Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
1.
Nat Commun ; 15(1): 2178, 2024 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-38467639

RESUMEN

Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3-11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Fosfatidilserinas , Receptor de Muerte Celular Programada 1 , Neoplasias Hepáticas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Microambiente Tumoral
2.
Oncology ; 2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-38061339

RESUMEN

Introduction We previously conducted a phase I/Ib study (NCT03712943) with regorafenib and nivolumab in patients with refractory metastatic mismatch repair proficient (pMMR) colorectal cancer (CRC). This study aimed to investigate the role of Xerna™ TME Panel in predicting the treatment response. Methods 22 archival pretreatment tumor samples were subjected to the Xerna™ TME Panel, a machine learning-based RNA-sequencing biomarker assay. The Xerna TME subtypes were evaluated for correlation with overall survival (OS), progression free survival (PFS), disease control rate (DCR), and other biomarkers including KRAS, PD-L1, CD8 expression, and Treg cells in tumor microenvironment. Results Based on Xerna™ TME Panel, four patients with immune active (IA) subtype and six patients with immune suppressed (IS) subtype were classified as biomarker-positive, and five with angiogenic (A) subtype and seven with immune desert (ID) subtype were biomarker-negative. While not reaching statistical significance, Xerna TME biomarker-positive patients seemed to have longer median PFS (7.9 vs. 4.1 months, P=0.254), median OS (15.75 vs. 11.9 months, P=0.378), and higher DCR (70% vs. 58%, P=0.675). The IA subtype in our cohort had higher levels of CD4+ FOXP3+ Treg cells, whereas the A subtype showed lower levels of Treg cells. Conclusion Xerna™ TME Panel analysis in patients with refractory metastatic pMMR CRC who were treated with regorafenib plus nivolumab might be of value for predictive clinical benefit. Further studies are needed to evaluate the predictive role of Xerna™ TME Panel analysis in patients with refractory metastatic pMMR CRC.

3.
Nat Commun ; 14(1): 6330, 2023 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-37816712

RESUMEN

Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to ß-glucan (odetiglucan) treatment by inhibiting liver metastasis. ß-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of ß-glucan, which also required T cells. Furthermore, ß-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , beta-Glucanos , Humanos , Animales , Ratones , Macrófagos del Hígado/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/patología
4.
Front Oncol ; 13: 1158345, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37251949

RESUMEN

Introduction: Most predictive biomarkers approved for clinical use measure single analytes such as genetic alteration or protein overexpression. We developed and validated a novel biomarker with the aim of achieving broad clinical utility. The Xerna™ TME Panel is a pan-tumor, RNA expression-based classifier, designed to predict response to multiple tumor microenvironment (TME)-targeted therapies, including immunotherapies and anti-angiogenic agents. Methods: The Panel algorithm is an artificial neural network (ANN) trained with an input signature of 124 genes that was optimized across various solid tumors. From the 298-patient training data, the model learned to discriminate four TME subtypes: Angiogenic (A), Immune Active (IA), Immune Desert (ID), and Immune Suppressed (IS). The final classifier was evaluated in four independent clinical cohorts to test whether TME subtype could predict response to anti-angiogenic agents and immunotherapies across gastric, ovarian, and melanoma datasets. Results: The TME subtypes represent stromal phenotypes defined by angiogenesis and immune biological axes. The model yields clear boundaries between biomarker-positive and -negative and showed 1.6-to-7-fold enrichment of clinical benefit for multiple therapeutic hypotheses. The Panel performed better across all criteria compared to a null model for gastric and ovarian anti-angiogenic datasets. It also outperformed PD-L1 combined positive score (>1) in accuracy, specificity, and positive predictive value (PPV), and microsatellite-instability high (MSI-H) in sensitivity and negative predictive value (NPV) for the gastric immunotherapy cohort. Discussion: The TME Panel's strong performance on diverse datasets suggests it may be amenable for use as a clinical diagnostic for varied cancer types and therapeutic modalities.

