Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
1.
Cancer ; 129(15): 2348-2359, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37080942

RESUMEN

BACKGROUND: E7130 is a novel anticancer agent created from a total synthetic study of norhalichondrin B. The authors report the E7130 dose-escalation part of a first-in-human study of patients with advanced solid tumors (NCT03444701). METHODS: Japanese patients ≥20 years of age were enrolled. E7130 was administered intravenously in two cycles: day 1 of a 21-day cycle (Q3W) or days 1 and 15 of a 28-day cycle (Q2W). Doses were escalated from 270 to 550 µg/m2 for the Q3W group or 25-400 µg/m2 for the Q2W group. The primary end point of the dose-escalation phase was safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs) and adverse events. Other end points included determination of the maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics. RESULTS: Forty-four patients were enrolled: 15 in the E7130 Q3W group and 29 in the Q2W group. Treatment-emergent adverse events (TEAEs) occurred in all patients; the most common TEAE overall was leukopenia (78.6%). Grade 3-4 TEAEs occurred in 93.3% of patients in the Q3W group and 86.2% of patients in the Q2W group. None had a TEAE resulting in study drug discontinuation, and no treatment-related deaths were reported. Per the DLT evaluation, the MTDs were determined as 480 µg/m2 Q3W and 300 µg/m2 Q2W. Significant changes in multiple plasma biomarkers, including vascular endothelial growth factor 3 and matrix metallopeptidase 9, were dose-dependent after initial doses of 350-480 µg/m2 . CONCLUSIONS: E7130 480 µg/m2 Q3W was chosen for the dose-expansion part over 300 µg/m2 Q2W primarily per dose-dependent biomarker results.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Factor A de Crecimiento Endotelial Vascular , Microambiente Tumoral , Neoplasias/patología , Antineoplásicos/efectos adversos , Biomarcadores , Microtúbulos/metabolismo , Microtúbulos/patología , Dosis Máxima Tolerada
2.
J Magn Reson Imaging ; 56(6): 1820-1831, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35524730

RESUMEN

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide insight into tumor perfusion. However, a method that can quantitatively measure the intra-tumor distribution of tumor voxel clusters with a distinct range of Ktrans and ve values remains insufficiently explored. HYPOTHESIS: Two-dimensional cluster analysis may quantify the distribution of a tumor voxel subregion with a distinct range of Ktrans and ve values in human breast cancer xenografts. STUDY TYPE: Prospective longitudinal study. ANIMAL MODEL: Twenty-two female athymic nude mice with MCF-7 xenograft, treated with E7130, a tumor-microenvironmental ameliorator, or saline. FIELD STRENGTH/SEQUENCE: 9.4 Tesla, turbo rapid acquisition with relaxation enhancement, and spoiled gradient-echo sequences. ASSESSMENT: We performed two-dimensional k-means clustering to identify tumor voxel clusters with a distinct range of Ktrans and ve values on Days 0, 2, and 5 after treatment, calculated the ratio of the number of tumor voxels in each cluster to the total number of tumor voxels, and measured the normalized distances defined as the ratio of the distance between each tumor voxel and the nearest tumor margin to a tumor radius. STATISTICAL TESTS: Unpaired t-tests, Dunnett's multiple comparison tests, and Chi-squared test were used. RESULTS: The largest and second largest clusters constituted 44.4% and 27.5% of all tumor voxels with cluster centroid values of Ktrans at 0.040 min-1 and 0.116 min-1 , and ve at 0.131 and 0.201, respectively. At baseline (Day 0), the average normalized distances for the largest and second largest clusters were 0.33 and 0.24, respectively. E7130-treated group showed the normalized distance of the initial largest cluster decreasing to 0.25, while that of the second largest cluster increasing to 0.31. Saline-treated group showed no change. DATA CONCLUSION: A two-dimensional cluster analysis might quantify the spatial distribution of a tumor subregion with a distinct range of Ktrans and ve values. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.


