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1.
Int J Biochem Cell Biol ; 107: 92-103, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30572025

RESUMEN

Ovarian cancer (OvCa) is the most lethal gynecological malignancy in the United States primarily due to lack of a reliable early diagnostic, high incidence of chemo-resistant recurrent disease as well as profuse tumor heterogeneity. Cancer stem cells (CSCs) continue to gain attention, as they are known to resist chemotherapy, self-renew and re-populate the bulk tumor with undifferentiated and differentiated cells. Moreover, CSCs appear to readily adapt to environmental, immunologic and pharmacologic cues. The plasticity and ability to inactivate or activate signaling pathways promoting their longevity has been, and continues to be, the challenge faced in developing successful CSC targeted therapies. Identifying and understanding unique ovarian CSC markers and the pathways they utilize could reveal new therapeutic opportunities that may offer alternative adjuvant treatment options. Herein, we will discuss the current state of ovarian CSC characterization, their contribution to disease resistance, recurrence and shed light on clinical trials that may target the CSC population.


Asunto(s)
Células Madre Neoplásicas/patología , Neoplasias Ováricas/patología , Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Transducción de Señal
2.
Clin Cancer Res ; 20(24): 6517-6528, 2014 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-25294905

RESUMEN

PURPOSE: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient-derived xenografts. EXPERIMENTAL DESIGN: Immunohistochemistry and FISH were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2, and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib, or the combination of trastuzumab and lapatinib. Acute and chronic posttreatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation. RESULTS: HER2 gene amplification (24%) correlated significantly with HER2 protein overexpression (55%). All models were impervious to single-agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2-amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant antitumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2-amplified models, and was associated with increased apoptosis and decreased proliferation. CONCLUSIONS: Although trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2-amplified USC and may be a promising avenue for future investigation.


Asunto(s)
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Amplificación de Genes/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/mortalidad , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Humanos , Lapatinib , Ratones , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Quinazolinas/farmacología , Receptor ErbB-2/metabolismo , Transducción de Señal/efectos de los fármacos , Trastuzumab , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/mortalidad , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Front Oncol ; 4: 171, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25072022

RESUMEN

INTRODUCTION: Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States because of chemoresistant recurrent disease. Our objective was to investigate the efficacy of inhibiting the Notch pathway with a γ-secretase inhibitor (GSI) in an OvCa patient-derived xenograft model as a single agent therapy and in combination with standard chemotherapy. METHODS: Immunocompromised mice bearing xenografts derived from clinically platinum-sensitive human ovarian serous carcinomas were treated with vehicle, GSI (MRK-003) alone, paclitaxel and carboplatin (P/C) alone, or the combination of GSI and P/C. Mice bearing platinum-resistant xenografts were given GSI with or without paclitaxel. Gene transcript levels of the Notch pathway target Hes1 were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. RESULTS: Expression of Notch1 and 3 was variable. GSI alone decreased tumor growth in two of three platinum-sensitive ovarian tumors (p < 0.05), as well as in one of three platinum-sensitive tumors (p = 0.04). The combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum-resistant ovarian tumors (all p < 0.05). The addition of GSI did not alter the effect of P/C in platinum-sensitive tumors. Interestingly, although the response of each tumor to chronic GSI exposure did not correlate with its endogenous level of Notch expression, GSI did negatively affect Notch signaling in an acute setting. CONCLUSION: Inhibiting the Notch signaling cascade with a GSI reduces primary human xenograft growth in vivo. GSI synergized with conventional cytotoxic chemotherapy only in the platinum-resistant OvCa models with single agent paclitaxel. These findings suggest inhibition of the Notch pathway in concert with taxane therapy may hold promise for treatment of platinum-resistant OvCa.

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