGFBP-4 tumor expression might be a step in the progression from primary to metastatic melanoma. Our data lend support to a recently-described novel tumor suppressor role of secreting IGFBPs in melanoma. However, data do not support the clinical utility of measuring levels of IGFBP-3 and -4 in sera of melanoma patients
PMCID:2627832
PMID: 19025658
ISSN: 1479-5876
CID: 92159
Shedding of distinct cryptic collagen epitope (HU177) in sera of melanoma patients
Ng, Bruce; Zakrzewski, Jan; Warycha, Melanie; Christos, Paul J; Bajorin, Dean F; Shapiro, Richard L; Berman, Russell S; Pavlick, Anna C; Polsky, David; Mazumdar, Madhu; Montgomery, Anthony; Liebes, Leonard; Brooks, Peter C; Osman, Iman
PURPOSE: Extracellular matrix remodeling during tumor growth plays an important role in angiogenesis. Our preclinical data suggest that a newly identified cryptic epitope (HU177) within collagen type IV regulates endothelial and melanoma cell adhesion in vitro and angiogenesis in vivo. In this study, we investigated the clinical relevance of HUI77 shedding in melanoma patient sera. EXPERIMENTAL DESIGN: Serum samples from 291 melanoma patients prospectively enrolled at the New York University Medical Center and 106 control subjects were analyzed for HU177 epitope concentration by a newly developed sandwich ELISA assay. HU177 serum levels were then correlated with clinical and pathologic parameters. RESULTS: Mean HU177 epitope concentration was 5.8 ng/mL (range, 0-139.8 ng/mL). A significant correlation was observed between HU177 concentration and nodular melanoma histologic subtype [nodular, 10.3 +/- 1.6 ng/mL (mean +/- SE); superficial spreading melanoma, 4.5 +/- 1.1 ng/mL; all others, 6.1 +/- 2.1 ng/mL; P = 0.01 by ANOVA test]. Increased HU177 shedding also correlated with tumor thickness (< or =1.00 mm, 3.8 +/- 1.1 ng/mL; 1.01-3.99 mm, 8.7 +/- 1.3 ng/mL; > or =4.00 mm, 10.3 +/- 2.4 ng/mL; P = 0.003 by ANOVA). After multivariate analysis controlling for thickness, the correlation between higher HU177 concentration and nodular subtype remained significant (P = 0.03). The mean HU177 epitope concentration in control subjects was 2.4 ng/mL. CONCLUSIONS: We report that primary melanoma can induce detectable changes in systemic levels of cryptic epitope shedding. Our data also support that nodular melanoma might be biologically distinct compared with superficial spreading type melanoma. As targeted interventions against cryptic collagen epitopes are currently undergoing phase I clinical trial testing, these findings indicate that patients with nodular melanoma may be more susceptible to such targeted therapies
PMCID:4035818
PMID: 18829505
ISSN: 1078-0432
CID: 92160
Impact of Socioeconomic Factors on Prostate Cancer Outcomes in Black Patients Treated with Surgery
Dash, Atreya; Lee, Peng; Zhou, Qin; Jean-Gilles, Jerome; Taneja, Samir; Satagopan, Jaya; Reuter, Victor; Gerald, William; Eastham, James; Osman, Iman
OBJECTIVES: The role of socioeconomic factors in the worse outcome of black men with prostate cancer remains unclear. To determine whether socioeconomic factors affect prostate cancer outcomes, we studied a cohort of only black patients to minimize known confounding factors. METHODS: We studied black men treated with radical prostatectomy at New York Veterans Administration Medical Center and Memorial Sloan-Kettering Cancer Center between 1990 and 2005. A centralized pathology review process determined the Gleason score of all cases. Prostate-specific antigen (PSA) recurrence at both sites was defined as PSA of 0.2 or greater with a confirmatory rise. By matching patients' home zip codes to the U.S. Census Bureau database, we obtained corresponding socioeconomic data regarding median household income (income) and percentage of population with a high school (degree). We analyzed income, education, and clinical and pathological parameters for the whole cohort. RESULTS: We studied 430 black patients. They resided in neighborhoods where median household income was $41,498.10 and mean percentage of high school graduates was 73.4%. A total of 88 patients (20.9%) had PSA recurrence. Median follow-up for survivors was 37 months. Neither income nor education evaluated as continuous or categorical variables were predictors of PSA recurrence. When evaluated as composite categorical variable, the combination of greater income and education did not predict disease-free survival. CONCLUSIONS: Data suggest that socioeconomic factors have limited impact on PSA recurrence in black men treated with radical prostatectomy. Thus, biologic factors might have a role in the poor outcomes in this population
PMCID:2946076
PMID: 18295314
ISSN: 1527-9995
CID: 76449