Asunto(s)
Neoplasias de la Mama , Medios de Contraste , Humanos , Ratones , Femenino , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Estudios Prospectivos , Ratones Desnudos , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Análisis por Conglomerados
3.
Cancer Sci ; 105(8): 1023-31, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24841832

RESUMEN

Most non-small-cell lung cancers (NSCLCs) harboring activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (EGFR-TKIs); however, they invariably develop resistance to these drugs. E7820 is an angiogenesis inhibitor that decreases integrin-α2 expression and is currently undergoing clinical trials. We investigated whether E7820 in combination with erlotinib, an EGFR-TKI, could overcome EGFR-TKI-resistance in the NSCLC cell lines A549 (KRAS; G12S), H1975 (EGFR; L858R/T790M), and H1650 (PTEN; loss, EGFR; exon 19 deletion), which are resistant to erlotinib. Immunohistochemical analysis was carried out in xenografted tumors to investigate anti-angiogenesis activity and endothelial cell apoptosis levels by endothelial cell marker CD31 and TUNEL staining, respectively. Treatment with E7820 (50 mg/kg) with erlotinib (60 mg/kg) showed a synergistic antitumor effect in three xenograft models. Immunohistochemical analysis indicated that combined treatment with E7820 and erlotinib significantly decreased microvessel density and increased apoptosis of tumor-associated endothelial cells compared with use of only one of the agents. This combination increased apoptosis in HUVECs through activation of both intrinsic and extrinsic apoptosis pathways in vitro. The combination of E7820 with erlotinib is an alternative strategy to overcome erlotinib resistance in NSCLC by enhancement of the anti-angiogenic activity of E7820.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Indoles/administración & dosificación , Neoplasias Pulmonares/patología , Sulfonamidas/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Clorhidrato de Erlotinib , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Ratones , Ratones Desnudos , Quinazolinas/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Cancer Sci ; 105(6): 723-30, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24689876

RESUMEN

Vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for the treatment of several tumor types; however, some tumors show intrinsic resistance to VEGFR inhibitors, and some patients develop acquired resistance to these inhibitors. Therefore, a strategy to overcome VEGFR inhibitor resistance is urgently required. Recent reports suggest that activation of the hepatocyte growth factor (HGF) pathway through its cognate receptor, Met, contributes to VEGFR inhibitor resistance. Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor. In in vitro experiments, addition of VEGF plus HGF enhanced cell growth and tube formation of HUVECs when compared with stimulation by either factor alone. Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance. This HGF-induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib. Conditioned medium from tumor cells producing high amounts of HGF also conferred resistance to inhibition by lenvatinib. In s.c. xenograft models based on various tumor cell lines with high HGF expression, treatment with lenvatinib alone showed weak antitumor effects, but treatment with lenvatinib plus golvatinib showed synergistic antitumor effects, accompanied by decreased tumor vessel density. These results suggest that HGF from tumor cells confers resistance to tumor endothelial cells against VEGFR inhibitors, and that combination therapy using VEGFR inhibitors with Met inhibitors may be effective for overcoming resistance to VEGFR inhibitors. Further evaluation in clinical trials is warranted.


Asunto(s)
Aminopiridinas/farmacología , Factor de Crecimiento de Hepatocito/antagonistas & inhibidores , Compuestos de Fenilurea/farmacología , Piperazinas/farmacología , Quinolinas/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Femenino , Factor de Crecimiento de Hepatocito/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Cancer Sci ; 105(10): 1334-42, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25060424

RESUMEN

Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor of microtubule dynamics. Some tubulin-binding drugs are known to have antivascular (antiangiogenesis or vascular-disrupting) activities that can target abnormal tumor vessels. Using dynamic contrast-enhanced MRI analyses, here we show that eribulin induces remodeling of tumor vasculature through a novel antivascular activity in MX-1 and MDA-MB-231 human breast cancer xenograft models. Vascular remodeling associated with improved perfusion was shown by Hoechst 33342 staining and by increased microvessel density together with decreased mean vascular areas and fewer branched vessels in tumor tissues, as determined by immunohistochemical staining for endothelial marker CD31. Quantitative RT-PCR analysis of normal host cells in the stroma of xenograft tumors showed that eribulin altered the expression of mouse (host) genes in angiogenesis signaling pathways controlling endothelial cell-pericyte interactions, and in the epithelial-mesenchymal transition pathway in the context of the tumor microenvironment. Eribulin also decreased hypoxia-associated protein expression of mouse (host) vascular endothelial growth factor by ELISA and human CA9 by immunohistochemical analysis. Prior treatment with eribulin enhanced the anti-tumor activity of capecitabine in the MDA-MB-231 xenograft model. These findings suggest that eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to elimination of inner tumor hypoxia. Because abnormal tumor microenvironments enhance both drug resistance and metastasis, the apparent ability of eribulin to reverse these aggressive characteristics may contribute to its clinical benefits.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Furanos/farmacología , Cetonas/farmacología , Moduladores de Tubulina/farmacología , Microambiente Tumoral/efectos de los fármacos , Remodelación Vascular/efectos de los fármacos , Animales , Neoplasias de la Mama/patología , Capecitabina , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Femenino , Fluorouracilo/análogos & derivados , Fluorouracilo/farmacología , Humanos , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Mol Cancer Ther ; 23(2): 235-247, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37816248