5.
Front Oncol ; 12: 869078, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35692755

RESUMEN

Imprime PGG (Imprime) is in late-stage clinical development as a combinatorial agent with several therapeutic modalities. Here we present pre-clinical mechanistic data supportive of Imprime, a soluble yeast ß-1,3/1,6-glucan pathogen-associated molecular pattern able to prime innate immune cells in a Dectin-1dependent manner. In tumor-free mice, Imprime evoked broad innate immune responses (type I interferon signature, mobilization of myeloid cells, dendritic cell and monocyte/macrophage expression of co-stimulatory ligands like CD86, and activation of natural killer cells). Imprime-mediated activation of myeloid cells also resulted in functional priming of antigen-specific CD8 T cell response. In tumor-bearing mice, Imprime monotherapy further resulted in activation of systemic and tumor infiltrating macrophages and enhanced cytotoxic CD8 T cell trafficking. Imprime enhanced the anti-tumor activity of several combinatorial agents in mouse cancer models; anti-tyrosinase-related protein 1 antibody in B16F10 melanoma experimental lung metastasis model, anti-vascular endothelial growth factor receptor 2 antibody in H1299 and H441 lung cancer, and anti-programmed cell death protein 1 antibody in MC38 colon cancer models. Mechanistically, combining Imprime with these combinatorial therapeutic agents elicited enhanced innate immune activation, supporting immunological synergy. Finally, Imprime treatment induced similar in vitro phenotypic and functional activation of human innate immune cells. Collectively, these data demonstrate Imprime's potential to orchestrate a broad, yet coordinated, anti-cancer immune response and complement existing cancer immunotherapies.

6.
J Immunol ; 202(10): 2945-2956, 2019 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-30988115

RESUMEN

Imprime PGG (Imprime) is an i.v. administered, yeast ß-1,3/1,6 glucan in clinical development with checkpoint inhibitors. Imprime-mediated innate immune activation requires immune complex formation with naturally occurring IgG anti-ß glucan Abs (ABA). We administered Imprime to healthy human volunteers to assess the necessity of ABA for Imprime-mediated immunopharmacodynamic (IPD) changes. Imprime (4 mg/kg) was administered i.v. in single and multiple infusions. Subsets of subjects were premedicated with antihistamine and corticosteroid. Peripheral blood was measured before, during and after Imprime administration for IPD changes (e.g., ABA, circulating immune complexes, complement activation, complete blood counts, cytokine/chemokine, and gene expression changes). IPD changes were analyzed based on pretreatment serum ABA levels: low-ABA (<20 µg/ml), mid-ABA (≥20-50 µg/ml), and high-ABA (≥50 µg/ml). At the end of infusion, free serum ABA levels decreased, circulating immune complex levels increased, and complement activation was observed. At ∼1-4 h after end of infusion, increased expression of cytokines/chemokines, a 1.5-4-fold increase in neutrophil and monocyte counts and a broad activation of innate immune genes were observed. Low-ABA subjects typically showed minimal IPD changes except when ABA levels rose above 20 µg/ml after repeated Imprime dosing. Mild-to-moderate infusion-related reactions occurred in subjects with ABA ≥20 µg/ml. Premedications alleviated some of the infusion-related reactions, but also inhibited cytokine responses. In conclusion, ABA levels, being critical for Imprime-mediated immune activation may provide a plausible, mechanism-based biomarker to identify patients most likely to respond to Imprime-based anticancer immunotherapy.


Asunto(s)
Adyuvantes Inmunológicos , Polisacáridos Fúngicos , Inmunoterapia , Neoplasias , Saccharomyces cerevisiae/química , beta-Glucanos , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacocinética , Anticuerpos Antifúngicos/sangre , Anticuerpos Antifúngicos/inmunología , Quimiocinas/sangre , Quimiocinas/inmunología , Femenino , Polisacáridos Fúngicos/administración & dosificación , Polisacáridos Fúngicos/química , Polisacáridos Fúngicos/farmacocinética , Humanos , Masculino , Neoplasias/sangre , Neoplasias/inmunología , Neoplasias/terapia , beta-Glucanos/administración & dosificación , beta-Glucanos/química , beta-Glucanos/farmacocinética
7.
Mol Cancer Ther ; 18(4): 856-867, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30787172

RESUMEN

Inhibition of VEGFR signaling is an effective treatment for renal cell carcinoma, but resistance continues to be a major problem. Recently, the sphingosine phosphate (S1P) signaling pathway has been implicated in tumor growth, angiogenesis, and resistance to antiangiogenic therapy. S1P is a bioactive lipid that serves an essential role in developmental and pathologic angiogenesis via activation of the S1P receptor 1 (S1P1). S1P1 signaling counteracts VEGF signaling and is required for vascular stabilization. We used in vivo and in vitro angiogenesis models including a postnatal retinal angiogenesis model and a renal cell carcinoma murine tumor model to test whether simultaneous inhibition of S1P1 and VEGF leads to improved angiogenic inhibition. Here, we show that inhibition of S1P signaling reduces the endothelial cell barrier and leads to excessive angiogenic sprouting. Simultaneous inhibition of S1P and VEGF signaling further disrupts the tumor vascular beds, decreases tumor volume, and increases tumor cell death compared with monotherapies. These studies suggest that inhibition of angiogenesis at two stages of the multistep process may maximize the effects of antiangiogenic therapy. Together, these data suggest that combination of S1P1 and VEGFR-targeted therapy may be a useful therapeutic strategy for the treatment of renal cell carcinoma and other tumor types.


Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Carcinoma de Células Renales/irrigación sanguínea , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Quimioterapia Combinada , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Humanos , Neoplasias Renales/irrigación sanguínea , Neoplasias Renales/patología , Lisofosfolípidos/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Esfingosina/análogos & derivados , Esfingosina/antagonistas & inhibidores , Sunitinib/farmacología , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Methods Mol Biol ; 1683: 371-382, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29082503

RESUMEN

Blood vessels are crucial components for normal tissue development and homeostasis, so it is not surprising that endothelial dysfunction and dysregulation results in a variety of different pathophysiological conditions. The large number of vascular-related disorders and the emergence of angiogenesis as a major hallmark of cancer has led to significant interest in the development of drugs that target the vasculature. While several in vivo models exist to study developmental and pathological states of blood vessels, few in vitro assays have been developed that capture the significant complexity of the vascular microenvironment. Here, we describe a high content endothelial colony forming cells (ECFC)/adipose-derived stem cell (ADSC) coculture assay that captures many elements of in vivo vascular biology and is ideal for in vitro screening of compounds for pro- or anti-angiogenic activities.


Asunto(s)
Bioensayo , Técnicas de Cocultivo , Células Endoteliales/citología , Células Madre Mesenquimatosas/citología , Neovascularización Fisiológica , Biomarcadores , Técnicas de Cultivo de Célula , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas/métodos , Células Endoteliales/metabolismo , Procesamiento de Imagen Asistido por Computador , Células Madre Mesenquimatosas/metabolismo , Microscopía , Neovascularización Fisiológica/efectos de los fármacos , Fenotipo , Células Madre/citología , Células Madre/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
9.
Pharmacol Ther ; 164: 204-25, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27288725

RESUMEN

Interaction of numerous signaling pathways in endothelial and mesangial cells results in exquisite control of the process of physiological angiogenesis, with a central role played by vascular endothelial growth factor receptor 2 (VEGFR-2) and its cognate ligands. However, deregulated angiogenesis participates in numerous pathological processes. Excessive activation of VEGFR-2 has been found to mediate tissue-damaging vascular changes as well as the induction of blood vessel expansion to support the growth of solid tumors. Consequently, therapeutic intervention aimed at inhibiting the VEGFR-2 pathway has become a mainstay of treatment in cancer and retinal diseases. In this review, we introduce the concepts of physiological and pathological angiogenesis, the crucial role played by the VEGFR-2 pathway in these processes, and the various inhibitors of its activity that have entered the clinical practice. We primarily focus on the development of ramucirumab, the antagonist monoclonal antibody (mAb) that inhibits VEGFR-2 and has recently been approved for use in patients with gastric, colorectal, and lung cancers. We examine in-depth the pre-clinical studies using DC101, the mAb to mouse VEGFR-2, which provided a conceptual foundation for the role of VEGFR-2 in physiological and pathological angiogenesis. Finally, we discuss further clinical development of ramucirumab and the future of targeting the VEGF pathway for the treatment of cancer.


