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1.
JCO Glob Oncol ; 9: e2300140, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37883726

RESUMO

PURPOSE: Biobanking helps source tissue and blood for studying cancer genomics. Access to biorepository resources in low- and middle-income countries is lacking. Memorial Sloan Kettering Cancer Center (MSK) and the American University of Beirut (AUB) established a joint tissue biorepository at AUB in Beirut, Lebanon. The undertaking encountered key challenges that were unanticipated. MATERIALS AND METHODS: Patients age 18 years or older were eligible for enrollment at AUB. After consent, biospecimens were obtained at the time of routine diagnostic and/or therapeutic interventions. Both normal and abnormal tissue and solid and/or liquid specimens were collected from varied body sites. Early on, declining consent was frequently observed, and this was highlighted for investigation to understand potential participants reasoning. RESULTS: Of 850 patients approached, 704 (70.8%) elected to consent and 293 (29.5%) declined participation. The number of declined consents led to an amendment permitting the documentation of reasons for same. Of 100 potential participants who declined to consent and to whom outreach was undertaken, 63% indicated lack of research awareness and 27% deferral to their primary physician or family member. A financial gain for AUB was cited as concern by 5%, cultural boundaries in 4%, and 1% expressed concern about confidentiality. Of the patients who elected to consent, 682 biospecimens were procured. CONCLUSION: The AUB-MSK biospecimen repository has provided a unique resource for interrogation. Patient participation rate was high, and analyses of those who elected not to consent (29%) provide important insights into educational need and the local and cultural awareness and norms.


Assuntos
Bancos de Espécimes Biológicos , Neoplasias , Humanos , Estados Unidos , Adolescente , Países em Desenvolvimento , Neoplasias/diagnóstico , Neoplasias/terapia , Genômica , Líbano
2.
PLoS One ; 9(8): e103896, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25083786

RESUMO

The development of breast cancer metastasis is accompanied by dynamic transcriptome changes and dramatic alterations in nuclear and chromatin structure. The basis of these changes is incompletely understood. The DNA methylome of primary breast cancers contribute to transcriptomic heterogeneity and different metastatic behavior. Therefore we sought to characterize methylome remodeling during regional metastasis. We profiled the DNA methylome and transcriptome of 44 matched primary breast tumors and regional metastases. Striking subtype-specific patterns of metastasis-associated methylome remodeling were observed, which reflected the molecular heterogeneity of breast cancers. These divergent changes occurred primarily in CpG island (CGI)-poor areas. Regions of methylome reorganization shared by the subtypes were also observed, and we were able to identify a metastasis-specific methylation signature that was present across the breast cancer subclasses. These alterations also occurred outside of CGIs and promoters, including sequences flanking CGIs and intergenic sequences. Integrated analysis of methylation and gene expression identified genes whose expression correlated with metastasis-specific methylation. Together, these findings significantly enhance our understanding of the epigenetic reorganization that occurs during regional breast cancer metastasis across the major breast cancer subtypes and reveal the nature of methylome remodeling during this process.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Ilhas de CpG/genética , Feminino , Humanos , Metilação , Regiões Promotoras Genéticas/genética
3.
Nat Genet ; 45(7): 791-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23685749

RESUMO

Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.


Assuntos
Carcinoma Adenoide Cístico/genética , Transformação Celular Neoplásica/genética , Mutação , Neoplasias das Glândulas Salivares/genética , Animais , Células COS , Carcinoma Adenoide Cístico/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Chlorocebus aethiops , Análise Mutacional de DNA , Perfilação da Expressão Gênica , Estudos de Associação Genética , Humanos , Modelos Biológicos , Mutação/fisiologia , Neoplasias das Glândulas Salivares/metabolismo , Transdução de Sinais/genética , Análise Serial de Tecidos
4.
Cell ; 151(5): 1068-82, 2012 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-23142051

RESUMO

Through in vivo selection of human cancer cell populations, we uncover a convergent and cooperative miRNA network that drives melanoma metastasis. We identify miR-1908, miR-199a-5p, and miR-199a-3p as endogenous promoters of metastatic invasion, angiogenesis, and colonization in melanoma. These miRNAs convergently target apolipoprotein E (ApoE) and the heat shock factor DNAJA4. Cancer-secreted ApoE suppresses invasion and metastatic endothelial recruitment (MER) by engaging melanoma cell LRP1 and endothelial cell LRP8 receptors, respectively, while DNAJA4 promotes ApoE expression. Expression levels of these miRNAs and ApoE correlate with human metastatic progression outcomes. Treatment of cells with locked nucleic acids (LNAs) targeting these miRNAs inhibits metastasis to multiple organs, and therapeutic delivery of these LNAs strongly suppresses melanoma metastasis. We thus identify miRNAs with dual cell-intrinsic/cell-extrinsic roles in cancer, reveal convergent cooperativity in a metastatic miRNA network, identify ApoE as an anti-angiogenic and metastasis-suppressive factor, and uncover multiple prognostic miRNAs with synergistic combinatorial therapeutic potential in melanoma.