RESUMEN

E7130 is a novel anticancer agent created from total synthetic study of the natural compound norhalichondrin B. In addition to inhibiting microtubule dynamics, E7130 also ameliorates tumor-promoting aspects of the tumor microenvironment (TME) by suppressing cancer-associated fibroblasts (CAF) and promoting remodeling of tumor vasculature. Here, we demonstrate TME amelioration by E7130 using multi-imaging modalities, including multiplexed mass cytometry [cytometry by time-of-flight (CyTOF)] analysis, multiplex IHC analysis, and MRI. Experimental solid tumors characterized by large numbers of CAFs in TME were treated with E7130. E7130 suppressed LAP-TGFß1 production, a precursor of TGFß1, in CAFs but not in cancer cells; an effect that was accompanied by a reduction of circulating TGFß1 in plasma. To our best knowledge, this is the first report to show a reduction of TGFß1 production in TME. Furthermore, multiplex IHC analysis revealed reduced cellularity and increased TUNEL-positive apoptotic cells in E7130-treated xenografts. Increased microvessel density (MVD) and collagen IV (Col IV), an extracellular matrix (ECM) component associated with endothelial cells, were also observed in the TME, and plasma Col IV levels were also increased by E7130 treatment. MRI revealed increased accumulation of a contrast agent in xenografts. Moreover, diffusion-weighted MRI after E7130 treatment indicated reduction of tumor cellularity and interstitial fluid pressure. Overall, our findings strongly support the mechanism of action that E7130 alters the TME in therapeutically beneficial ways. Importantly, from a translational perspective, our data demonstrated MRI as a noninvasive biomarker to detect TME amelioration by E7130, supported by consistent changes in plasma biomarkers.


Asunto(s)
Antimitóticos , Fibroblastos Asociados al Cáncer , Neoplasias Experimentales , Neoplasias , Animales , Humanos , Fibroblastos Asociados al Cáncer/patología , Remodelación Vascular , Microambiente Tumoral , Células Endoteliales/patología , Neoplasias/tratamiento farmacológico , Antimitóticos/farmacología
7.
Cancer Res Commun ; 4(1): 226-235, 2024 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-38181055

RESUMEN

PURPOSE: E7389-LF is a liposomal formulation of eribulin that contributes to tumor vascular remodeling. The phase II part of this phase Ib/II study assessed the efficacy/safety of E7389-LF in combination with nivolumab in several disease cohorts; herein, we report results from the small cell lung cancer (SCLC) cohort. EXPERIMENTAL DESIGN: Patients with unresectable/measurable SCLC and disease progression with first-line platinum-based chemotherapy with/without an immune checkpoint inhibitor (ICI) were enrolled to receive E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously every 3 weeks. The primary objective of this part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory assessments included overall survival (OS) and biomarkers. RESULTS: Thirty-four patients were enrolled. By the data cut-off date (May 31, 2022), 29 (85.3%) had discontinued. Efficacy/biomarker analyses included 33 patients (1 had their diagnosis changed postenrollment); the ORR of E7389-LF plus nivolumab was 24.2% [95% confidence interval (CI): 11.1-42.3], the median PFS was 3.98 months (95% CI: 2.63-4.40), and, at a median follow-up of 10.6 months, the median OS was not reached (95% CI: not estimable). Notably, 27 of 33 patients (81.8%) had received an ICI as their prior first-line therapy. Treatment-related, treatment-emergent adverse events occurred in 97.1% (any grade) and 82.4% (grade ≥3) of enrolled patients; the most common event was neutropenia. Changes in vascular and immune-related plasma markers were observed. CONCLUSIONS: E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks showed notable antitumor activity as second-line therapy for SCLC; no new safety signals were observed compared with either agent as monotherapy. SIGNIFICANCE: This phase II part of a phase Ib/II study assessed liposomal eribulin (E7389-LF) plus nivolumab in 34 patients with pretreated SCLC; 8 of 33 evaluable patients (including 6/27 pretreated with ICIs) had objective responses. The combination was tolerable; increases in vasculature-related biomarkers tended to correlate with responses.