Asunto(s)
Neoplasias/tratamiento farmacológico , Neoplasias/fisiopatología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/fisiopatología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Resistencia a Antineoplásicos/fisiología , Quimioterapia Combinada , Humanos , Ramucirumab
10.
Anticancer Res ; 36(6): 2683-96, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27272777

RESUMEN

BACKGROUND: The vascular endothelial growth factor (VEGF) pathway plays an important role in growth and progression of human cancer, including colorectal carcinomas (CRC). The key mediators of VEGF signaling are VEGFR1, VEGFR2, and VEGFR3, part of a family of related receptor tyrosine kinases. The relative expression, activity, or interplay among these receptors may determine the response of CRC patients to anti-angiogenic therapies. MATERIALS AND METHODS: We developed technically sound immunohistochemical (IHC) assays to quantify VEGFR1, 2 and 3, and using a well-annotated CRC tissue microarray (TMA), we carried out comprehensive comparative evaluation of the three VEGFRs in archival primary CRC tissues (n=84). For each TMA core, tumor cell VEGFR1 expression was reported as H-score (range=0-300); vascular VEGFR2/VEGFR3 expression was manually scored as the number of receptor-positive tumor stromal vessels. Each case was defined as VEGFR1/ VEGFR2/VEGFR3-negative, low, medium or high. RESULTS: Based on the differential expression of the three VEGFRs, eight VEGFR staining profiles were observed: Triple VEGFR positive (n=12, 14%), VEGFR1 predominant (n=17, 20%), VEGFR2 predominant (n=7, 8%), VEGFR3 predominant (n=1, 1%), VEGFR1/2 predominant (n=39, 46%), VEGFR1/3 predominant (n=2, 2%), VEGFR2/3 predominant (n=3, 4%), and triple-VEGFR-negative (n=3, 4%). CONCLUSION: Herein we demonstrated heterogeneity of expression of VEGFRs in human CRC stromal vessels and tumor cells. The observed VEGFR expression-based subsets of human CRCs may reflect differences in biology of pathologic angiogenesis in primary CRC tissues. Furthermore, the heterogeneity of expression of VEGFRs unraveled in this analysis merits independent validation in larger cohorts of primary and metastatic human CRC tissues and in pertinent experimental models treated with various anti-angiogenic therapies.


Asunto(s)
Neoplasias Colorrectales/química , Receptor 1 de Factores de Crecimiento Endotelial Vascular/análisis , Receptor 2 de Factores de Crecimiento Endotelial Vascular/análisis , Receptor 3 de Factores de Crecimiento Endotelial Vascular/análisis , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/análisis , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad
11.
Cancer Res ; 76(9): 2573-86, 2016 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-27197264

RESUMEN

Treatment of metastatic gastric cancer typically involves chemotherapy and monoclonal antibodies targeting HER2 (ERBB2) and VEGFR2 (KDR). However, reliable methods to identify patients who would benefit most from a combination of treatment modalities targeting the tumor stroma, including new immunotherapy approaches, are still lacking. Therefore, we integrated a mouse model of stromal activation and gastric cancer genomic information to identify gene expression signatures that may inform treatment strategies. We generated a mouse model in which VEGF-A is expressed via adenovirus, enabling a stromal response marked by immune infiltration and angiogenesis at the injection site, and identified distinct stromal gene expression signatures. With these data, we designed multiplexed IHC assays that were applied to human primary gastric tumors and classified each tumor to a dominant stromal phenotype representative of the vascular and immune diversity found in gastric cancer. We also refined the stromal gene signatures and explored their relation to the dominant patient phenotypes identified by recent large-scale studies of gastric cancer genomics (The Cancer Genome Atlas and Asian Cancer Research Group), revealing four distinct stromal phenotypes. Collectively, these findings suggest that a genomics-based systems approach focused on the tumor stroma can be used to discover putative predictive biomarkers of treatment response, especially to antiangiogenesis agents and immunotherapy, thus offering an opportunity to improve patient stratification. Cancer Res; 76(9); 2573-86. ©2016 AACR.