Assuntos
Apolipoproteínas E/metabolismo , Melanoma/genética , MicroRNAs/metabolismo , Metástase Neoplásica/genética , Neovascularização Patológica/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP40/metabolismo , Humanos , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , MicroRNAs/antagonistas & inibidores , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Oligonucleotídeos/farmacologia
5.
Head Neck ; 33(9): 1340-5, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21837706

RESUMO

BACKGROUND: Expression of p16 is a marker for human papillomavirus (HPV)-related carcinogenesis in head and neck cancer. The purpose of this study is to determine if p16 immunoreactivity is associated with aberrant expression of components of the PI3 kinase pathway. METHODS: A tissue microarray (TMA) was constructed for 46 archived tonsillar squamous cell carcinoma specimens. Clinical demographics of these patients were analyzed, and the TMA was interrogated with antibodies directed against p16, phosphorylated Akt(Ser473), phosphorylated S6(Ser240/244), phosphorylated S6(Ser235/236), phosphorylated 4E-BP1(Thr37/46), phosphorylated eIF4E(Ser209), PTEN, p21, and p53. RESULTS: There was a significant correlation between history of tobacco abuse (>10 pack/years) and absence of p16 expression (p = .01). Expression of p16 was significantly associated with immunoreactivity of p21 (p = .02), PTEN (p = .02), and phosphorylated eIF4E (p = .03). There was no evidence of association between p16 status and expression of phosphorylated S6, phosphorylated 4E-BP1, or p53. CONCLUSION: p16 positive tonsillar squamous cell carcinoma is characterized by expression of phosphorylated eIF4E that may occur via a mammalian target of rapamycin (mTOR)-independent mechanism.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Fator de Iniciação 4E em Eucariotos/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Tonsilares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidor p16 de Quinase Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Estudos Retrospectivos , Fumar/epidemiologia , Análise Serial de Tecidos
6.
Clin Cancer Res ; 15(16): 5049-59, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19671852

RESUMO

PURPOSE: In breast cancer, somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes. Our aim was to determine the prognostic implications of PIK3CA mutations in breast cancer. EXPERIMENTAL DESIGN: Archival formalin-fixed paraffin-embedded primary breast tumors, from 590 patients selected for known vital status with a median follow-up of 12.8 years and a tumor >1 cm, were genotyped for PIK3CA mutations. Mutation rates and associations between mutation site and clinicopathologic characteristics were assessed. Progression-free survival, overall survival, and breast cancer-specific survival were examined using Kaplan-Meier or competing risk methodology. RESULTS: PIK3CA mutation is identified in 32.5% of breast cancers. PIK3CA mutation significantly associates with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. Patients with PIK3CA mutated tumors have significant improvement in overall survival (P = 0.03) and breast cancer-specific survival (P = 0.004). Analysis for PIK3CA mutation site-specific associations reveals that the H1047R kinase domain mutation highly associates with node negativity (P = 0.007), whereas helical domain hotspot mutations associate with older age at diagnosis (P = 0.004). CONCLUSION: This study defines the positive prognostic significance of PIK3CA mutations. This work is clinically relevant, as it will significantly affect the design of clinical trials planned for phosphatidylinositol 3-kinase-targeted therapy. Future work may define a population of older age breast cancer patients in whom therapy can be minimized.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA/métodos , Inibidores Enzimáticos/uso terapêutico , Feminino , Seguimentos , Ligação Genética , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Mutação/fisiologia , Inibidores de Fosfoinositídeo-3 Quinase , Polimorfismo de Nucleotídeo Único , Prognóstico , Análise Serial de Tecidos , Resultado do Tratamento
7.
Clin Cancer Res ; 15(11): 3842-9, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19435838