Asunto(s)
Furanos , Cetonas , Neoplasias Pulmonares , Policétidos Poliéteres , Carcinoma Pulmonar de Células Pequeñas , Alcaloides de la Vinca , Humanos , Nivolumab/efectos adversos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Alcaloides de la Vinca/uso terapéutico , Biomarcadores
8.
Clin Cancer Res ; 30(7): 1264-1272, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38295160

RESUMEN

PURPOSE: E7389-LF is a liposomal formulation of the microtubule dynamics inhibitor eribulin and has shown preliminary efficacy in the treatment of gastric cancer. Study 120, a phase Ib/II open-label study, assessed efficacy and safety of E7389-LF in combination with nivolumab, a programmed cell death (PD)-1 inhibitor. This report focuses on the gastric cancer cohort within the expansion phase. PATIENTS AND METHODS: Eligible patients had unresectable, measurable gastric cancer, progression following a platinum drug plus fluoropyrimidine (1L), and a taxane-containing regimen (2L). The primary objective of the expansion phase was objective response rate, secondary objectives included safety and PFS, and exploratory objectives included overall survival and biomarker evaluation. Patients received E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks, both as intravenous infusions. Tumor responses were assessed every 6 weeks by the investigators per RECIST v1.1. Plasma and tumor biomarkers were assessed. RESULTS: In the 31 patients who received E7389-LF in combination with nivolumab, the objective response rate was 25.8% [confidence interval (CI), 11.9-44.6]. The median progression-free survival was 2.69 months (95% CI, 1.91-2.99) and median overall survival was 7.85 months (95% CI, 4.47-not estimable). The most common treatment-related TEAE of any grade were neutropenia (77.4%), leukopenia (74.2%), and decreased appetite (51.6%). E7389-LF in combination with nivolumab significantly increased CD8-positive cells at C2D1 (P = 0.039), and six of seven vascular markers and four IFNγ-related markers showed increases from C1D1. CONCLUSIONS: Promising antitumor activity was observed with E7389-LF in combination with nivolumab in patients with gastric cancer, and no new safety signals were observed, compared with either monotherapy.


Asunto(s)
Nivolumab , Policétidos Poliéteres , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Furanos/efectos adversos , Cetonas/efectos adversos , Moduladores de Tubulina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
9.
Mol Cancer Ther ; 22(4): 499-510, 2023 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-36696578

RESUMEN

Eribulin is a microtubule dynamics inhibitor with tumor microenvironment modulation activity such as vascular remodeling activity. Here, we investigated antitumor and immunomodulatory activities of eribulin and its liposomal formulation (eribulin-LF) as monotherapies or in combination with anti-programmed death 1 (PD-1) Ab. The antitumor activity of eribulin or eribulin-LF as monotherapy or in combination with anti-PD-1 Ab was examined in a P-glycoprotein-knockout 4T1 model. Eribulin and eribulin-LF showed stronger antitumor activity in immunocompetent mice compared with immunodeficient mice, indicating that they have immunomodulatory activity that underlies its antitumor activity. Combination therapy of eribulin and eribulin-LF with anti-PD-1 Ab showed antitumor activity, and the combination activity of eribulin-LF with anti-PD-1 Ab was observed at a lower dose and longer interval of administration compared with that using eribulin. To examine the immunomodulatory activity of eribulin and eribulin-LF and its underlying mechanisms, we performed flow cytometry, IHC, and gene expression profiling. IHC and flow cytometry revealed that eribulin-LF increased microvessel density and intratumoral populations of cytotoxic T cells and natural killer cells rather than eribulin. Gene expression profiling demonstrated that eribulin-LF induces IFNγ signaling. Furthermore, IHC also showed that eribulin-LF increased infiltration of CD8-positive cells together with increased CD31-positive cells. Eribulin-LF also increased ICAM-1 expression, which is essential for lymphocyte adhesion to vascular endothelial cells. In conclusion, eribulin showed combination antitumor activity with anti-PD-1 Ab via immunomodulation due to its vascular remodeling activity, and the liposomal formulation showed improved antitumor activity over the standard formulation.


