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1.
BMJ Open Respir Res ; 8(1)2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34969771

RESUMEN

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA1-6). Signalling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA1 antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD. METHODS AND ANALYSIS: This phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort. ETHICS AND DISSEMINATION: This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT04308681.


Asunto(s)
Fibrosis Pulmonar Idiopática , Receptores del Ácido Lisofosfatídico , Adulto , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Lisofosfolípidos/uso terapéutico , Receptores del Ácido Lisofosfatídico/uso terapéutico , Capacidad Vital
2.
J Nucl Med ; 59(3): 529-535, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29025984

RESUMEN

The programmed death protein (PD-1) and its ligand (PD-L1) play critical roles in a checkpoint pathway cancer cells exploit to evade the immune system. A same-day PET imaging agent for measuring PD-L1 status in primary and metastatic lesions could be important for optimizing drug therapy. Herein, we have evaluated the tumor targeting of an anti-PD-L1 adnectin after 18F-fluorine labeling. Methods: An anti-PD-L1 adnectin was labeled with 18F in 2 steps. This synthesis featured fluorination of a novel prosthetic group, followed by a copper-free click conjugation to a modified adnectin to generate 18F-BMS-986192. 18F-BMS-986192 was evaluated in tumors using in vitro autoradiography and PET with mice bearing bilateral PD-L1-negative (PD-L1(-)) and PD-L1-positive (PD-L1(+)) subcutaneous tumors. 18F-BMS-986192 was evaluated for distribution, binding, and radiation dosimetry in a healthy cynomolgus monkey. Results:18F-BMS-986192 bound to human and cynomolgus PD-L1 with a dissociation constant of less than 35 pM, as measured by surface plasmon resonance. This adnectin was labeled with 18F to yield a PET radioligand for assessing PD-L1 expression in vivo. 18F-BMS-986192 bound to tumor tissues as a function of PD-L1 expression determined by immunohistochemistry. Radioligand binding was blocked in a dose-dependent manner. In vivo PET imaging clearly visualized PD-L1 expression in mice implanted with PD-L1(+), L2987 xenograft tumors. Two hours after dosing, a 3.5-fold-higher uptake (2.41 ± 0.29 vs. 0.82 ± 0.11 percentage injected dose per gram, P < 0.0001) was observed in L2987 than in control HT-29 (PD-L1(-)) tumors. Coadministration of 3 mg/kg ADX_5322_A02 anti-PD-L1 adnectin reduced tumor uptake at 2 h after injection by approximately 70%, whereas HT-29 uptake remained unchanged, demonstrating PD-L1-specific binding. Biodistribution in a nonhuman primate showed binding in the PD-L1-rich spleen, with rapid blood clearance through the kidneys and bladder. Binding in the PD-L1(+) spleen was reduced by coadministration of BMS-986192. Dosimetry estimates indicate that the kidney is the dose-limiting organ, with an estimated human absorbed dose of 2.20E-01 mSv/MBq. Conclusion:18F-BMS-986192 demonstrated the feasibility of noninvasively imaging the PD-L1 status of tumors by small-animal PET studies. Clinical studies with 18F-BMS-986192 are under way to measure PD-L1 expression in human tumors.


Asunto(s)
Antígeno B7-H1/metabolismo , Radioisótopos de Flúor , Neoplasias/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Radiofármacos/síntesis química , Animales , Femenino , Regulación Neoplásica de la Expresión Génica , Células HT29 , Humanos , Marcaje Isotópico , Ligandos , Macaca fascicularis , Ratones , Radiofármacos/metabolismo , Radiofármacos/farmacocinética , Distribución Tisular
3.
Bioorg Med Chem ; 25(20): 5407-5414, 2017 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-28803798

RESUMEN

Cancer immunotherapy, unlike traditional cytotoxic chemotherapeutic treatments, engages the immune system to identify cancer cells and stimulate immune responses. The Programmed Death-1 (PD-1) protein is an immunoinhibitory receptor expressed by activated cytotoxic T-lymphocytes (CTL) that seek out and destroy cancer cells. Multiple cancer types express and upregulate the Programmed Death-Ligand 1 (PD-L1) and 2 (PD-L2) which bind to PD-1 as an immune escape mechanism. Nivolumab is a fully human IgG4 anti-PD-1 monoclonal antibody (mAb) approved for treatment of multiple cancer types. This study reports the preparation and in vivo evaluation of 89Zr labeled nivolumab in healthy non-human primates (NHP) as a preliminary study of biodistribution and clearance. The radiochemical and in vivo stabilities of the 89Zr complex were shown to be acceptable for imaging. Three naïve NHPs were intravenously injected with tracer only or tracer co-injected with nivolumab followed by co-registered by positron emission tomography (PET) and magnetic resonance imaging (MRI), acquired for eight days following injection. Image-derived standardized uptake values (SUV) were quantified by region of interest (ROI) analysis. Radioactivity in the spleen was significantly reduced by addition of excess nivolumab compared to the tracer only study at all imaging time points. Liver uptake of the radiotracer was consistent as a clearance organ with minimal signal from other tissues: lung, muscle, brain, heart, and kidney. The results indicate specific biodistribution to the spleen, which can be blocked by co-administration of excess nivolumab. Distribution to other organs is consistent with elimination pathways of antibodies, with primary clearance through the liver.


Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Tomografía de Emisión de Positrones , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/química , Relación Dosis-Respuesta a Droga , Macaca fascicularis , Imagen por Resonancia Magnética , Masculino , Estructura Molecular , Nivolumab , Relación Estructura-Actividad , Distribución Tisular
4.
Magn Reson Imaging ; 37: 195-202, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27919785

RESUMEN

BACKGROUND: Diffusion-weighted MRI (DWI) signal attenuation is often not mono-exponential (i.e. non-Gaussian diffusion) with stronger diffusion weighting. Several non-Gaussian diffusion models have been developed and may provide new information or higher sensitivity compared with the conventional apparent diffusion coefficient (ADC) method. However the relative merits of these models to detect tumor therapeutic response is not fully clear. METHODS: Conventional ADC, and three widely-used non-Gaussian models, (bi-exponential, stretched exponential, and statistical model), were implemented and compared for assessing SW620 human colon cancer xenografts responding to barasertib, an agent known to induce apoptosis via polyploidy. Bayesian Information Criterion (BIC) was used for model selection among all three non-Gaussian models. RESULTS: All of tumor volume, histology, conventional ADC, and three non-Gaussian DWI models could show significant differences between control and treatment groups after four days of treatment. However, only the non-Gaussian models detected significant changes after two days of treatment. For any treatment or control group, over 65.7% of tumor voxels indicate the bi-exponential model is strongly or very strongly preferred. CONCLUSION: Non-Gaussian DWI model-derived biomarkers are capable of detecting tumor earlier chemotherapeutic response of tumors compared with conventional ADC and tumor volume. The bi-exponential model provides better fitting compared with statistical and stretched exponential models for the tumor and treatment models used in the current work.


Asunto(s)
Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/tratamiento farmacológico , Imagen de Difusión por Resonancia Magnética/métodos , Dimetilsulfóxido/administración & dosificación , Organofosfatos/uso terapéutico , Quinazolinas/uso terapéutico , Animales , Teorema de Bayes , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Desnudos , Modelos Estadísticos , Inhibidores de Proteínas Quinasas/uso terapéutico
5.
PLoS One ; 8(3): e58938, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23554961

RESUMEN

BACKGROUND: Non-invasive imaging biomarkers of cellular proliferation hold great promise for quantifying response to personalized medicine in oncology. An emerging approach to assess tumor proliferation utilizes the positron emission tomography (PET) tracer 3'-deoxy-3'[(18)F]-fluorothymidine, [(18)F]-FLT. Though several studies have associated serial changes in [(18)F]-FLT-PET with elements of therapeutic response, the degree to which [(18)F]-FLT-PET quantitatively reflects proliferative index has been continuously debated for more that a decade. The goal of this study was to elucidate quantitative relationships between [(18)F]-FLT-PET and cellular metrics of proliferation in treatment naïve human cell line xenografts commonly employed in cancer research. METHODS AND FINDINGS: [(18)F]-FLT-PET was conducted in human cancer xenograft-bearing mice. Quantitative relationships between PET, thymidine kinase 1 (TK1) protein levels and immunostaining for proliferation markers (Ki67, TK1, PCNA) were evaluated using imaging-matched tumor specimens. Overall, we determined that [(18)F]-FLT-PET reflects TK1 protein levels, yet the cell cycle specificity of TK1 expression and the extent to which tumors utilize thymidine salvage for DNA synthesis decouple [(18)F]-FLT-PET data from standard estimates of proliferative index. CONCLUSIONS: Our findings illustrate that [(18)F]-FLT-PET reflects tumor proliferation as a function of thymidine salvage pathway utilization. Unlike more general proliferation markers, such as Ki67, [(18)F]-FLT PET reflects proliferative indices to variable and potentially unreliable extents. [(18)F]-FLT-PET cannot discriminate moderately proliferative, thymidine salvage-driven tumors from those of high proliferative index that rely primarily upon de novo thymidine synthesis. Accordingly, the magnitude of [(18)F]-FLT uptake should not be considered a surrogate of proliferative index. These data rationalize the diversity of [(18)F]-FLT-PET correlative results previously reported and suggest future best-practices when [(18)F]-FLT-PET is employed in oncology.


Asunto(s)
Didesoxinucleósidos , Neoplasias/diagnóstico , Tomografía de Emisión de Positrones , Animales , Biomarcadores/metabolismo , Línea Celular Tumoral , Proliferación Celular , Didesoxinucleósidos/metabolismo , Modelos Animales de Enfermedad , Células HCT116 , Humanos , Inmunohistoquímica , Ratones , Mutación , Neoplasias/genética , Neoplasias/metabolismo , Timidina/metabolismo , Trasplante Heterólogo
6.
J Nucl Med ; 54(3): 424-30, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23341544

RESUMEN

UNLABELLED: Selective inhibition of oncogenic targets and associated signaling pathways forms the basis of personalized cancer medicine. The clinical success of (V600E)BRAF inhibition in melanoma, coupled with the emergence of acquired resistance, underscores the importance of rigorously validating quantitative biomarkers of treatment response in this and similar settings. Because constitutive activation of BRAF leads to proliferation in tumors, we explored 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET to noninvasively quantify changes in tumor proliferation that are associated with pharmacologic inhibition of (V600E)BRAF downstream effectors and that precede changes in tumor volume. METHODS: Human colorectal cancer (CRC) cell lines expressing (V600E)BRAF were used to explore relationships between upregulation of p27 and phosphorylation of BRAF downstream effectors on small-molecule (V600E)BRAF inhibitor exposure. Athymic nude mice bearing (V600E)BRAF-expressing human CRC cell line xenografts were treated with a small-molecule (V600E)BRAF inhibitor (or vehicle) daily for 10 d. Predictive (18)F-FLT PET was conducted before changes in tumor volume occurred. Correlations were evaluated among PET, inhibition of phosphorylated MEK (p-MEK) and phosphorylated-ERK (p-ERK) by Western blot, tumor proliferation by histology, and small-molecule exposure by matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS). RESULTS: Treatment of CRC cell lines with PLX4720 reduced proliferation associated with target inhibition and upregulation of p27. In vivo, PLX4720 treatment reduced (18)F-FLT uptake, but not (18)F-FDG uptake, in Lim2405 xenografts before quantifiable differences in xenograft volume. Reduced (18)F-FLT PET reflected a modest, yet significant, reduction of Ki67 immunoreactivity, inhibition of p-MEK and p-ERK, and elevated tumor cell p27 protein levels. Both (18)F-FLT PET and (18)F-FDG PET accurately reflected a lack of response in HT-29 xenografts, which MALDI imaging mass spectrometry suggested may have stemmed from limited PLX4720 exposure. CONCLUSION: We used preclinical models of CRC to demonstrate (18)F-FLT PET as a sensitive predictor of response to (V600E)BRAF inhibitors. Because (18)F-FLT PET predicted reduced proliferation associated with attenuation of BRAF downstream effectors, yet (18)F-FDG PET did not, these data suggest that (18)F-FLT PET may represent an alternative to (18)F-FDG PET for quantifying clinical responses to BRAF inhibitors.


Asunto(s)
Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/terapia , Didesoxinucleósidos , Terapia Molecular Dirigida , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos , Radioisótopos de Flúor , Humanos , Indoles/uso terapéutico , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Desnudos , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Inhibidores de Proteínas Quinasas/uso terapéutico , Radiofármacos , Sulfonamidas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
7.
PLoS One ; 7(7): e41714, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22911846

RESUMEN

Measurements of apparent diffusion coefficient (ADC) using magnetic resonance imaging (MRI) have been suggested as potential imaging biomarkers for monitoring tumor response to treatment. However, conventional pulsed-gradient spin echo (PGSE) methods incorporate relatively long diffusion times, and are usually sensitive to changes in cell density and necrosis. Diffusion temporal spectroscopy using the oscillating gradient spin echo (OGSE) sequence is capable of probing short length scales, and may detect significant intracellular microstructural changes independent of gross cell density changes following anti-cancer treatment. To test this hypothesis, SW620 xenografts were treated by barasertib (AZD1152), a selective inhibitor of Aurora B kinase which causes SW620 cancer cells to develop polyploidy and increase in size following treatment, ultimately leading to cell death through apoptosis. Following treatment, the ADC values obtained by both the PGSE and low frequency OGSE methods increased. However, the ADC values at high gradient frequency (i.e. short diffusion times) were significantly lower in treated tumors, consistent with increased intracellular restrictions/hindrances. This suggests that ADC values at long diffusion times are dominated by tumor microstructure at long length scales, and may not convey unambiguous information of subcellular space. While the diffusion temporal spectroscopy provides more comprehensive means to probe tumor microstructure at various length scales. This work is the first study to probe intracellular microstructural variations due to polyploidy following treatment using diffusion MRI in vivo. It is also the first observation of post-treatment ADC changes occurring in opposite directions at short and long diffusion times. The current study suggests that temporal diffusion spectroscopy potentially provides pharmacodynamic biomarkers of tumor early response which distinguish microstructural variations following treatment at both the subcellular and supracellular length scales.


Asunto(s)
Antineoplásicos/uso terapéutico , Imagen de Difusión por Resonancia Magnética/métodos , Neoplasias/tratamiento farmacológico , Análisis Espectral/métodos , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Desnudos , Neoplasias/patología , Fantasmas de Imagen , Marcadores de Spin , Factores de Tiempo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Ann Nucl Med ; 26(9): 757-63, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22821337

RESUMEN

Molecular imaging biomarkers of proliferation hold great promise for quantifying response to personalized medicine. One such approach utilizes the positron emission tomography (PET) tracer 3'-deoxy-3'[18F]-fluorothymidine ([18F]FLT), an investigational agent whose uptake reflects thymidine salvage-dependent DNA synthesis. The goal of this study was to evaluate [18F]FLT-PET in the setting of Ménétrier's disease (MD), a rare, premalignant hyperproliferative disorder of the stomach treatable with cetuximab therapy. Over 15 months, a patient with confirmed MD underwent cetuximab therapy and was followed with sequential [18F]FLT-PET. For comparison to MD, an [18F]FLT-PET study was conducted in another patient to quantify uptake in a normal stomach. Prior to cetuximab therapy, stomach tissue in MD was easily visualized with [18F]FLT-PET, with pre-treatment uptake levels exceeding normal stomach uptake by approximately fourfold. Diminished [18F]FLT-PET in MD was observed following the initial and subsequent doses of cetuximab and correlated with clinical resolution of the disease. To our knowledge, this study reports the first clinical use of [18F]FLT-PET to assess proliferation in a premalignant disorder. We illustrate that the extent of MD involvement throughout the stomach could be easily visualized using [18F]FLT-PET, and that response to cetuximab could be followed quantitatively and non-invasively in sequential [18F]FLT-PET studies. Thus, [18F]FLT-PET appears to have potential to monitor response to treatment in this and potentially other hyperproliferative disorders.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Didesoxinucleósidos , Gastritis Hipertrófica/diagnóstico por imagen , Gastritis Hipertrófica/tratamiento farmacológico , Imagen Multimodal , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Anticuerpos Monoclonales Humanizados/uso terapéutico , Cetuximab , Femenino , Gastritis Hipertrófica/patología , Humanos , Persona de Mediana Edad , Resultado del Tratamiento
9.
J Nucl Med ; 53(2): 287-94, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22251555

RESUMEN

UNLABELLED: There is a critical need to develop and rigorously validate molecular imaging biomarkers to aid diagnosis and characterization of primary brain tumors. Elevated expression of translocator protein (TSPO) has been shown to predict disease progression and aggressive, invasive behavior in a variety of solid tumors. Thus, noninvasive molecular imaging of TSPO expression could form the basis of a novel, predictive cancer imaging biomarker. In quantitative preclinical PET studies, we evaluated a high-affinity pyrazolopyrimidinyl-based TSPO imaging ligand, N,N-diethyl-2-(2-(4-(2-(18)F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ((18)F-DPA-714), as a translational probe for quantification of TSPO levels in glioma. METHODS: Glioma-bearing rats were imaged with (18)F-DPA-714 in a small-animal PET system. Dynamic images were acquired simultaneously on injection of (18)F-DPA-714 (130-200 MBq/0.2 mL). Blood was collected to derive the arterial input function (AIF), with high-performance liquid chromatography radiometabolite analysis performed on selected samples for AIF correction. Compartmental modeling was performed using the corrected AIF. Specific tumor cell binding of DPA-714 was evaluated by radioligand displacement of (3)H-PK 11195 with DPA-714 in vitro and displacement of (18)F-DPA-714 with an excess of DPA-714 in vivo. Immediately after imaging, tumor and healthy brain tissues were harvested for validation by Western blotting and immunohistochemistry. RESULTS: (18)F-DPA-714 was found to preferentially accumulate in tumors, with modest uptake in the contralateral brain. Infusion with DPA-714 (10 mg/kg) displaced (18)F-DPA-714 binding by greater than 60% on average. Tumor uptake of (18)F-DPA-714 was similar to another high-affinity TSPO imaging ligand, (18)F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline, and agreed with ex vivo assay of TSPO levels in tumor and healthy brain. CONCLUSION: These studies illustrate the feasibility of using (18)F-DPA-714 for visualization of TSPO-expressing brain tumors. Importantly, (18)F-DPA-714 appears suitable for quantitative assay of tumor TSPO levels in vivo. Given the relationship between elevated TSPO levels and poor outcome in oncology, these studies suggest the potential of (18)F-DPA-714 PET to serve as a novel predictive cancer imaging modality.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Proteínas Portadoras/metabolismo , Radioisótopos de Flúor , Regulación Neoplásica de la Expresión Génica , Glioma/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Pirazoles , Pirimidinas , Receptores de GABA-A/metabolismo , Acetanilidas/metabolismo , Animales , Transporte Biológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Estudios de Factibilidad , Glioma/genética , Glioma/metabolismo , Masculino , Pirazoles/metabolismo , Pirimidinas/metabolismo , Ratas
10.
Cancer Discov ; 1(4): 338-51, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22049316

RESUMEN

Most estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. ER downregulation with fulvestrant or small interfering RNA (siRNA) inhibited estrogen-independent growth. Chromatin immunoprecipitation identified ER genomic binding activity in estrogen-deprived cells and primary breast tumors treated with aromatase inhibitors. Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients' tumors. siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth. Long-term estrogen-deprived cells hyperactivate phosphatidylinositol 3-kinase (PI3K) independently of ER/E2F. Fulvestrant combined with the pan-PI3K inhibitor BKM120 induced regression of ER(+) xenografts. These data support further development of ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for treatment of antiestrogen-resistant breast cancers.


Asunto(s)
Neoplasias de la Mama/genética , Factores de Transcripción E2F/genética , Factores de Transcripción E2F/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Estrógenos/deficiencia , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Regulación hacia Abajo , Resistencia a Antineoplásicos , Moduladores de los Receptores de Estrógeno/farmacología , Estrógenos/metabolismo , Estrógenos/farmacología , Femenino , Expresión Génica , Humanos , Ratones , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Transcripción Genética
11.
Cancer Res ; 71(21): 6773-84, 2011 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-21908557

RESUMEN

Estrogen receptor α (ER)-positive breast cancers adapt to hormone deprivation and become resistant to antiestrogens. In this study, we sought to identify kinases essential for growth of ER(+) breast cancer cells resistant to long-term estrogen deprivation (LTED). A kinome-wide siRNA screen showed that the insulin receptor (InsR) is required for growth of MCF-7/LTED cells. Knockdown of InsR and/or insulin-like growth factor-I receptor (IGF-IR) inhibited growth of 3 of 4 LTED cell lines. Inhibition of InsR and IGF-IR with the dual tyrosine kinase inhibitor OSI-906 prevented the emergence of hormone-independent cells and tumors in vivo, inhibited parental and LTED cell growth and PI3K/AKT signaling, and suppressed growth of established MCF-7 xenografts in ovariectomized mice, whereas treatment with the neutralizing IGF-IR monoclonal antibody MAB391 was ineffective. Combined treatment with OSI-906 and the ER downregulator fulvestrant more effectively suppressed hormone-independent tumor growth than either drug alone. Finally, an insulin/IGF-I gene expression signature predicted recurrence-free survival in patients with ER(+) breast cancer treated with the antiestrogen tamoxifen. We conclude that therapeutic targeting of both InsR and IGF-IR should be more effective than targeting IGF-IR alone in abrogating resistance to endocrine therapy in breast cancer.


Asunto(s)
Adenocarcinoma/patología , Neoplasias de la Mama/patología , Estrógenos , Factor I del Crecimiento Similar a la Insulina/fisiología , Insulina/fisiología , Proteínas de Neoplasias/fisiología , Neoplasias Hormono-Dependientes/fisiopatología , Receptor IGF Tipo 1/fisiología , Receptor de Insulina/fisiología , Transducción de Señal/fisiología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/fisiopatología , Animales , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/fisiopatología , Línea Celular Tumoral/efectos de los fármacos , Supervivencia sin Enfermedad , Estradiol/análogos & derivados , Estradiol/uso terapéutico , Moduladores de los Receptores de Estrógeno/uso terapéutico , Femenino , Fulvestrant , Regulación Neoplásica de la Expresión Génica , Humanos , Imidazoles/uso terapéutico , Ratones , Ratones Desnudos , Proteínas de Neoplasias/análisis , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Pirazinas/uso terapéutico , Interferencia de ARN , Distribución Aleatoria , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Receptores de Estrógenos/análisis , Tamoxifeno/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Front Biosci (Landmark Ed) ; 16(2): 393-410, 2011 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-21196177

RESUMEN

Molecular imaging comprises a range of techniques, spanning not only several imaging modalities but also many disease states and organ sites. While advances in new technology platforms have enabled a deeper understanding of the cellular and molecular basis of malignancy, reliable non-invasive imaging metrics remain an important tool for both diagnostics and patient management. Furthermore, the non- invasive nature of molecular imaging can overcome shortcomings associated with traditional biological approaches and provide valuable information relevant to patient care. Integration of information from multiple imaging techniques has the potential to provide a more comprehensive understanding of specific tumor characteristics, tumor status, and treatment response.


Asunto(s)
Imagen Molecular/métodos , Neoplasias/diagnóstico , Diagnóstico por Imagen , Didesoxinucleósidos/metabolismo , Fluorodesoxiglucosa F18 , Humanos , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Tomografía de Emisión de Positrones , Timidina Quinasa/metabolismo
13.
Bioconjug Chem ; 20(11): 2185-9, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19883074

RESUMEN

Double drugs are obtained when two pharmacologically active entities are covalently joined to improve potency. We conjugated the viridin Wm with a self-activating linkage to cetuximab and demonstrated the retention of immunoreactivity by the conjugate. Though cetuximab lacked a growth inhibitory activity against A549 cells, the Wm-cetuximab conjugate had an antiproliferative IC(50) of 155 nM in vitro. The chemistry of attaching a self-releasing Wm to clinically approved antibodies is general and, in selected instances, may yield antibody-based double drugs with improved efficacy.


Asunto(s)
Androstadienos/química , Anticuerpos Monoclonales/química , Antineoplásicos/síntesis química , Diseño de Fármacos , Androstadienos/farmacología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cetuximab , Reactivos de Enlaces Cruzados , Sinergismo Farmacológico , Humanos , Inmunoconjugados , Inmunosupresores/síntesis química , Concentración 50 Inhibidora , Wortmanina
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