RESUMO

PURPOSE: To evaluate whether pretreatment magnetic resonance imaging (MRI)/MR spectroscopic imaging (MRSI) findings and molecular markers in surgical specimens correlate with each other and with pretreatment clinical variables (biopsy Gleason score, clinical stage, and prostate-specific antigen level) and whether they contribute incremental value in predicting prostate cancer recurrence. EXPERIMENTAL DESIGN: Eighty-eight prostate cancer patients underwent MRI/MRSI before radical prostatectomy; imaging findings were scored on a scale of 1 to 7 (no tumor seen-lymph node metastasis). Ki-67, phospho-Akt, and androgen receptor expression in surgical specimens were assessed by immunohistochemistry. To examine correlations between markers and imaging scores, Spearman's correlation was used. To test whether markers and imaging scores differed by clinical stage or Gleason score, Wilcoxon's rank sum test was used. To examine time to recurrence, the methods of Kaplan-Meier were used. Cox proportional hazards models were built and their concordance indices (C-indices) were calculated to evaluate prediction of recurrence. RESULTS: All markers correlated moderately strongly with MRI/MRSI score (all correlation coefficients >0.5). Markers and MRI/MRSI score were strongly associated with clinical stage and biopsy Gleason score (P < 0.01 for all). At last follow-up, 27 patients had recurrence. C-indices for MRI/MRSI score and all markers were associated with time to recurrence and ranged from 0.78 to 0.89. A Cox model combining all clinical predictors had a C-index of 0.89; the C-index increased to 0.95 when MRI/MRSI score was added and to 0.97 when markers were also added. CONCLUSIONS: MRI/MRSI findings and molecular markers correlated well with each other and contributed incremental value to clinical variables in predicting prostate cancer recurrence.


Assuntos
Biomarcadores Tumorais/análise , Imageamento por Ressonância Magnética/métodos , Neoplasias da Próstata/patologia , Idoso , Humanos , Imuno-Histoquímica/estatística & dados numéricos , Estimativa de Kaplan-Meier , Antígeno Ki-67/análise , Imageamento por Ressonância Magnética/estatística & dados numéricos , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Fosfoproteínas/análise , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-akt/análise , Receptores Androgênicos/análise , Índice de Gravidade de Doença
8.
Radiology ; 250(3): 803-12, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19244047

RESUMO

PURPOSE: To retrospectively assess whether magnetic resonance (MR) imaging and MR spectroscopic imaging and selected molecular markers correlate with each other and with clinically insignificant and significant prostate cancer (PCa), as defined at surgical pathologic analysis. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant study and waived informed consent. Eighty-nine men (mean age, 63 years; range, 46-79 years) with biopsy-proved PCa underwent combined endorectal MR imaging and MR spectroscopic imaging before radical prostatectomy. Suspicion of clinically insignificant PCa was retrospectively and separately recorded for MR imaging and combined MR imaging and MR spectroscopic imaging by using a scale of 0-3. Clinically insignificant PCa was pathologically defined as organ-confined cancer of 0.5 cm(3) or less without poorly differentiated elements. Prostatectomy specimens underwent immunohistochemical analysis for three molecular markers: Ki-67, phospho-Akt (pAkt), and androgen receptor (AR). To examine differences in marker levels for clinically insignificant and significant cancer, a Wilcoxon rank sum test was used. To examine correlations between marker levels and MR imaging or combined MR imaging and MR spectroscopic imaging scores, the Spearman correlation was used. RESULTS: Twenty-one (24%) patients had clinically insignificant and 68 (76%) had clinically significant PCa at surgical pathologic review. All markers were significantly correlated with MR imaging and combined MR imaging and MR spectroscopic imaging findings (all correlation coefficients >0.5). In differentiating clinically insignificant from clinically significant PCa, areas under the receiver operating characteristic curves for Ki-67, AR, pAkt, MR imaging, and combined MR imaging and MR spectroscopic imaging were 0.75, 0.78, 0.80, 0.85, and 0.91, respectively. CONCLUSION: The use of pretreatment MR imaging or combined MR imaging and MR spectroscopic imaging and molecular marker analyses of biopsy samples could facilitate better treatment selection. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/250/3/803/DC1.


Assuntos
Antígeno Ki-67/análise , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/análise , Receptores Androgênicos/análise , Idoso , Biomarcadores/análise , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/metabolismo , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estatística como Assunto , Distribuição Tecidual
9.
Int J Radiat Oncol Biol Phys ; 69(1): 62-9, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17707266

RESUMO

PURPOSE: To determine whether prostate cancer local recurrence after radiation therapy (RT) occurs at the site of primary tumor by retrospectively comparing the tumor location on pre-RT and post-RT magnetic resonance imaging (MRI) and using step-section pathology after salvage radical prostatectomy (SRP) as the reference standard. METHODS AND MATERIALS: Nine patients with localized prostate cancer were treated with intensity modulated RT (69-86.4 Gy), and had pre-RT and post-RT prostate MRI, biopsy-proven local recurrence, and SRP. The location and volume of lesions on pre-RT and post-RT MRI were correlated with step-section pathology findings. Tumor foci >0.2 cm(3) and/or resulting in extraprostatic disease on pathology were considered clinically significant. RESULTS: All nine significant tumor foci (one in each patient; volume range, 0.22-8.63 cm(3)) were detected both on pre-RT and post-RT MRI and displayed strikingly similar appearances on pre-RT and post-RT MRI and step-section pathology. Two clinically insignificant tumor foci (

Assuntos
Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/patologia , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Prostatectomia , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada , Estudos Retrospectivos , Terapia de Salvação , Carga Tumoral
10.
BJU Int ; 100(2): 259-63, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17555476

RESUMO

UNLABELLED: The importance of markers in urological cancer is well recognised and many attempts are being made to find one which will be of prognostic significance. Authors from New York found that low expression of p27Kip1 in patients with bladder cancer was a significant predictor of pelvic recurrence, progression to metastasis and death. Authors from Switzerland examined patients with a primary solitary distal ureteric TCC; they found that distal ureteric resection in such patients is feasible, and that the long-term oncological outcome appears to be comparable to more radical treatment of this condition. OBJECTIVE: To define the prognostic significance of p27(Kip1) expression in bladder cancer for overall, disease-specific, metastasis-free and pelvic recurrence-free survival, and to identify clinical and pathological correlates of p27(Kip1) immunophenotypes. PATIENTS AND METHODS: Tumour samples from 128 evaluable patients with bladder cancer were assessed by immunohistochemistry for p27(Kip1) and E2F-1 expression. Immunoreactivity of p27(Kip1) was correlated with clinicopathological variables, E2F-1 immunoreactivity, and outcome. Multivariate analysis was used to assess predictors of outcome. The median follow-up was 30.9 months overall and 105.7 months in the 32 patients alive at the last follow-up. RESULTS: The fraction of tumour cells with p27(Kip1) nuclear immunoreactivity was <5% in 15, 5-25% in 30, 25-50% in 19, 50-75% in 51, and > or = 75% in 13 patients. High-grade tumours and those with lower E2F-1 nuclear reactivity had a lower mean percentage p27(Kip1) reactivity (P = 0.047 and 0.011, respectively). On multivariate analysis, the percentage p27(Kip1) reactivity was a significant independent predictor of pelvic recurrence (P = 0.017), progression to metastases (P = 0.046), death from disease (P = 0.008), and death from any cause (P = 0.017), with a low expression portending a worse prognosis. Suspicion of vascular invasion was a significant independent predictor of progression to metastases (P = 0.002), death from disease, and death from any cause (both P < 0.001). Lymph node involvement was a significant independent predictor of progression to metastases (P = 0.006). CONCLUSIONS: Low expression of p27(Kip1) was a significant independent predictor of pelvic recurrence, progression to metastasis, death from disease and death from any cause, in patients with bladder cancer.


Assuntos
Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Fator de Transcrição E2F1/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias da Bexiga Urinária/patologia , Seguimentos , Humanos , Imuno-Histoquímica , Análise Multivariada , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/mortalidade
11.
Clin Cancer Res ; 11(10): 3836-45, 2005 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-15897584

RESUMO

PURPOSE: Flavopiridol potently enhances the effect of irinotecan with cures in colorectal cancer xenografts, and is associated with modulation of several molecular targets, including p21, Differentiation-related gene 1 (Drg1), and p53. We initiated a phase I trial of the sequential combination of irinotecan followed by flavopiridol to determine the maximal tolerated dose of this combination therapy. PATIENTS AND METHODS: Forty-five patients with advanced solid tumors were enrolled. Irinotecan was administered first (100 or 125 mg/m(2)) followed 7 hours later by escalating flavopiridol (10-70 mg/m(2)) given weekly over 1 hour for 4 of 6 weeks. At the maximal tolerated dose, the pharmacokinetic analysis was expanded and pre- and posttreatment tumor biopsies were done. RESULTS: At irinotecan 100 mg/m(2), dose-limiting diarrhea and myelosuppression were observed with flavopiridol 70 mg/m(2). At irinotecan 125 mg/m(2), we observed dose-limiting hyperbilirubinemia, fatigue, and myelosuppression at flavopiridol 60 mg/m(2). Peak flavopiridol concentrations of >/=2 mumol/L were achieved above flavopiridol 50 mg/m(2). No significant pharmacokinetic interactions with irinotecan were noted. Baseline serum bilirubin significantly predicted cycle 1 dose-limiting toxicity and neutropenia. We observed partial responses in three patients and prolonged stable disease (i.e., >6 months) in 36% of patients including adrenocortical cancer and hepatocellular cancer. Patients with wild-type p53 and either no change or low posttreatment biopsy p21 and a decrease in Drg1 expression showed stable or responsive disease to the combination therapy. CONCLUSIONS: The recommended phase II dose with irinotecan 100 mg/m(2) is flavopiridol 60 mg/m(2) and with irinotecan 125 mg/m(2) is flavopiridol 50 mg/m(2). Toxicity can be predicted by baseline bilirubin. Clinical activity is encouraging and may correlate to changes in p21 and Drg1 levels in patients with wild type p53 tumors following therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bilirrubina/análise , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Proteínas de Ciclo Celular/biossíntese , Inibidor de Quinase Dependente de Ciclina p21 , Esquema de Medicação , Interações Medicamentosas , Feminino , Flavonoides/administração & dosagem , Flavonoides/efeitos adversos , Flavonoides/farmacocinética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Irinotecano , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Resultado do Tratamento , Proteína Supressora de Tumor p53/biossíntese
12.
Clin Cancer Res ; 11(9): 3296-302, 2005 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15867226

RESUMO

PURPOSE: The differentiation-related gene-1 (Drg1) is a recently identified gene down-regulated in malignancy and a putative suppressor of colorectal cancer metastases. Its expression is associated with improved survival in patients with prostate or breast cancer. Drg1 expression is also associated with resistance to irinotecan therapy in preclinical colorectal cancer models. The clinical evaluation of Drg1 in colorectal cancer has been limited. We performed this study to evaluate the role of Drg1 in a large cohort of patients with metastatic colorectal cancer who were irinotecan naive. EXPERIMENTAL DESIGN: We examined Drg1 expression by immunohistochemistry in 131 patients with metastatic colorectal cancer enrolled in a clinical trial of adjuvant fluorouracil-based therapy from 1991 to 1995. We correlated expression of Drg1 to numerous clinical and tumor related variables and to patient outcomes, including a subset of patients who recurred and received irinotecan-based therapy. RESULTS: Drg1 expression was identified in all metastatic tissue samples. There was a trend for unilobar metastases with high Drg1 expression (P = 0.07) and a suggestion of improved 2-year survival (82.4% versus 69.6%, P = 0.148). High Drg1 expression suggested irinotecan resistance (P = 0.07). CONCLUSIONS: In colorectal cancer, Drg1 expression may be associated with a less aggressive, indolent colorectal cancer. High Drg1 may also be associated with relative resistance to irinotecan. The role of Drg1 in malignancy continues to be defined.


Assuntos
Camptotecina/análogos & derivados , Proteínas de Ciclo Celular/biossíntese , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Feminino , Fluoruracila/administração & dosagem , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Irinotecano , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Resultado do Tratamento
13.
Mol Cancer Ther ; 3(8): 921-32, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15299075

RESUMO

Current treatments for advanced stage, hormone-resistant prostate cancer are largely ineffective, leading to high patient mortality and morbidity. To fulfill this unmet medical need, we used global gene expression profiling to identify new potential antibody-drug conjugate (ADC) targets that showed maximal prostate cancer-specific expression. TMEFF2, a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor-like domain, had limited normal tissue distribution and was highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific monoclonal antibody (mAb) to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naïve and hormone-resistant disease. To evaluate anti-TMEFF2 mAbs as potential ADCs, one mAb was conjugated to the cytotoxic agent auristatin E via a cathepsin B-sensitive valine-citrulline linker. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2. Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Proteínas de Membrana/química , Proteínas de Membrana/imunologia , Proteínas de Neoplasias/química , Proteínas de Neoplasias/imunologia , Oligopeptídeos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/química , Antineoplásicos/química , Encéfalo/metabolismo , Membrana Celular/metabolismo , Proliferação de Células , Clonagem Molecular , DNA Complementar/metabolismo , Citometria de Fluxo , Folistatina/química , Humanos , Hibridomas/química , Imuno-Histoquímica , Cinética , Metástase Linfática , Masculino , Camundongos , Microscopia de Fluorescência , Dados de Sequência Molecular , Metástase Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Oligopeptídeos/química , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Homologia de Sequência de Aminoácidos , Ressonância de Plasmônio de Superfície , Fatores de Tempo , Transfecção
15.
Clin Cancer Res ; 9(15): 5642-51, 2003 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-14654547

RESUMO

PURPOSE: To characterize the expression profile of p73 in human normal tissues by immunohistochemistry (IHC) and to analyze the correlation between p73 expression and bladder cancer progression. EXPERIMENTAL DESIGN: CJDp73 was characterized for p73alpha detection in Western blot and IHC through its application to isoform-transfected 293 cells. Normal tissues were analyzed by IHC with the CJDp73 antiserum. Transitional cell carcinoma (TCC)-derived cell lines were subjected to reverse transcription-PCR and Western blot. TCC tissue microarrays were analyzed for p73alpha expression by IHC, and the results were statistically analyzed. RESULTS: p73 immunostaining was nuclear and restricted to epithelial cells of certain organs such as squamous epithelium of the epidermis and transitional epithelium of the bladder. The expression was also observed in certain specialized glandular epithelia such as acinar cells of breast and parotid gland. Four of seven TCC-derived cell lines had low to undetectable p73alpha protein levels. We found undetectable or low p73alpha expression in 104 of 154 (68%) TCC cases, this phenotype being more frequently observed in invasive tumors when compared with superficial lesions. This association was statistically significant (P < 0.0001). We also observed a significant association between p53, p63, and p73alpha alterations with bladder cancer progression (P < 0.0001). CONCLUSIONS: p73alpha plays a tumor suppressor role in bladder cancer, and its inactivation occurs through an epigenetic mechanism, most probably involving protein degradation.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Regulação da Expressão Gênica , Genes Supressores de Tumor , Neoplasias/genética , Proteínas Nucleares/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular , Proteínas de Ligação a DNA/análise , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Neoplasias/patologia , Proteínas Nucleares/análise , RNA/genética , RNA/isolamento & purificação , RNA Neoplásico/genética , RNA Neoplásico/isolamento & purificação , Proteínas Recombinantes/análise , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Proteína Tumoral p73 , Proteínas Supressoras de Tumor
16.
Clin Cancer Res ; 9(10 Pt 1): 3578-88, 2003 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-14506144

RESUMO

PURPOSE: To evaluate the safety, pharmacokinetics, and biological activity of suberoylanilide hydroxamic acid (SAHA) administered by 2-h i.v. infusion in patients with advanced cancer. EXPERIMENTAL DESIGN: SAHA was administered for 3 days every 21 days in part A and 5 days for 1-3 weeks in part B. Dose escalation proceeded independently in patients with solid tumor and hematological malignancies (part B only). Pharmacokinetic studies were performed along with assessment of acetylated histones in peripheral blood mononuclear cells and tumor tissues. RESULTS: No dose-limiting toxicities were observed in 8 patients enrolled in part A (75, 150, 300, 600, and 900 mg/m(2)/day). Among 12 hematological and 17 solid tumor patients enrolled in part B (300, 600, and 900 mg/m(2)/day), therapy was delayed > or = 1 week for grade 3/4 leukopenia and/or thrombocytopenia in 2 of 5 hematological patients at 600 mg/m(2)/day x 5 days for 3 weeks. The maximal-tolerated dose was 300 mg/m(2)/day x 5 days for 3 weeks for hematological patients. One solid patient on 900 mg/m(2)/day x 5 days for 3 weeks developed acute respiratory distress and grade 3 hypotension. The cohort was expanded to 6 patients, and no additional dose-limiting toxicities were observed. Mean terminal half-life ranged from 21 to 58 min, and there was dose-proportional increase in area under the curve. An accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion was observed at higher dose levels. Posttherapy tumor biopsies showed an accumulation of acetylated histones by immunohistochemistry. Four (2 lymphoma and 2 bladder) patients had objective tumor regression with clinical improvement in tumor related symptoms. CONCLUSIONS: Daily i.v. SAHA is well tolerated, inhibits the biological target in vivo, and has antitumor activity in solid and hematological tumors.


Assuntos
Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/administração & dosagem , Acetilação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Área Sob a Curva , Biópsia , Relação Dose-Resposta a Droga , Feminino , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacocinética , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Pele/patologia , Fatores de Tempo , Resultado do Tratamento , Vorinostat
17.
Clin Cancer Res ; 9(7): 2613-9, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12855638

RESUMO

PURPOSE: The purpose is to investigate the clinical relevance of altered patterns of p27 and Skp2 expression in African-American patients with localized prostate cancer. The abundance of p27, an inhibitor of cell proliferation, is controlled by Skp2-dependent proteolysis. EXPERIMENTAL DESIGN: A well-characterized cohort of 162 African-Americans who underwent radical prostatectomy at the Veterans Affairs Medical Center of New York between 1990 and 2000 was studied. We analyzed p27 and Skp2 expression by immunohistochemistry. Altered expression of p27 (defined as <40% tumor cells expressing the protein) and Skp2 (defined as > or ==" BORDER="0">20% tumor cells expressing the protein) were correlated with clinicopathological parameters and time to prostate-specific antigen (PSA) recurrence. RESULTS: Altered expression of p27 and Skp2 was observed in 112 of 162 (69.1%) and 93 of 162 (57.4%) cases, respectively. Inverse patterns of Skp2 and p27 protein expression were seen in 87 of 162 (53.7%) cases. A marginally significant association was found between Skp2 overexpression and extracapsular extension (P = 0.065). Moreover, patients with Skp2 overexpression had a 2.77 years decreased median time to PSA recurrence compared with patients with low Skp2 expression; however, the difference was not statistically significant. In multivariate analysis, only tumor grade and stage independently predicted PSA recurrence in this cohort. CONCLUSIONS: Our data suggest a role for Skp2 overexpression in prostate cancer pathogenesis that might not be exclusively related to p27 degradation. More studies are needed to determine the mechanistic role of Skp2 in prostate cancer.


Assuntos
Proteínas de Ciclo Celular/biossíntese , Neoplasias da Próstata/metabolismo , Proteínas Quinases Associadas a Fase S/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Negro ou Afro-Americano , Anticorpos Monoclonais , População Negra , Estudos de Coortes , Inibidor de Quinase Dependente de Ciclina p27 , Citoplasma/metabolismo , Intervalo Livre de Doença , Humanos , Imuno-Histoquímica , Masculino , Análise Multivariada , Fenótipo , Antígeno Prostático Específico/sangue , Ligação Proteica , Recidiva , Fatores de Tempo , Resultado do Tratamento
18.
Clin Cancer Res ; 8(10): 3226-31, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12374693

RESUMO

PURPOSE: Human tumors are dependent on angiogenesis for growth, and vascular endothelial growth factor (VEGF) is a major regulator of this process. We aimed to study clinical utility of a recombinant humanized monoclonal anti-VEGF antibody (rhu alpha VEGF) in the treatment of the CWR22R androgen-independent xenograft model of prostate cancer. EXPERIMENTAL DESIGN: rhu alpha VEGF has previously shown clinical activity in several xenograft cancer models. We administered 5 mg/kg rhu alpha VEGF i.p. twice weekly as a single agent and together with paclitaxel to established CWR22R xenografts. RESULTS: rhu alphaVEGF inhibited established tumor growth by 85% (P < 0.01 for trajectories of the average tumor volumes of the groups) at 3 weeks, but after cessation of rhu alpha VEGF treatment, tumor regrowth ensued. A paclitaxel dosage of 6.25 mg/kg s.c. five times/week slowed tumor growth (72% compared with controls at 3 weeks, P = 0.02). The combination of paclitaxel and rhu alpha VEGF resulted in greater inhibition of tumor growth than that observed with either agent alone (98% growth inhibition, P = 0.024 versus rhualpha VEGF alone and P = 0.02 versus paclitaxel alone). Paclitaxel alone had no antiangiogenic effects at the dosage studied, whereas rhu alpha VEGF had significant inhibition of angiogenesis, noted by microvessel density and CD34 staining. CONCLUSIONS: rhu alpha VEGF has cytostatic clinical activity in this androgen-independent prostate cancer xenograft model, and the addition of paclitaxel demonstrates increased clinical activity.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Fatores de Crescimento Endotelial/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Linfocinas/imunologia , Neoplasias da Próstata/tratamento farmacológico , Androgênios/farmacologia , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose , Western Blotting , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Técnicas Imunoenzimáticas , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Paclitaxel/uso terapêutico , Neoplasias da Próstata/patologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
19.
Am J Pathol ; 160(4): 1215-21, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11943706

RESUMO

Alveolar soft part sarcoma (ASPS) is an unusual tumor of young adults with the characteristic presence on ultrastructural analysis of rhomboid or rectangular cytoplasmic crystals. These membrane-bound crystals are known to form within specific PAS-diastase-resistant electron-dense cytoplasmic granules. The composition of these crystals and the dense granules from which they are derived has remained elusive. After the detection of strong discrete granular cytoplasmic immunoreactivity in ASPS for monocarboxylate transporter 1 (MCT1) in the course of a broad immunohistochemical characterization of an MCT1 antibody, we studied the expression of MCT1 and its interacting partner, CD147, in a panel of 10 ASPS cases using appropriate antibodies. MCT1 is one of a family of widely expressed proton-linked transporters for monocarboxylates such as lactate and pyruvate. In all normal and neoplastic tissues studied to date, MCT1 immunoreactivity is limited to the cell surface. We find that the periodic acid-Schiff-diastase-resistant cytoplasmic granules of ASPS are strongly immunoreactive for MCT1 and CD147. Specifically, intense cytoplasmic granular positivity for MCT1 and CD147 was found in 7 of 10 and 8 of 10 ASPSs, respectively. Ultrastructural immunohistochemistry with immunogold labeling confirmed that the MCT1 immunoreactivity localized to the cytoplasmic electron-dense granules in ASPS. Western blot analysis of several ASPS cases confirmed that the protein reactive with the MCT1 antibody and that reactive with the CD147 antibody both migrated at the size expected for MCT1 and CD147, respectively. Thus, ASPS cells seem to accumulate MCT1-CD147 complexes in the specific cytoplasmic granules known to undergo crystallization. The possible basis for the overproduction or impaired surface localization of these proteins in ASPS remains unclear.


Assuntos
Antígenos CD , Antígenos de Neoplasias , Antígenos de Superfície , Proteínas Aviárias , Proteínas Sanguíneas , Grânulos Citoplasmáticos/metabolismo , Neoplasias Pulmonares/metabolismo , Glicoproteínas de Membrana/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Alvéolos Pulmonares , Simportadores/metabolismo , Adulto , Basigina , Western Blotting , Grânulos Citoplasmáticos/ultraestrutura , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/ultraestrutura , Masculino , Glicoproteínas de Membrana/ultraestrutura , Microscopia Eletrônica , Transportadores de Ácidos Monocarboxílicos/ultraestrutura , Simportadores/ultraestrutura
20.
Clin Cancer Res ; 8(3): 679-83, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11895895

RESUMO

PURPOSE: To evaluate the safety and pharmacokinetics of BCL-2 antisense oligonucleotide (G3139) administered by prolonged i.v. infusion in patients with advanced cancer. EXPERIMENTAL DESIGN: A total of 35 patients was treated in cohorts of 3-6 with 0.6-6.9 mg/kg/day of BCL-2 antisense oligonucleotide as a continuous infusion for 14 or 21 days. Plasma levels of intact antisense oligonucleotide were measured in all patients. RESULTS: G3139 was generally well tolerated. At the highest dose level examined in this study (6.9 mg/kg/day), fatigue and transient reversible elevations of serum transaminases (grades 2-3) became apparent after >or=7 days of treatment. Both reactions were believed to be drug related. Pharmacokinetic analyses showed that steady-state plasma concentrations of G3139 were reached approximately 10 h after starting the infusion and increased linearly across the range of doses administered

Assuntos
Antineoplásicos/administração & dosagem , Genes bcl-2/genética , Neoplasias/tratamento farmacológico , Oligonucleotídeos Antissenso/administração & dosagem , Tionucleotídeos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Western Blotting , Estudos de Coortes , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Neoplasias/metabolismo , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/farmacocinética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Segurança , Tionucleotídeos/efeitos adversos , Tionucleotídeos/farmacocinética , Transaminases/sangue
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