Asunto(s)
Liposomas , Remodelación Vascular , Animales , Ratones , Células Endoteliales , Línea Celular Tumoral
10.
Clin Cancer Res ; 29(8): 1460-1467, 2023 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-36730323

RESUMEN

PURPOSE: In the dose-expansion part of this open-label, phase I study, we explored the efficacy and safety of E7389-LF (liposomal formulation of eribulin) in Japanese patients with advanced gastric cancer. PATIENTS AND METHODS: Patients with advanced gastric cancer who had been previously treated with ≥2 lines of chemotherapy received E7389-LF 2.0 mg/m2 every 3 weeks (the previously determined maximum tolerated dose, the primary objective of Study 114). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), and safety; exploratory objectives included disease control rate (DCR) and clinical benefit rate (CBR), as well as pharmacodynamic measurements of serum biomarkers. RESULTS: As of June 24, 2021, 34 patients were enrolled and treated (10 from the original dose-expansion cohort, expanded to include 24 additional patients). Six patients had partial responses, for an ORR of 17.6% [95% confidence interval (CI), 6.8-34.5], and the median PFS was 3.7 months (95% CI, 2.7-4.8). The DCR was 79.4% (95% CI, 62.1-91.3), and the CBR was 32.4% (95% CI, 17.4-50.5). Overall, 32 patients (94.1%) experienced treatment-related adverse events, and 26 patients (76.5%) experienced grade ≥3 events, most commonly neutropenia (41.2%) and leukopenia (29.4%). Of the 8 endothelial cell/vasculature markers tested in this study, 7 were significantly increased among patients treated with E7389-LF; these changes were generally consistent regardless of best overall response. CONCLUSIONS: E7389-LF 2.0 mg/m2 every 3 weeks was tolerable and showed preliminary activity for the treatment of patients with gastric cancer.


Asunto(s)
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Furanos/efectos adversos , Cetonas/efectos adversos , Supervivencia sin Progresión
11.
Cancer Res Commun ; 3(7): 1189-1199, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37435605

RESUMEN

Purpose: To determine a recommended dose of liposomal eribulin (E7389-LF) in combination with nivolumab in patients with advanced solid tumors, and to evaluate the safety, efficacy, pharmacokinetics, and biomarker impact of this regimen. Experimental Design: Japanese patients with advanced, nonresectable, or recurrent solid tumors and no existing alternative standard/effective therapy (except nivolumab monotherapy) were assigned to either E7389-LF 1.7 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 1.1 mg/m2 plus nivolumab 240 mg every 2 weeks, or E7389-LF 1.4 mg/m2 plus nivolumab 240 mg every 2 weeks. Primary objectives were to evaluate the safety/tolerability of each dose cohort and to determine the recommended phase II dose (RP2D). Secondary/exploratory objectives, including safety [dose-limiting toxicities (DLT) and adverse events (AE)], pharmacokinetics, efficacy [including objective response rate (ORR)], and biomarker results were used in determining the RP2D. Results: Twenty-five patients were enrolled to treatment [E7389-LF 1.7 mg/mg2 every 3 weeks (n = 6), E7389-LF 2.1 mg/m2 every 3 weeks (n = 6), E7389-LF 1.1 mg/m2 every 2 weeks (n = 7), E7389-LF 1.4 mg/m2 every 2 weeks (n = 6)]. Twenty-four patients were evaluated for DLTs, of whom 3 had DLTs (1 at E7389-LF 1.7 mg/m2 every 3 weeks, 1 at 1.1 mg/m2 every 2 weeks, and 1 at 1.4 mg/m2 every 2 weeks). All patients had ≥1 treatment-related treatment-emergent AE (TEAE); 68.0% had ≥1 grade 3-4 treatment-related TEAE. Changes in vasculature and IFN-related biomarkers were seen in each cohort. The overall ORR was 16%. Conclusions: E7389-LF plus nivolumab was tolerable overall; the recommended dose for future study was 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks. Significance: This phase Ib part of a phase Ib/II study assessed the tolerability and activity of a liposomal formulation of eribulin (E7389-LF) plus nivolumab in 25 patients with advanced solid tumors. The combination was tolerable overall; 4 patients had a partial response. Vasculature and immune-related biomarker levels increased, suggesting vascular remodeling.


Asunto(s)
Neoplasias , Alcaloides de la Vinca , Humanos , Furanos/efectos adversos , Cetonas/efectos adversos , Liposomas , Neoplasias/tratamiento farmacológico , Nivolumab/efectos adversos
12.
Eur J Cancer ; 168: 108-118, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35500404

