RESUMEN
The phosphatidylinositol 3-kinase (PI3K) pathway is a central mediator of vascular endothelial growth factor (VEGF)-driven angiogenesis. The discovery of small molecule inhibitors that selectively target PI3K or PI3K and mammalian target of rapamycin (mTOR) provides an opportunity to pharmacologically determine the contribution of these key signaling nodes in VEGF-A-driven tumor angiogenesis in vivo. This study used an array of micro-vascular imaging techniques to monitor the antivascular effects of selective class I PI3K, mTOR, or dual PI3K/mTOR inhibitors in colorectal and prostate cancer xenograft models. Micro-computed tomography (micro-CT) angiography, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), vessel size index (VSI) MRI, and DCE ultrasound (DCE-U/S) were employed to quantitatively evaluate the vascular (structural and physiological) response to these inhibitors. GDC-0980, a dual PI3K/mTOR inhibitor, was found to reduce micro-CT angiography vascular density, while VSI MRI demonstrated a significant reduction in vessel density and an increase in mean vessel size, consistent with a loss of small functional vessels and a substantial antivascular response. DCE-MRI showed that GDC-0980 produces a strong functional response by decreasing the vascular permeability/perfusion-related parameter, K (trans). Interestingly, comparable antivascular effects were observed for both GDC-980 and GNE-490 (a selective class I PI3K inhibitor). In addition, mTOR-selective inhibitors did not affect vascular density, suggesting that PI3K inhibition is sufficient to generate structural changes, characteristic of a robust antivascular response. This study supports the use of noninvasive microvascular imaging techniques (DCE-MRI, VSI MRI, DCE-U/S) as pharmacodynamic assays to quantitatively measure the activity of PI3K and dual PI3K/mTOR inhibitors in vivo.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Inhibidores Enzimáticos , Neoplasias/diagnóstico , Neovascularización Patológica/diagnóstico , Angiografía/métodos , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Xenoinjertos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Imagen por Resonancia Magnética/métodos , Ratones , Imagen Multimodal , Neoplasias/metabolismo , Neoplasias/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Pirimidinas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Carga Tumoral/efectos de los fármacos , Ultrasonografía/métodos , Microtomografía por Rayos X/métodosRESUMEN
Resistance to anti-angiogenic therapy can occur via several potential mechanisms. Unexpectedly, recent studies showed that short-term inhibition of either VEGF or VEGFR enhanced tumour invasiveness and metastatic spread in preclinical models. In an effort to evaluate the translational relevance of these findings, we examined the consequences of long-term anti-VEGF monoclonal antibody therapy in several well-validated genetically engineered mouse tumour models of either neuroendocrine or epithelial origin. Anti-VEGF therapy decreased tumour burden and increased overall survival, either as a single agent or in combination with chemotherapy, in all four models examined. Importantly, neither short- nor long-term exposure to anti-VEGF therapy altered the incidence of metastasis in any of these autochthonous models, consistent with retrospective analyses of clinical trials. In contrast, we observed that sunitinib treatment recapitulated previously reported effects on tumour invasiveness and metastasis in a pancreatic neuroendocrine tumour (PNET) model. Consistent with these results, sunitinib treatment resulted in an up-regulation of the hypoxia marker GLUT1 in PNETs, whereas anti-VEGF did not. These results indicate that anti-VEGF mediates anti-tumour effects and therapeutic benefits without a paradoxical increase in metastasis. Moreover, these data underscore the concept that drugs targeting VEGF ligands and receptors may affect tumour metastasis in a context-dependent manner and are mechanistically distinct from one another.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Anticuerpos Antiidiotipos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/inmunología , Adenocarcinoma/genética , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada , Ingeniería Genética , Indoles/uso terapéutico , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Ratones , Tumores Neuroendocrinos/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Pirroles/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/genética , Sunitinib , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
The low rate of approval of novel anti-cancer agents underscores the need for better preclinical models of therapeutic response as neither xenografts nor early-generation genetically engineered mouse models (GEMMs) reliably predict human clinical outcomes. Whereas recent, sporadic GEMMs emulate many aspects of their human disease counterpart more closely, their ability to predict clinical therapeutic responses has never been tested systematically. We evaluated the utility of two state-of-the-art, mutant Kras-driven GEMMs--one of non-small-cell lung carcinoma and another of pancreatic adenocarcinoma--by assessing responses to existing standard-of-care chemotherapeutics, and subsequently in combination with EGFR and VEGF inhibitors. Standard clinical endpoints were modeled to evaluate efficacy, including overall survival and progression-free survival using noninvasive imaging modalities. Comparisons with corresponding clinical trials indicate that these GEMMs model human responses well, and lay the foundation for the use of validated GEMMs in predicting outcome and interrogating mechanisms of therapeutic response and resistance.
Asunto(s)
Modelos Animales de Enfermedad , Ingeniería Genética , Mutación/genética , Neoplasias/genética , Neoplasias/terapia , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Clorhidrato de Erlotinib , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Quinazolinas/uso terapéutico , Análisis de Supervivencia , Factor A de Crecimiento Endotelial Vascular/inmunología , GemcitabinaRESUMEN
PURPOSE: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti-vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials. EXPERIMENTAL DESIGN: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab. RESULTS: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico
, Anticuerpos Monoclonales/uso terapéutico
, Neoplasias Colorrectales/irrigación sanguínea
, Neoplasias Colorrectales/tratamiento farmacológico
, Diagnóstico por Imagen
, Factor A de Crecimiento Endotelial Vascular/inmunología
, Adolescente
, Animales
, Anticuerpos Monoclonales/farmacología
, Anticuerpos Monoclonales Humanizados
, Bevacizumab
, Línea Celular Tumoral
, Sistemas de Liberación de Medicamentos
, Femenino
, Humanos
, Ratones
, Ratones Desnudos
, Neovascularización Patológica/tratamiento farmacológico
, Ensayos Antitumor por Modelo de Xenoinjerto
RESUMEN
We studied the directional response of the coupled-eardrum system in the northern leopard frog, Rana pipiens pipiens. Eardrum behavior closely approximates a linear time-invariant system, with a highly correlated input-output relationship between the eardrum pressure difference and the eardrum velocity. Variations in the eardrum transfer function at frequencies below 800 Hz indicate the existence of an extratympanic sound transmission pathway which can interfere with eardrum motions. The eardrum velocity was shown to shift in phase as a function of sound incident angle, which was a direct result of the phase-shift of the eardrum pressure difference. We used two laser-Doppler vibrometers to measure the interaural vibration time difference (IVTD) and the interaural vibration amplitude difference (IVAD) between the motions of the two eardrums. The coupled-eardrum system enhanced the IVTD and IVAD by a factor of 3 and 3 dB, respectively, when compared to an isolated-eardrum system of the same size. Our findings are consistent with the time-delay sensitivity of other coupled-eardrum systems such as those found in crickets and flies.