Asunto(s)
Neoplasias Gástricas/clasificación , Neoplasias Gástricas/genética , Transcriptoma/genética , Microambiente Tumoral/genética , Animales , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biología Computacional/métodos , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica/métodos , Xenoinjertos , Humanos , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Ratones , Neovascularización Patológica/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Análisis de Matrices Tisulares , Factor A de Crecimiento Endotelial Vascular/metabolismo
12.
PLoS One ; 11(3): e0150585, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26954567

RESUMEN

SDF-1 and CXCR4 are a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. Overexpression of CXCR4 is a hallmark of many hematological malignancies including acute myeloid leukemia, chronic lymphocytic leukemia and non-Hodgkin's lymphoma, and generally correlates with a poor prognosis. In this study, we developed a humanized anti-CXCR4 monoclonal antibody, LY2624587 as a potent CXCR4 antagonist that was advanced into clinical study for cancer. LY2624587 blocked SDF-1 binding to CXCR4 with an IC50 of 0.26 nM, and inhibited SDF-1-induced GTP binding with a Kb of 0.66 nM. In human lymphoma U937 and leukemia CCRF-CEM cells expressing endogenous CXCR4, LY2624587 inhibited SDF-1-induced cell migration with IC50 values of 3.7 and 0.26 nM, respectively. This antibody also inhibited CXCR4 and SDF-1 mediated cell signaling including activation of MAPK and AKT in tumor cells expressing CXCR4. Bifocal microscopic and flow cytometry analyses revealed that LY2624587 mediated receptor internalization and caused CXCR4 down-regulation on the cell surface. In human hematologic cancer cells, LY2624587 caused dose dependent apoptosis in vitro and in vivo. In mouse xenograft models developed with human leukemia and lymphoma cells expressing high levels of CXCR4, LY2624587 exhibited dose-dependent tumor growth inhibition and provided significant survival benefit in a disseminated lymphoma model. Collectively, we have demonstrated that CXCR4 inhibition by LY2624587 has the potential for the treatment of human hematological malignancies.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Hematológicas/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Animales , Anexina A5/metabolismo , Caspasa 3/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Quimiocina CXCL12/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Ratones , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores CXCR4/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Mol Cancer Ther ; 14(2): 480-90, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25504752

RESUMEN

Emerging evidence demonstrates that stromal cell-derived factor 1 (SDF-1) and CXCR4, a chemokine and chemokine receptor pair, play important roles in tumorigenesis. In this report, we describe a small cyclic peptide, LY2510924, which is a potent and selective CXCR4 antagonist currently in phase II clinical studies for cancer. LY2510924 specifically blocked SDF-1 binding to CXCR4 with IC50 value of 0.079 nmol/L, and inhibited SDF-1-induced GTP binding with Kb value of 0.38 nmol/L. In human lymphoma U937 cells expressing endogenous CXCR4, LY2510924 inhibited SDF-1-induced cell migration with IC50 value of 0.26 nmol/L and inhibited SDF-1/CXCR4-mediated intracellular signaling. LY2510924 exhibited a concentration-dependent inhibition of SDF-1-stimulated phospho-ERK and phospho-Akt in tumor cells. Biochemical and cellular analyses revealed that LY2510924 had no apparent agonist activity. Pharmacokinetic analyses suggested that LY2510924 had acceptable in vivo stability and a pharmacokinetic profile similar to a typical small-molecular inhibitor in preclinical species. LY2510924 showed dose-dependent inhibition of tumor growth in human xenograft models developed with non-Hodgkin lymphoma, renal cell carcinoma, lung, and colon cancer cells that express functional CXCR4. In MDA-MB-231, a breast cancer metastatic model, LY2510924 inhibited tumor metastasis by blocking migration/homing process of tumor cells to the lung and by inhibiting cell proliferation after tumor cell homing. Collectively, the preclinical data support further investigation of LY2510924 in clinical studies for cancer.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Mamarias Experimentales/patología , Metástasis de la Neoplasia/patología , Péptidos Cíclicos/farmacología , Receptores CXCR4/antagonistas & inhibidores , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quimiocina CXCL12 , Modelos Animales de Enfermedad , Perros , Estabilidad de Medicamentos , Femenino , Humanos , Macaca fascicularis , Masculino , Ratones Endogámicos C57BL , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacocinética , Ratas Sprague-Dawley , Receptores CXCR4/agonistas , Receptores CXCR4/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
14.
PLoS One ; 9(9): e106901, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25210890