RESUMEN

BACKGROUND: A liposomal formulation of eribulin, E7389-LF, may provide improved pharmacokinetics and allow increased access to tumour tissues. This expansion of a phase 1 study assessed the safety and efficacy of E7389-LF in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. METHODS: Patients received E7389-LF 2.0 mg/m2 every three weeks. Tumour assessments were conducted every six weeks by the investigator by Response Evaluation Criteria in Solid Tumours v1.1. All adverse events were monitored and recorded. Serum biomarker assessments were conducted. RESULTS: Of 28 patients included, 75.0% had hormone receptor-positive breast cancer (HR+ BC) and 25.0% had triple-negative breast cancer (TNBC). The most common grade ≥3 treatment-related treatment-emergent adverse events included neutropenia (67.9%), leukopenia (42.9%), thrombocytopenia (32.1%), and febrile neutropenia (25.0%). Rates of neutropenia and febrile neutropenia were lower among patients who received prophylactic pegfilgrastim. Objective response rate was 35.7% (95% confidence interval [CI]: 18.6-55.9) for all patients and 42.9% (95% CI: 21.8-66.0) for patients with HR+ BC. Median progression-free survival was 5.7 months (95% CI: 3.9-8.3). The median overall survival was 18.3 months (95% CI: 13.2-not estimable). Among the 54 biomarkers assessed, 27, including 5 of 7 vascular markers, were significantly altered by E7389-LF treatment from baseline to any time point. CONCLUSION: E7389-LF was tolerable and favourable antitumour activity was observed, particularly in patients with HR+ BC. Prophylactic pegfilgrastim can be considered in patients at high risk for neutropenia and febrile neutropenia. GOV NUMBER: NCT03207672.


Asunto(s)
Neoplasias de la Mama , Furanos , Cetonas , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Estudios de Cohortes , Composición de Medicamentos , Neutropenia Febril , Femenino , Furanos/efectos adversos , Humanos , Cetonas/efectos adversos , Liposomas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico
13.
Clin Cancer Res ; 28(9): 1783-1791, 2022 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-35180771

RESUMEN

PURPOSE: We report the dose-escalation part of a phase I study of liposomal eribulin (E7389-LF) in Japanese patients with advanced solid tumors and no alternative standard therapy. PATIENTS AND METHODS: Patients ≥20 years old were enrolled. E7389-LF doses of 1.0 to 1.5 mg/m2 once every two weeks (Q2W) or 1.0 to 2.5 mg/m2 once every three weeks (Q3W) were planned. The primary objective was to determine the MTD by evaluating dose-limiting toxicities (DLT). Secondary objectives included safety/tolerability assessments, objective response rate (ORR), and progression-free survival; serum biomarker assessment was an exploratory objective. RESULTS: Twenty-one patients were enrolled and treated; 12 in the Q3W group (1.0 mg/m2, n = 3; 1.5 mg/m2, n = 3; 2.0 mg/m2, n = 6) and 9 in the Q2W group (1.0 mg/m2, n=3; 1.5 mg/m2, n = 6). The Q3W and Q2W MTDs were 2.0 mg/m2 and 1.5 mg/m2, respectively. One patient receiving 2.0 mg/m2 Q3W had a DLT of grade 3 febrile neutropenia. The most common grade 3 treatment-emergent adverse events were neutropenia (66.7% in Q3W and Q2W) and leukopenia (Q3W, 58.3%; Q2W, 33.3%). One patient in the Q3W group (2.0 mg/m2) and 3 in the Q2W group (1.0 mg/m2, n = 1; 1.5 mg/m2, n = 2) achieved a partial response [overall ORR, 19.0%; 95% confidence interval (CI), 5.4-41.9]. Endothelial [TEK receptor tyrosine kinase (TEK), intercellular adhesion molecule 1 (ICAM1), vascular endothelial growth factor receptor 3 (VEGFR3), platelet/endothelial cell adhesion molecule 1 (PECAM1)], vasculature (collagen IV), and immune-related [interferon gamma (IFNγ), C-X-C motif chemokine ligand 11 (CXCL11), C-X-C motif chemokine ligand 10 (CXCL10)] biomarker levels were increased. CONCLUSIONS: E7389-LF was well tolerated at 2.0 mg/m2 Q3W and 1.5 mg/m2 Q2W. Considering the toxicity profile of both regimens, the recommended dose was 2.0 mg/m2 Q3W. Expansion cohorts are ongoing.


Asunto(s)
Neoplasias , Factor A de Crecimiento Endotelial Vascular , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores , Quimiocinas , Relación Dosis-Respuesta a Droga , Furanos , Humanos , Japón , Cetonas , Ligandos , Liposomas , Dosis Máxima Tolerada , Neoplasias/patología , Adulto Joven
14.
Cancer Res ; 81(4): 1052-1062, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33408116

RESUMEN

The Wnt/ß-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between ß-catenin and CREB binding protein, which is part of the Wnt/ß-catenin signaling pathway, disrupts the Wnt/ß-catenin signaling pathway in HEK293 and adenomatous polyposis coli (APC)-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of ApcMin /+ mice, in which mutation of Apc activates the Wnt/ß-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA sequencing data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and IHC analysis showed that E7386 induced infiltration of CD8+ cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/ß-catenin signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody. SIGNIFICANCE: These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/ß-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/patología , Fragmentos de Péptidos/metabolismo , Pirazinas/farmacología , Sialoglicoproteínas/metabolismo , Triazinas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismo , Animales , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Genes APC , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Ratones Transgénicos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fragmentos de Péptidos/antagonistas & inhibidores , Unión Proteica/efectos de los fármacos , Pirazinas/uso terapéutico , Sialoglicoproteínas/antagonistas & inhibidores , Triazinas/uso terapéutico , Vía de Señalización Wnt/genética , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , beta Catenina/antagonistas & inhibidores
15.
Anticancer Res ; 40(12): 6699-6712, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33288563

RESUMEN

BACKGROUND/AIM: There is no established standard chemotherapy after administration of the combination endocrine plus CDK4/6 inhibitor therapy for luminal-type breast cancer. We used patient-derived xenograft (PDX) models to determine the antitumor activity of eribulin and capecitabine after endocrine therapy plus CDK4/6 inhibitor. MATERIALS AND METHODS: We examined the antitumor activity of fulvestrant, palbociclib, eribulin, and capecitabine in 4 luminal-type breast cancer PDX models (OD-BRE-0188, -0438, -0450, -0745). In OD-BRE-0438, we determined the antitumor activity of chemotherapy after fulvestrant-palbociclib treatment. We also performed immunohistochemical analysis to explore the effects of treatment on E-cadherin in tumor tissues. RESULTS: Fulvestrant, fulvestrant-palbociclib and chemotherapy had antitumor activity in the 4 PDX models. In OD-BRE-0438 (the most resistant to fulvestrant-palbociclib), eribulin had superior antitumor activity to capecitabine after fulvestrant plus palbociclib. Only eribulin tended to increase E-cadherin expression. CONCLUSION: Eribulin had superior antitumor activity to capecitabine after fulvestrant-palbociclib in the OD-BRE-0438 model.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Fulvestrant/uso terapéutico , Furanos/uso terapéutico , Cetonas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Femenino , Fulvestrant/farmacología , Furanos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Cetonas/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacología
16.
Cancer Res ; 62(21): 6116-23, 2002 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-12414636

RESUMEN

In the process of angiogenesis, endothelial adhesion molecules play a significant role in vascular morphogenesis, in coordination with angiogenic factor signaling. Here we report that a novel angiogenesis inhibitor, E7820 (an aromatic sulfonamide derivative), inhibited in vitro proliferation and tube formation of human umbilical vascular endothelial cell (HUVEC). E7820 decreased integrin alpha2, 3, 5, and beta1 in confluent culture of HUVEC, and integrin alpha2 was initially suppressed in mRNA level, followed by decrement of integrins alpha3, 5, and beta1. The inhibition of integrin alpha2 expression in HUVEC showed dose dependence but did not alter the level of CD31. Up-regulation of integrin alpha2 by phorbol 12-myristate 13-acetate abrogated the inhibitory effect of E7820 on tube formation within type I collagen gel, whereas addition of antibody against integrin alpha2 canceled the phorbol 12-myristate 13-acetate effect. These results suggest that E7820 inhibited tube formation through the suppression of integrin alpha2. Oral administration of E7820 remarkably resulted in inhibition of tumor-induced angiogenesis in mouse dorsal air sac model, and tumor growth of human colorectal tumor cell lines (WiDr and LoVo) was inhibited in xenotransplanted model in mice. This is the first time that a small molecule has been shown to modulate integrins, and this finding may provide the basis for a new approach to antiangiogenic therapy through the suppression of integrin alpha2 on endothelium.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Endotelio Vascular/efectos de los fármacos , Indoles/farmacología , Integrina alfa2/biosíntesis , Sulfonamidas/farmacología , Animales , División Celular/efectos de los fármacos , Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/tratamiento farmacológico , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Femenino , Humanos , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Clin Cancer Res ; 10(4): 1430-8, 2004 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-14977846

RESUMEN

We reported previously that an angiogenesis inhibitor, E7820, inhibits in vitro tube formation of human umbilical vein endothelial cell through the suppression of integrin alpha2 expression. Here we describe the antiangiogenic and antitumor effects of E7820 in mice and discuss the feasibility of using platelet integrin alpha2 expression on platelets as a biological marker of the efficacy of E7820. Oral administration of E7820 significantly inhibited basic fibroblast growth factor-induced angiogenesis in Matrigel implants and human colon WiDr tumor-induced angiogenesis in a dorsal air sac model. Twice-daily treatment with E7820 clearly inhibited the s.c. tumor growth of seven tumor cell lines derived from human colon, breast, pancreas, and kidney, and completely suppressed the growth of human pancreatic KP-1 and human colon LoVo cell lines. Moreover, E7820 significantly inhibited the growth of KP-1 and human colon tumor Colo320DM cells orthotopically implanted in the pancreas and cecum, respectively. The efficacy of E7820 was comparable in the s.c. and orthotopic transplantation models. Immunohistochemical analyses using anti-CD31 antibody showed that E7820 significantly reduced microvessel density in orthotopically implanted KP-1 tumor. E7820 reduced integrin alpha2 expression on a megakaryocytic cell line, Dami cells, induced by phorbol 12-myristate 13-acetate treatment. It also decreased the expression level of integrin alpha2 on platelets withdrawn from mice bearing s.c. KP-1 tumor at a dosage close to that affording antitumor activity. These data demonstrate that E7820 showed a broad-spectrum antitumor effect in mice through inhibition of angiogenesis and indicate that the decrease of integrin alpha2 on platelets might serve as a biological marker for the antitumor efficacy of E7820.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Biomarcadores de Tumor , Indoles/farmacología , Integrina alfa2/biosíntesis , Sulfonamidas/farmacología , Animales , Anticuerpos Monoclonales/química , Antineoplásicos/farmacología , Plaquetas/metabolismo , División Celular , Línea Celular Tumoral , Células Cultivadas , Relación Dosis-Respuesta a Droga , Endotelio Vascular/citología , Femenino , Citometría de Flujo , Humanos , Ratones , Trasplante de Neoplasias , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/biosíntesis , Factores de Tiempo , Venas Umbilicales/citología
18.
Vasc Cell ; 6: 18, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25197551

RESUMEN

BACKGROUND: Lenvatinib is an oral inhibitor of multiple receptor tyrosine kinases (RTKs) targeting vascular endothelial growth factor receptor (VEGFR1-3), fibroblast growth factor receptor (FGFR1-4), platelet growth factor receptor α (PDGFR α), RET and KIT. Antiangiogenesis activity of lenvatinib in VEGF- and FGF-driven angiogenesis models in both in vitro and in vivo was determined. Roles of tumor vasculature (microvessel density (MVD) and pericyte coverage) as biomarkers for lenvatinib were also examined in this study. METHOD: We evaluated antiangiogenesis activity of lenvatinib against VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. Effects of lenvatinib on in vivo angiogenesis, which was enhanced by overexpressed VEGF or FGF in human pancreatic cancer KP-1 cells, were examined in the mouse dorsal air sac assay. We determined antitumor activity of lenvatinib in a broad panel of human tumor xenograft models to test if vascular score, which consisted of high MVD and low pericyte coverage, was associated with sensitivity to lenvatinib treatment. Vascular score was also analyzed using human tumor specimens with 18 different types of human primary tumors. RESULT: Lenvatinib inhibited VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. In vivo angiogenesis induced by overexpressed VEGF (KP-1/VEGF transfectants) or FGF (KP-1/FGF transfectants) was significantly suppressed with oral treatments of lenvatinib. Lenvatinib showed significant antitumor activity in KP-1/VEGF and five 5 of 7 different types of human tumor xenograft models at between 1 to 100 mg/kg. We divided 19 human tumor xenograft models into lenvatinib-sensitive (tumor-shrinkage) and relatively resistant (slow-growth) subgroups based on sensitivity to lenvatinib treatments at 100 mg/kg. IHC analysis showed that vascular score was significantly higher in sensitive subgroup than relatively resistant subgroup (p < 0.0004). Among 18 types of human primary tumors, kidney cancer had the highest MVD, while liver cancer had the lowest pericyte coverage, and cancers in Kidney and Stomach had highest vascular score. CONCLUSION: These results indicated that Lenvatinib inhibited VEGF- and FGF-driven angiogenesis and showed a broad spectrum of antitumor activity with a wide therapeutic window. MVD and pericyte-coverage of tumor vasculature might be biomarkers and suggest cases that would respond for lenvatinib therapy.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA