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1.
Proc Natl Acad Sci U S A ; 109(45): E3119-27, 2012 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-23071298

RESUMO

Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Amplificação de Genes , Terapia de Alvo Molecular , Receptor ErbB-2/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/patologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diagnóstico por Imagem , Modelos Animais de Doenças , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/patologia , Lapatinib , Camundongos , Necrose , Neovascularização Patológica/tratamento farmacológico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Análise de Sobrevida , Trastuzumab , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nat Cancer ; 5(7): 1102-1120, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38565920

RESUMO

The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP-TEAD protein-protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.


Assuntos
Via de Sinalização Hippo , Proteínas Serina-Treonina Quinases , Fatores de Transcrição , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Fatores de Transcrição/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Camundongos , Linhagem Celular Tumoral , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Sinalização YAP/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas de Ligação a DNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição de Domínio TEA , Proteínas ras/metabolismo , Feminino , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
4.
Am J Pathol ; 179(5): 2220-32, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21945411

RESUMO

Fibroblast growth factors (FGFs) participate in embryonic development, in maintenance of tissue homeostasis in the adult, and in various diseases. FGF-binding proteins (FGFBP) are secreted proteins that chaperone FGFs stored in the extracellular matrix to their receptor, and can thus modulate FGF signaling. FGFBP1 (alias BP1, FGF-BP1, or HBp17) expression is required for embryonic survival, can modulate FGF-dependent vascular permeability in embryos, and is an angiogenic switch in human cancers. To determine the function of BP1 in vivo, we generated tetracycline-regulated conditional BP1 transgenic mice. BP1-expressing adult mice are viable, fertile, and phenotypically indistinguishable from their littermates. Induction of BP1 expression increased mouse primary fibroblast motility in vitro, increased angiogenic sprouting into subcutaneous matrigel plugs in animals and accelerated the healing of excisional skin wounds. FGF-receptor kinase inhibitors blocked these effects. Healing skin wounds showed increased macrophage invasion as well as cell proliferation after BP1 expression. Also, BP1 expression increased angiogenesis during the healing of skin wounds as well as after ischemic injury to hindlimb skeletal muscles. We conclude that BP1 can enhance FGF effects that are required for the healing and repair of injured tissues in adult animals.


Assuntos
Proteínas de Transporte/metabolismo , Fibroblastos/metabolismo , Neovascularização Fisiológica/fisiologia , Cicatrização/fisiologia , Animais , Proteínas de Transporte/genética , Movimento Celular , Células Cultivadas , Fator 2 de Crescimento de Fibroblastos/farmacologia , Membro Posterior/irrigação sanguínea , Peptídeos e Proteínas de Sinalização Intercelular , Peptídeos e Proteínas de Sinalização Intracelular , Isquemia/metabolismo , Isquemia/fisiopatologia , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Recombinantes , Pele/lesões , Transgenes/fisiologia
5.
Cancer Cell ; 39(11): 1531-1547.e10, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34624218

RESUMO

Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how cancer treatments could be personalized based on CAFs in a patient's tumor. We have established a living biobank of CAFs derived from biopsies of patients' non-small lung cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC. By functionally interrogating CAF heterogeneity using the same therapeutics received by patients, we identify three functional subtypes: (1) robustly protective of cancers and highly expressing HGF and FGF7; (2) moderately protective of cancers and highly expressing FGF7; and (3) those providing minimal protection. These functional differences among CAFs are governed by their intrinsic TGF-ß signaling, which suppresses HGF and FGF7 expression. This CAF functional classification correlates with patients' clinical response to targeted therapies and also associates with the tumor immune microenvironment, therefore providing an avenue to guide personalized treatment.


Assuntos
Fibroblastos Associados a Câncer/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Fator 7 de Crescimento de Fibroblastos/genética , Fator de Crescimento de Hepatócito/genética , Neoplasias Pulmonares/patologia , Biópsia , Fibroblastos Associados a Câncer/química , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Medicina de Precisão , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral , Regulação para Cima
6.
Nat Cancer ; 2(4): 414-428, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-34179825

RESUMO

Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2 (HER2+) breast cancer, and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here, we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in brain. We determine that this phenotype is an adaptation to decreased lipid availability in brain relative to other tissues, resulting in a site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase (FASN) reduces HER2+ breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.


Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/tratamento farmacológico , Ácido Graxo Sintases/genética , Ácidos Graxos/uso terapêutico , Feminino , Humanos , Microambiente Tumoral
7.
NPJ Breast Cancer ; 5: 4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30675514

RESUMO

The effective treatment of cerebral metastases from HER2-positive breast cancer remains an unmet need. Recent studies indicate that activated astrocytes and brain endothelial cells exert chemoprotective effects on cancer cells through direct physical interaction. Here we report that the endothelin axis mediates protection of HER2-amplified brain metastatic breast cancers to the anti-HER2 antibody-drug conjugate ado-trastuzumab emtansine (T-DM1). Macitentan, a dual inhibitor of endothelin receptors A and B, improves the efficacy of T-DM1 against breast cancers grown in the brain. We show that direct contact of brain stroma with cancer cells is required for protection to T-DM1. Our data suggest that targeting the endothelin axis may be beneficial when anti-signaling agent and cytotoxic agent are combined. These findings may contribute to the development of therapeutic approaches with enhanced efficacy in the brain microenvironment.

9.
Stem Cells ; 25(11): 2936-44, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17690182

RESUMO

Despite rapid advances in the stem cell field, the ability to identify and track transplanted or migrating stem cells in vivo is limited. To overcome this limitation, we used magnetic resonance imaging (MRI) to detect and follow transplanted stem cells over a period of 28 days in mice using an established myocardial infarction model. Pluripotent mouse embryonic stem (mES) cells were expanded and induced to differentiate into beating cardiomyocytes in vitro. The cardiac-differentiated mES cells were then loaded with superparamagnetic fluorescent microspheres (1.63 microm in diameter) and transplanted into ischemic myocardium immediately following ligation and subsequent reperfusion of the left anterior descending coronary artery. To identify the transplanted stem cells in vivo, MRI was performed using a Varian Inova 4.7 Tesla scanner. Our results show that (a) the cardiac-differentiated mES were effectively loaded with superparamagnetic microspheres in vitro, (b) the microsphere-loaded mES cells continued to beat in culture prior to transplantation, (c) the transplanted mES cells were readily detected in the heart in vivo using noninvasive MRI techniques, (d) the transplanted stem cells were detected in ischemic myocardium for the entire 28-day duration of the study as confirmed by MRI and post-mortem histological analyses, and (e) concurrent functional MRI indicated typical loss of cardiac function, although significant amelioration of remodeling was noted after 28 days in hearts that received transplanted stem cells. These results demonstrate that it is feasible to simultaneously track transplanted stem cells and monitor cardiac function in vivo over an extended period using noninvasive MRI techniques.


Assuntos
Células-Tronco Embrionárias/citologia , Imageamento por Ressonância Magnética/métodos , Miócitos Cardíacos/citologia , Animais , Células-Tronco Embrionárias/transplante , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microesferas , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/cirurgia , Miócitos Cardíacos/transplante , Transplante de Células-Tronco/métodos
10.
Cancer Res ; 66(2): 1191-8, 2006 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-16424058

RESUMO

The activity of growth factors is crucial for tumor progression. We previously characterized a secreted fibroblast growth factor-binding protein (FGF-BP1) as a chaperone molecule, which enhances the biological functions of FGFs by releasing FGFs from the extracellular matrix. Here, we characterize the frequency and pattern of FGF-BP1 expression during the malignant progression of pancreas and colorectal carcinoma. For this, we generated monoclonal antibodies that detect FGF-BP1 protein in formalin-fixed, paraffin-embedded tissues and applied in situ hybridization to detect FGF-BP1 mRNA in adjacent tissue sections. FGF-BP1 protein and mRNA were found up-regulated (>70% positive) in parallel (r = 0.70, P < 0.0001) in colon adenoma (n = 9) as well as primary (n = 46) and metastatic (n = 71) colorectal cancers relative to normal colon epithelia (all P < 0.0001, versus normal). Similarly, pancreatitis (n = 17), pancreatic intraepithelial neoplasia (n = 80), and pancreatic adenocarcinoma (n = 67) showed a significant up-regulation of FGF-BP1 compared with normal pancreas (n = 42; all P < 0.0001, relative to normal). Furthermore, the biological activity of FGF-BP1 is neutralized by one of the antibodies, suggesting the potential for antibody-based therapeutic targeting. We propose that the up-regulation of the secreted FGF-BP1 protein during initiation of pancreas and colon neoplasia could make this protein a possible serum marker indicating the presence of high-risk premalignant lesions.


Assuntos
Adenocarcinoma/genética , Proteínas de Transporte/biossíntese , Neoplasias do Colo/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/patologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Proteínas de Transporte/fisiologia , Transformação Celular Neoplásica , Neoplasias do Colo/patologia , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Hibridização In Situ , Peptídeos e Proteínas de Sinalização Intercelular , Neoplasias Pancreáticas/patologia , Pancreatite/genética , Pancreatite/patologia , Pancrelipase/fisiologia , RNA Mensageiro/biossíntese , Medição de Risco , Células Tumorais Cultivadas , Regulação para Cima
11.
Cell Rep ; 21(11): 3298-3309, 2017 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-29241554

RESUMO

Personalized cancer therapy is based on a patient's tumor lineage, histopathology, expression analyses, and/or tumor DNA or RNA analysis. Here, we aim to develop an in vitro functional assay of a patient's living cancer cells that could complement these approaches. We present methods for developing cell cultures from tumor biopsies and identify the types of samples and culture conditions associated with higher efficiency of model establishment. Toward the application of patient-derived cell cultures for personalized care, we established an immunofluorescence-based functional assay that quantifies cancer cell responses to targeted therapy in mixed cell cultures. Assaying patient-derived lung cancer cultures with this method showed promise in modeling patient response for diagnostic use. This platform should allow for the development of co-clinical trial studies to prospectively test the value of drug profiling on tumor-biopsy-derived cultures to direct patient care.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias/tratamento farmacológico , Medicina de Precisão/métodos , Cultura Primária de Células/métodos , Acrilamidas , Aminopiridinas , Quinase do Linfoma Anaplásico , Compostos de Anilina , Biomarcadores Tumorais/metabolismo , Biópsia , Crizotinibe , Receptores ErbB/genética , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/uso terapêutico , Células Alimentadoras/citologia , Imunofluorescência/métodos , Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Queratina-18/genética , Queratina-18/metabolismo , Queratina-8/genética , Queratina-8/metabolismo , Lactamas , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mutação , Neoplasias/classificação , Neoplasias/genética , Neoplasias/patologia , Piperazinas/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Células Tumorais Cultivadas
12.
Sci Transl Med ; 9(391)2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28539475

RESUMO

Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptor ErbB-3/metabolismo , Animais , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Feminino , Camundongos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/genética
13.
Cell Res ; 26(9): 973-4, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27514701

RESUMO

Astrocytes are emerging as essential regulators of brain metastasis progression. In a current issue of Nature, Chen et al. identify a novel mechanism of astrocyte-carcinoma interaction and exploit vulnerabilities therein to slow brain metastatic growth in pre-clinical models.


Assuntos
Astrócitos , Neoplasias Encefálicas , Encéfalo , Junções Comunicantes , Humanos , Nucleotídeos Cíclicos
14.
J Natl Cancer Inst ; 108(2)2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26547932

RESUMO

BACKGROUND: Central nervous system (CNS) metastases represent a major problem in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer because of the disappointing efficacy of HER2-targeted therapies against brain lesions. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in murine models of brain metastases. METHODS: We treated female nude mice bearing BT474 or MDA-MB-361 brain metastases (n = 9-11 per group) or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. Data were analyzed with one-way analysis of variance (ANOVA), Kaplan-Meier analysis, and Coefficient of Determination. All statistical tests were two-sided. RESULTS: T-DM1 delayed the growth of HER2-positive breast cancer brain metastases compared with trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a survival benefit (median survival for BT474 tumors: 28 days for trastuzumab vs 112 days for T-DM1, hazard ratio = 6.2, 95% confidence interval = 6.1 to 85.84, P < .001). No difference in drug distribution or HER2-signaling was revealed between the two groups. However, T-DM1 led to a statistically significant increase in tumor cell apoptosis (one-way ANOVA for ApopTag, P < .001), which was associated with mitotic catastrophe. CONCLUSIONS: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven or PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Maitansina/análogos & derivados , Receptor ErbB-2/análise , Ado-Trastuzumab Emtansina , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Western Blotting , Neoplasias Encefálicas/química , Neoplasias da Mama/química , Proliferação de Células/efeitos dos fármacos , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Perfilação da Expressão Gênica , Estimativa de Kaplan-Meier , Maitansina/administração & dosagem , Maitansina/farmacologia , Camundongos , Camundongos Nus , Análise em Microsséries , Microscopia Eletrônica , Razão de Chances , Trastuzumab , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cancer Cell ; 27(2): 163-75, 2015 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-25670078

RESUMO

Brain metastasis is an end stage in breast cancer progression. Traditional treatment options have minimal efficacy, and overall survival is on the order of months. The incidence of brain metastatic disease is increasing with the improved management of systemic disease and prolongation of survival. Unfortunately, the targeted therapies that control systemic disease have diminished efficacy against brain lesions. There are reasons to be optimistic, however, as emerging therapies have shown promise in preclinical and early clinical settings. This review discusses recent advances in breast cancer brain metastasis therapy and potential approaches for successful treatment.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Terapia de Alvo Molecular , Patologia Molecular , Receptor ErbB-2/genética
17.
J Natl Cancer Inst ; 107(4)2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25710962

RESUMO

BACKGROUND: Matrix metalloproteinase (MMP) 14 may mediate tumor progression through vascular and immune-modulatory effects. METHODS: Orthotopic murine breast tumors (4T1 and E0771 with high and low MMP14 expression, respectively; n = 5-10 per group) were treated with an anti-MMP14 inhibitory antibody (DX-2400), IgG control, fractionated radiation therapy, or their combination. We assessed primary tumor growth, transforming growth factor ß (TGFß) and inducible nitric oxide synthase (iNOS) expression, macrophage phenotype, and vascular parameters. A linear mixed model with repeated observations, with Mann-Whitney or analysis of variance with Bonferroni post hoc adjustment, was used to determine statistical significance. All statistical tests were two-sided. RESULTS: DX-2400 inhibited tumor growth compared with IgG control treatment, increased macrophage numbers, and shifted the macrophage phenotype towards antitumor M1-like. These effects were associated with a reduction in active TGFß and SMAD2/3 signaling. DX-2400 also transiently increased iNOS expression and tumor perfusion, reduced tissue hypoxia (median % area: control, 20.2%, interquartile range (IQR) = 6.4%-38.9%; DX-2400: 1.2%, IQR = 0.2%-3.2%, P = .044), and synergistically enhanced radiation therapy (days to grow to 800mm(3): control, 12 days, IQR = 9-13 days; DX-2400 plus radiation, 29 days, IQR = 26-30 days, P < .001) in the 4T1 model. The selective iNOS inhibitor, 1400W, abolished the effects of DX-2400 on vessel perfusion and radiotherapy. On the other hand, DX-2400 was not capable of inducing iNOS expression or synergizing with radiation in E0771 tumors. CONCLUSION: MMP14 blockade decreased immunosuppressive TGFß, polarized macrophages to an antitumor phenotype, increased iNOS, and improved tumor perfusion, resulting in reduced primary tumor growth and enhanced response to radiation therapy, especially in high MMP14-expressing tumors.


Assuntos
Amidinas/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Benzilaminas/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Macrófagos/efeitos dos fármacos , Metaloproteinase 14 da Matriz/efeitos dos fármacos , Metaloproteinase 14 da Matriz/metabolismo , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Fracionamento da Dose de Radiação , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoglobulina G/sangue , Macrófagos/enzimologia , Neoplasias Mamárias Experimentais , Camundongos , Neovascularização Patológica , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima
18.
Cancer Cell ; 28(1): 70-81, 2015 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-26144315

RESUMO

We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lactamas Macrocíclicas/administração & dosagem , Neoplasias/tratamento farmacológico , Receptores Proteína Tirosina Quinases/genética , Aminopiridinas , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Lactamas , Lactamas Macrocíclicas/farmacologia , Camundongos , Mutação , Células NIH 3T3 , Neoplasias/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Pirazóis , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Cancer Discov ; 4(1): 42-52, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24163374

RESUMO

Colorectal cancers harboring KRAS or BRAF mutations are refractory to current targeted therapies. Using data from a high-throughput drug screen, we have developed a novel therapeutic strategy that targets the apoptotic machinery using the BCL-2 family inhibitor ABT-263 (navitoclax) in combination with a TORC1/2 inhibitor, AZD8055. This combination leads to efficient apoptosis specifically in KRAS- and BRAF-mutant but not wild-type (WT) colorectal cancer cells. This specific susceptibility results from TORC1/2 inhibition leading to suppression of MCL-1 expression in mutant, but not WT, colorectal cancers, leading to abrogation of BIM/MCL-1 complexes. This combination strategy leads to tumor regressions in both KRAS-mutant colorectal cancer xenograft and genetically engineered mouse models of colorectal cancer, but not in the corresponding KRAS-WT colorectal cancer models. These data suggest that the combination of BCL-2/BCL-XL inhibitors with TORC1/2 inhibitors constitutes a promising targeted therapy strategy to treat these recalcitrant cancers.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Morfolinas/uso terapêutico , Complexos Multiproteicos/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Mutantes , Camundongos Nus , Morfolinas/farmacologia , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras) , Sulfonamidas/farmacologia , Proteína bcl-X/antagonistas & inibidores , Proteínas ras/genética
20.
Nat Rev Clin Oncol ; 8(6): 344-56, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21487419

RESUMO

Brain metastases are a serious obstacle in the treatment of patients with solid tumors and contribute to the morbidity and mortality of these cancers. It is speculated that the frequency of brain metastasis is increasing for several reasons, including improved systemic therapy and survival, and detection of metastases in asymptomatic patients. The lack of preclinical models that recapitulate the clinical setting and the exclusion of patients with brain metastases from most clinical trials have slowed progress. Molecular factors contributing to brain metastases are being elucidated, such as genes involved in cell adhesion, extravasation, metabolism, and cellular signaling. Furthermore, the role of the unique brain microenvironment is beginning to be explored. Although the presence and function of the blood-brain barrier in metastatic tumors is still poorly understood, it is likely that some tumor cells are protected from therapeutics by the blood-tumor barrier, creating a sanctuary site. This Review discusses what is known about the biology of brain metastases, what preclinical models are available to study the disease, and which novel therapeutic strategies are being studied in patients.


Assuntos
Barreira Hematoencefálica , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Neoplasias/patologia , Neoplasias/terapia , Animais , Modelos Animais de Doenças , Humanos
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