RESUMEN

Vascular endothelial growth factor (VEGF) plays a dominant role in angiogenesis. While inhibitors of the VEGF pathway are approved for the treatment of a number of tumor types, the effectiveness is limited and evasive resistance is common. One mechanism of evasive resistance to inhibition of the VEGF pathway is upregulation of other pro-angiogenic factors such as fibroblast growth factor (FGF) and epidermal growth factor (EGF). Numerous in vitro assays examine angiogenesis, but many of these assays are performed in media or matrix with multiple growth factors or are driven by VEGF. In order to study angiogenesis driven by other growth factors, we developed a basal medium to use on a co-culture cord formation system of adipose derived stem cells (ADSCs) and endothelial colony forming cells (ECFCs). We found that cord formation driven by different angiogenic factors led to unique phenotypes that could be differentiated and combination studies indicate dominant phenotypes elicited by some growth factors. VEGF-driven cords were highly covered by smooth muscle actin, and bFGF-driven cords had thicker nodes, while EGF-driven cords were highly branched. Multiparametric analysis indicated that when combined EGF has a dominant phenotype. In addition, because this assay system is run in minimal medium, potential proangiogenic molecules can be screened. Using this assay we identified an inhibitor that promoted cord formation, which was translated into in vivo tumor models. Together this study illustrates the unique roles of multiple anti-angiogenic agents, which may lead to improvements in therapeutic angiogenesis efforts and better rational for anti-angiogenic therapy.


Asunto(s)
Neovascularización Patológica/metabolismo , Células Madre/citología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/crecimiento & desarrollo , Línea Celular , Medios de Cultivo , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Factor de Crecimiento Epidérmico/administración & dosificación , Sangre Fetal , Factores de Crecimiento de Fibroblastos/administración & dosificación , Humanos , Músculo Liso/citología , Músculo Liso/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Pericitos/citología , Pericitos/efectos de los fármacos , Células Madre/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores
15.
J Hematol Oncol ; 6: 31, 2013 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-23622716

RESUMEN

BACKGROUND: Anti-VEGF therapy reduces tumor blood vessels, however, some vessels always remain. These VEGF insensitive vessels may help support continued tumor growth and metastases. Many in vitro assays examining multiple steps of the angiogenic process have been described, but the majority of these assays are sensitive to VEGF inhibition. There has been little focus on the development of high-throughput, in vitro assays to model the vessels that are insensitive to VEGF inhibition. METHODS: Here, we describe a fixed end-point and kinetic, high-throughput stem cell co-culture model of cord formation. RESULTS: In this system, cords develop within 24 hours, at which point they begin to lose sensitivity to VEGF inhibitors, bevacizumab, and ramucirumab. Consistent with the hypothesis that other angiogenic factors maintain VEGF-independent vessels, pharmacologic intervention with a broad spectrum anti-angiogenic antagonist (suramin), a vascular disrupting agent (combretastatin), or a combination of VEGF and Notch pathway inhibitors reduced the established networks. In addition, we used our in vitro approach to develop an in vivo co-implant vasculogenesis model that connects with the endogenous vasculature to form functional blood vessels. Similar to the in vitro system, over time these vessels become insensitive to VEGF inhibition. CONCLUSION: Together, these models may be used to identify novel drugs targeting tumor vessels that are not sensitive to VEGF inhibition.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Ensayos Analíticos de Alto Rendimiento/métodos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adipocitos/citología , Adipocitos/efectos de los fármacos , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Técnicas de Cocultivo , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Neovascularización Fisiológica/efectos de los fármacos , Células Madre/citología , Células Madre/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo
16.
Invest New Drugs ; 31(4): 833-44, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23275061

RESUMEN

The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia, including cell proliferation, survival, apoptosis, scattering and motility, invasion, and angiogenesis. MET over-expression (with or without gene amplification), aberrant autocrine or paracrine ligand production, and missense MET mutations are mechanisms that lead to activation of the MET pathway in tumors and are associated with poor prognostic outcome. We report here preclinical development of a potent, orally bioavailable, small-molecule inhibitor LY2801653 targeting MET kinase. LY2801653 is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a dissociation constant (Ki) of 2 nM, a pharmacodynamic residence time (Koff) of 0.00132 min(-1) and t1/2 of 525 min. LY2801653 demonstrated in vitro effects on MET pathway-dependent cell scattering and cell proliferation; in vivo anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects. LY2801653 also maintained potency against 13 MET variants, each bearing a single-point mutation. In subsequent nonclinical characterization, LY2801653 was found to have potent activity against several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2 and against the serine/threonine kinases MKNK1/2. The potential value of MET and other inhibited targets within a number of malignancies (such as colon, bile ducts, and lung) is discussed. LY2801653 is currently in phase 1 clinical testing in patients with advanced cancer (trial I3O-MC-JSBA, NCT01285037).


Asunto(s)
Indazoles/farmacología , Niacinamida/análogos & derivados , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Tetrazoles/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Indazoles/administración & dosificación , Indazoles/química , Ratones , Mutación/genética , Niacinamida/administración & dosificación , Niacinamida/química , Niacinamida/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Tetrazoles/administración & dosificación , Tetrazoles/química , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Drug Discov Today ; 18(11-12): 510-22, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22944609

RESUMEN

Targeting multiple hallmarks of cancer with drug combinations may provide unique opportunities for cancer therapeutics; however, phenotypic quantification is necessary to understand in vivo mechanisms of action of each drug alone or in combination. Immunohistochemistry (IHC) can quantify phenotypic changes, but traditional methods are not amenable for high-throughput drug discovery. In this article, we describe a high-content method to quantify changes in tumor angiogenesis, vascular normalization, hypoxia, tumor cell proliferation, and apoptosis using IHC. This method to quantify tumor model phenotypes can be useful for cancer drug discovery by increasing the understanding of: (i) tumor models used in efficacy studies, (ii) changes occurring during the growth of the tumor, and (iii) novel mechanisms of actions of cancer therapeutics.


Asunto(s)
Antineoplásicos , Descubrimiento de Drogas , Inmunohistoquímica , Neoplasias/metabolismo , Animales , Antineoplásicos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología
18.
Mol Cancer Res ; 10(6): 739-49, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22516348

RESUMEN

The roles of cholecystokinin 2 receptor (CCK2R) in numerous physiologic processes in the gastrointestinal tract and central nervous system are well documented. There has been some evidence that CCK2R alterations play a role in cancers, but the functional significance of these alterations for tumorigenesis is unknown. We have identified six mutations in CCK2R among a panel of 140 colorectal cancers and 44 gastric cancers. We show that these mutations increase receptor activity, activate multiple downstream signaling pathways, increase cell migration, and promote angiogenesis. Our findings suggest that somatic mutations in CCK2R may promote tumorigenesis through deregulated receptor activity and highlight the importance of evaluating CCK2R inhibitors to block both the normal and mutant forms of the receptor.


Asunto(s)
Transformación Celular Neoplásica/genética , Neoplasias Colorrectales/genética , Mutación , Receptor de Colecistoquinina B/genética , Neoplasias Gástricas/genética , Animales , Movimiento Celular/genética , Forma de la Célula/genética , Transformación Celular Neoplásica/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Análisis Mutacional de ADN , Células Endoteliales/metabolismo , Células Endoteliales/fisiología , Células HEK293 , Humanos , Immunoblotting , Ratones , Microscopía Fluorescente , Células 3T3 NIH , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/fisiopatología , Neovascularización Fisiológica/genética , Neovascularización Fisiológica/fisiología , Fenotipo , Interferencia de ARN , Receptor de Colecistoquinina B/metabolismo , Receptor de Colecistoquinina B/fisiología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Transfección , Factor A de Crecimiento Endotelial Vascular/metabolismo
20.
Invest New Drugs ; 30(3): 936-49, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21360050

RESUMEN

LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRß, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.


Asunto(s)
Acetanilidas/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Acetanilidas/síntesis química , Acetanilidas/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Animales , Células CHO , Línea Celular Tumoral , Cricetinae , Cricetulus , Perros , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ratones Desnudos , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA