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1.
BMC Cancer ; 23(1): 1039, 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37891555

RESUMO

BACKGROUND: The immune checkpoint HERV-H LTR-associating 2 (HHLA2) is expressed in kidney cancer and various other tumor types. Therapeutics targeting HHLA2 or its inhibitory receptor KIR3DL3 are being developed for solid tumors, including renal cell carcinoma (RCC). However, the regulation of HHLA2 expression remains poorly understood. A better understanding of HHLA2 regulation in tumor cells and the tumor microenvironment is crucial for the successful translation of these therapeutic agents into clinical applications. METHODS: Flow cytometry and quantitative real-time PCR were used to analyze HHLA2 expression in primary kidney tumors ex vivo and during in vitro culture. HHLA2 expression in A498 and 786-O ccRCC cell lines was examined in vitro and in subcutaneous tumor xenografts in NSG mice. Monocytes and dendritic cells were analyzed for HHLA2 expression. We tested a range of cytokines and culture conditions, including hypoxia, to induce HHLA2 expression. RESULTS: Analysis of HHLA2 expression revealed that HHLA2 is expressed on tumor cells in primary kidney tumors ex vivo; however, its expression gradually diminishes during a 4-week in vitro culture period. A498 and 786-O ccRCC tumor cell lines do not express HHLA2 in vitro, but HHLA2 expression was observed when grown as subcutaneous xenografts in NSG immunodeficient mice. Induction experiments using various cytokines and culture conditions failed to induce HHLA2 expression in A498 and 786-O tumor cell lines in vitro. Analysis of HHLA2 expression in monocytes and dendritic cells demonstrated that only IL-10 and BMP4, along with IL-1ß and IL-6 to a lesser extent, modestly enhanced HHLA2 protein and mRNA expression. CONCLUSIONS: HHLA2 expression is induced on kidney cancer cells in vivo by a tumor microenvironmental signal that is not present in vitro. HHLA2 expression is differentially regulated in kidney cancer epithelial cells and monocytes. Cytokines, particularly IL10, that induce HHLA2 expression in monocytes fail to upregulate HHLA2 expression in tumor cell lines in vitro. These findings underscore the importance of the interplay between tumor cell and tumor microenvironmental signals in the regulation of HHLA2. Further investigation is warranted to elucidate the mechanisms involved in HHLA2 regulation and its implications for therapeutic development.


Assuntos
Carcinoma de Células Renais , Retrovirus Endógenos , Neoplasias Renais , Humanos , Animais , Camundongos , Carcinoma de Células Renais/genética , Retrovirus Endógenos/metabolismo , Neoplasias Renais/genética , Citocinas/metabolismo , Células Mieloides/metabolismo , Imunoglobulinas/genética , Microambiente Tumoral
2.
Radiology ; 298(2): 332-340, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33258745

RESUMO

Background Tumor perfusion may inform therapeutic response and resistance in metastatic renal cell carcinoma (RCC) treated with antiangiogenic therapy. Purpose To determine if arterial spin labeled (ASL) MRI perfusion changes are associated with tumor response and disease progression in metastatic RCC treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Materials and Methods In this prospective study (ClinicalTrials.gov identifier: NCT00749320), metastatic RCC perfusion was measured with ASL MRI before and during sunitinib or pazopanib therapy between October 2008 and March 2014. Objective response rate (ORR) and progression-free survival (PFS) were calculated. Perfusion was compared between responders and nonresponders at baseline, at week 2, after cycle 2 (12 weeks), after cycle 4 (24 weeks), and at disease progression and compared with the ORR by using the Wilcoxon rank sum test and with PFS by using the log-rank test. Results Seventeen participants received sunitinib (mean age, 59 years ± 7.0 [standard deviation]; 11 men); 11 participants received pazopanib (mean age, 63 years ± 6.6; eight men). Responders had higher baseline tumor perfusion than nonresponders (mean, 404 mL/100 g/min ± 213 vs 199 mL/100 g/min ± 136; P = .02). Perfusion decreased from baseline to week 2 (-53 mL/100 g/min ± 31; P < .001), after cycle 2 (-65 mL/100 g/min ± 25; P < .001), and after cycle 4 (-79 mL/100 g/min ± 15; P = .008). Interval reduction in perfusion at those three time points was not associated with ORR (P = .63, .29, and .27, respectively) or PFS (P = .28, .27, and .32). Perfusion increased from cycle 4 to disease progression (51% ± 11; P < .001). Conclusion Arterial spin labeled perfusion MRI may assist in identifying responders to vascular endothelial growth factor receptor tyrosine kinase inhibitors and may help detect early evidence of disease progression in patients with metastatic renal cell carcinoma. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Goh and De Vita in this issue.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Sunitinibe/uso terapêutico , Adulto , Idoso , Carcinoma de Células Renais/secundário , Feminino , Humanos , Indazóis , Neoplasias Renais/secundário , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Tirosina Quinases/antagonistas & inibidores , Marcadores de Spin
3.
Genet Med ; 22(8): 1366-1373, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32341571

RESUMO

PURPOSE: Plasma cell-free DNA (cfDNA) variant analysis is commonly used in many cancer subtypes. Cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) has shown high sensitivity for cancer detection. To date, studies have not compared the sensitivity of both methods in a single cancer subtype. METHODS: cfDNA from 40 metastatic RCC (mRCC) patients was subjected to targeted panel variant analysis. For 34 of 40, cfMeDIP-seq was also performed. A separate cohort of 38 mRCC patients were used in cfMeDIP-seq analysis to train an RCC classifier. RESULTS: cfDNA variant analysis detected 21 candidate variants in 11 of 40 mRCC patients (28%), after exclusion of 2 germline variants and 6 variants reflecting clonal hematopoiesis. Among 23 patients with parallel tumor sequencing, cfDNA analysis alone identified variants in 9 patients (39%), while cfDNA analysis focused on tumor sequencing variant findings improved the sensitivity to 52%. In 34 mRCC patients undergoing cfMeDIP-seq, cfDNA variant analysis identified variants in 7 (21%), while cfMeDIP-seq detected all mRCC cases (100% sensitivity) with 88% specificity in 34 control subjects. In 5 patients with cfDNA variants and serial samples, variant frequency correlated with response to therapy. CONCLUSION: cfMeDIP-seq is significantly more sensitive for mRCC detection than cfDNA variant analysis. However, cfDNA variant analysis may be useful for monitoring response to therapy.


Assuntos
Carcinoma de Células Renais , Ácidos Nucleicos Livres , Neoplasias Renais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Ácidos Nucleicos Livres/genética , DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Plasma
4.
Cancer ; 125(14): 2400-2408, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30951193

RESUMO

BACKGROUND: In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC). METHODS: In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate. RESULTS: Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group. CONCLUSIONS: Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.


Assuntos
Receptores de Activinas Tipo II/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Axitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptores de Activinas Tipo II/administração & dosagem , Receptores de Activinas Tipo II/efeitos adversos , Receptores de Activinas Tipo II/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Axitinibe/administração & dosagem , Axitinibe/efeitos adversos , Carcinoma de Células Renais/mortalidade , Diarreia/etiologia , Método Duplo-Cego , Fadiga/etiologia , Feminino , Humanos , Hipertensão/etiologia , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Fragmentos Fc das Imunoglobulinas/metabolismo , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/metabolismo
5.
Am J Pathol ; 187(10): 2337-2347, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28736316

RESUMO

Tumors induce their heterogeneous vasculature by secreting vascular endothelial growth factor (VEGF)-A. Anti-VEGF/VEGF receptor (VEGFR) drugs treat cancer, but the underlying mechanisms remain unclear. An adenovirus expressing VEGF-A (Ad-VEGF-A164) replicates the tumor vasculature in mice without tumor cells. Mother vessels (MV) are the first angiogenic vessel type to form in tumors and after Ad-VEGF-A164. Multiday treatments with a VEGF trap reverted MV back to normal microvessels. We now show that, within hours, a single dose of several anti-VEGF drugs collapsed MV to form glomeruloid microvascular proliferations (GMP), accompanied by only modest endothelial cell death. GMP, common in many human cancers but of uncertain origin, served as an intermediary step in MV reversion to normal microvessels. The vasodisruptive drug combretastatin CA4 also targeted MV selectively but acted differently, extensively killing MV endothelium. Antivascular changes were quantified with a novel Evans blue dye assay that measured vascular volumes. As in tumors, Ad-VEGF-A164 strikingly increased endothelial nitric oxide synthase (eNOS) expression. The eNOS inhibitor N(G)-Nitro-l-arginine methyl ester mimicked anti-VEGF/VEGFR drugs, rapidly collapsing MV to GMP. Inhibition of eNOS reduces synthesis of its vasodilatory product, nitric oxide, leading to arterial contraction. Patients and mice receiving anti-VEGF/VEGFR drugs develop hypertension, reflecting systemic arterial contraction. Together, anti-VEGF/VEGFR drugs act in part by inhibiting eNOS, causing vasocontraction, MV collapse to GMP, and subsequent reversion of GMP to normal microvessels, all without extensive vascular killing.


Assuntos
Inibidores da Angiogênese/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adenoviridae/metabolismo , Animais , Bibenzilas/farmacologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Hipertensão/patologia , Camundongos Endogâmicos C57BL , Camundongos Nus , Microvasos/efeitos dos fármacos , Microvasos/patologia , Modelos Biológicos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
6.
Cancer ; 123(4): 576-582, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-27727447

RESUMO

BACKGROUND: Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy. METHODS: Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent. Prior treatment with immunotherapeutic agents and ≤1 mammalian target of rapamycin inhibitors was permitted. The primary endpoint of the study was progression-free survival. Additional endpoints included response rate and safety, and overall survival (OS) performed post hoc. RESULTS: A total of 40 patients were enrolled with a median of 3 prior therapies (range, 1-5 prior therapies), 78% of whom had intermediate-risk disease by second-line International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Although the current study did not achieve its primary endpoint based on the 2-month progression-free survival, a median OS of 21.7 months was observed. Four patients (10%) demonstrated a partial response, with a median duration of response of 5.9 months. No grade 3/4 treatment-related adverse events were observed in >5% of patients (adverse events were graded and recorded for each patient using Common Terminology Criteria for Adverse Events [version 4.0]); the most frequent grade 1/2 treatment-related adverse events were fatigue (30%), weight gain (18%), constipation (15%), and nausea (15%). Biomarker studies demonstrated an increase in S1P concentrations with therapy. Comprehensive genomic profiling of 3 patients with a clinical benefit of >24 months indicated von Hippel-Lindau (VHL) and polybromo-1 (PBRM1) alterations. CONCLUSIONS: The encouraging OS and favorable safety profile observed with sonepcizumab should prompt further investigation of the agent in combination with VEGF-directed agents or checkpoint inhibitors. Cancer 2017;123:576-582. © 2016 American Cancer Society.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Lisofosfolipídeos/antagonistas & inibidores , Esfingosina/análogos & derivados , Fator A de Crescimento do Endotélio Vascular/genética , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Proteínas de Ligação a DNA , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Lisofosfolipídeos/imunologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas Nucleares/genética , Esfingosina/antagonistas & inibidores , Esfingosina/imunologia , Fatores de Transcrição/genética , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Proteína Supressora de Tumor Von Hippel-Lindau/genética
7.
AJR Am J Roentgenol ; 209(2): W85-W92, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28570097

RESUMO

OBJECTIVE: The purpose of this study was to evaluate the median versus mean attenuation obtained from histograms in the response assessment of renal cell carcinoma (RCC) target lesions in patients treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors. MATERIALS AND METHODS: Imaging findings of 19 patients with RCC and treated with a VEGFR tyrosine kinase inhibitor that included a baseline study and at least two follow-up studies were retrospectively analyzed. Histograms of target lesions were created from ROI measurements, and mean and median lesion attenuation were obtained. Shift of mean and median was used to classify response of lesions between baseline CT and the first follow-up examination according to the Choi criteria; morphology, attenuation, size, and structure (MASS) criteria; and the Response Evaluation Criteria in Solid Tumors (RECIST). RECIST classification of the last follow-up CT examination was considered the reference standard. RESULTS: Among the 19 patients (six women, 13 men; mean age, 60 ± 8 [SD] years; body mass index, 24.5 ± 4.6 kg/m2), three (16%) had evidence of disease progression; nine (47%), partial response; and seven (37%), stable disease. Temporal change in the shape of the histograms from or to gaussian occurred in 11 of the 19 (58%) lesions, which accounted for a significant difference between mean (64.3 ± 38.5 HU) and median (71.0 ± 36.5 HU) lesion attenuation (p < 0.001). According to the shift of median for outcome analysis, the number of properly classified lesions increased from 12 of 19 (63%) to 13 of 19 (68%) for the Choi criteria and from 14 of 19 (74%) to 15 of 19 (79%) for the MASS criteria. CONCLUSION: Mean and median attenuation of RCC target lesions differed significantly. Use of shift of median rather than shift of mean increased the number of accurate classifications of lesions at the first follow-up CT examination.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Carcinoma de Células Renais/patologia , Meios de Contraste , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
8.
Magn Reson Med ; 76(4): 1102-15, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26507361

RESUMO

PURPOSE: In balanced steady state free precession (bSSFP), the signal intensity has a well-known dependence on the off-resonance frequency, or, equivalently, the phase advance between successive radiofrequency (RF) pulses. The signal profile can be used to resolve the contributions from the spectrally separated metabolites. This work describes a method based on use of a variable RF phase advance to acquire spatial and spectral data in a time-efficient manner for hyperpolarized 13C MRI. THEORY AND METHODS: The technique relies on the frequency response from a bSSFP acquisition to acquire relatively rapid, high-resolution images that may be reconstructed to separate contributions from different metabolites. The ability to produce images from spectrally separated metabolites was demonstrated in vitro, as well as in vivo following administration of hyperpolarized 1-13C pyruvate in mice with xenograft tumors. RESULTS: In vivo images of pyruvate, alanine, pyruvate hydrate, and lactate were reconstructed from four images acquired in 2 s with an in-plane resolution of 1.25 × 1.25 mm(2) and 5 mm slice thickness. CONCLUSION: The phase advance method allowed acquisition of spectroscopically selective images with high spatial and temporal resolution. This method provides an alternative approach to hyperpolarized 13C spectroscopic MRI that can be combined with other techniques such as multiecho or fluctuating equilibrium bSSFP. Magn Reson Med 76:1102-1115, 2016. © 2015 Wiley Periodicals, Inc.


Assuntos
Alanina/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Ácido Láctico/metabolismo , Imageamento por Ressonância Magnética/métodos , Neoplasias Experimentais/metabolismo , Ácido Pirúvico/metabolismo , Processamento de Sinais Assistido por Computador , Células A549 , Algoritmos , Animais , Biomarcadores Tumorais/metabolismo , Isótopos de Carbono/farmacocinética , Linhagem Celular Tumoral , Humanos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Camundongos , Camundongos Nus , Imagem Molecular/métodos , Neoplasias Experimentais/patologia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
9.
J Clin Oncol ; 42(22): 2691-2701, 2024 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-38701382

RESUMO

PURPOSE: Both clear cell and papillary renal cell carcinomas (RCCs) overexpress kidney injury molecule-1 (KIM-1). We investigated whether plasma KIM-1 (pKIM-1) may be a useful risk stratification tool among patients with suspicious renal masses. METHODS: Prenephrectomy pKIM-1 was measured in two independent cohorts of patients with renal masses. Cohort 1, from the prospective K2 trial, included 162 patients found to have clear cell RCC (cases) and 162 patients with benign renal masses (controls). Cohort 2 included 247 patients with small (cT1a) renal masses from an academic biorepository, of whom 184 had RCC. We assessed the relationship between pKIM-1, surgical pathology, and clinical outcomes. RESULTS: In Cohort 1, pKIM-1 distinguished RCC versus benign masses with area under the receiver operating curve (AUC-ROC, 0.81 [95% CI, 0.76 to 0.86]). In Cohort 2 (cT1a only), pKIM-1 distinguished RCC versus benign masses (AUC-ROC, 0.74 [95% CI, 0.67 to 0.80]) and the addition of pKIM-1 to an established nomogram for predicting malignancy improved the model AUC-ROC (0.65 [95% CI, 0.57 to 0.74] v 0.78 [95% CI, 0.72 to 0.85]). A pKIM-1 cutpoint identified using Cohort 2 demonstrated sensitivity of 92.5% and specificity of 60% for identifying RCC in Cohort 1. In long-term follow-up of RCC cases (Cohort 1), higher prenephrectomy pKIM-1 was associated with worse metastasis-free survival (multivariable MFS hazard ratio [HR] 1.29 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.53) and overall survival (multivariable OS HR 1.31 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.54). In long-term follow-up of Cohort 2, no metastatic events occurred, consistent with the favorable prognosis of resected cT1a RCC. CONCLUSION: Among patients with renal masses, pKIM-1 is associated with malignant pathology, worse MFS, and risk of death. pKIM-1 may be useful for selecting patients with renal masses for intervention versus surveillance.


Assuntos
Carcinoma de Células Renais , Receptor Celular 1 do Vírus da Hepatite A , Neoplasias Renais , Humanos , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/cirurgia , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Receptor Celular 1 do Vírus da Hepatite A/sangue , Biomarcadores Tumorais/sangue , Estudos Prospectivos , Curva ROC , Nefrectomia , Adulto , Prognóstico , Valor Preditivo dos Testes
10.
Cancer Immunol Res ; 12(6): 704-718, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38552171

RESUMO

The checkpoint immunotherapeutic pembrolizumab induces responses in a small minority of patients with metastatic castration-resistant prostate cancer (mCRPC). Radium-223 (R223) may increase immunogenicity of bone metastases and increase pembrolizumab (P) activity. In a randomized phase II study, we assessed the effect of R223+P compared with R223 on tumor immune infiltration, safety, and clinical outcomes in patients with mCRPC. The primary endpoint was differences in CD4+ and CD8+ T-cell infiltrate in 8-week versus baseline bone metastasis biopsies; secondary endpoints were safety, radiographic progression-free survival (rPFS), and overall survival (OS). Of the 42 treated patients (29 R223+P, 13 R223), 18 R223+P and 8 R223 patients had evaluable paired tumor biopsies. Median fold-change of CD4+ T cells was -0.7 (range: -9.3 to 4.7) with R223+P and 0.1 (-11.1 to 3.7) with R223 (P = 0.66); for CD8+ T cells, median fold-change was -0.6 (-7.4 to 5.3) with R223+P and -1.3 (-3.1 to 4.8) with R223 (P = 0.66). Median rPFS and OS was 6.1 (95% confidence interval: 2.7-11.0) and 16.9 months [12.7-not reached (NR)], respectively, with R223+P and 5.7 (2.6-NR) and 16.0 (9.0-NR), respectively, with R223. Although R223+P was well tolerated with no unexpected toxicity, the combination did not improve efficacy. High-dimensional flow cytometry demonstrated minimal immune modulation with R223, whereas R223+P induced CTLA-4 expression on circulating CD4+ T cells. Clinical responders possessed lower circulating frequencies of Ki67+ T and myeloid cells at baseline and higher circulating frequencies of TIM-3+ T and myeloid cells by week 9. Although R223+P did not induce T-cell infiltration into the tumor microenvironment, exhaustion of induced peripheral T-cell immune responses may dampen the combination's clinical activity.


Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias de Próstata Resistentes à Castração , Rádio (Elemento) , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/radioterapia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Idoso , Rádio (Elemento)/uso terapêutico , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias Ósseas/tratamento farmacológico , Linfócitos T CD8-Positivos/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
11.
Cancer ; 118(19): 4777-84, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22282219

RESUMO

BACKGROUND: Treatment of high-risk localized prostate cancer remains inadequate. The authors performed a phase 2 multicenter trial of neoadjuvant docetaxel plus bevacizumab before radical prostatectomy. METHODS: Eligibility included any of the following: prostate-specific antigen (PSA) >20 ng/mL or PSA velocity >2 ng/mL/y, cT3 disease, any biopsy Gleason score 8 to 10, and Gleason score 7 with T3 disease by endorectal magnetic resonance imaging (MRI) at 1.5 T. Also, those with ≥50% biopsy cores involved and either Gleason score 7, PSA >10, or cT2 disease were eligible. Patients were treated with docetaxel 70 mg/m(2) every 3 weeks for 6 cycles and bevacizumab 15 mg/m(2) every 3 weeks for 5 cycles. The primary endpoint was partial response by endorectal MRI. RESULTS: Forty-one patients were treated. Median age was 55 years (range, 40-66 years). Baseline characteristics included: median PSA, 10.1 ng/mL; cT2, 49%, cT3, 32%; and Gleason score 8 to 10, 73%. Thirty-eight of 41 (93%) patients completed all 6 cycles. Grade ≥3 adverse events were rare, although 3 of 41 (7%) experienced febrile neutropenia. Twelve patients (29%; 95% confidence interval [CI], 16%-45%) achieved a >50% reduction in tumor volume, and 9 patients (22%; 95% CI, 11%-38%) achieved a >50% post-treatment decline in PSA. Thirty-seven of the 41 patients underwent radical prostatectomy; there were no complete pathologic responses. CONCLUSIONS: Neoadjuvant docetaxel and bevacizumab is safe, and results in reductions in both tumor volume and serum PSA, in men with high-risk localized prostate cancer. The role of neoadjuvant chemotherapy in prostate cancer, and perioperative antiangiogenic therapy in general, requires further elucidation through ongoing and planned trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Terapia Neoadjuvante/métodos , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Docetaxel , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neutropenia/induzido quimicamente , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Medição de Risco , Fatores de Risco , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Resultado do Tratamento
12.
J Transl Med ; 9: 220, 2011 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-22188900

RESUMO

BACKGROUND: Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model. METHODS: Mice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10. RESULTS: Tumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion. CONCLUSIONS: A modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.


Assuntos
Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/patologia , Camundongos , Camundongos Nus , Microvasos/efeitos dos fármacos , Microvasos/patologia , Niacinamida/análogos & derivados , Perfusão , Compostos de Fenilureia , Sorafenibe , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Mol Cell Oncol ; 8(4): 1918529, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616864

RESUMO

Resistance to tyrosine kinase inhibitors of the vascular endothelial growth factor receptor inevitably develops in most patients with metastatic kidney cancer. Our recent findings demonstrate that addition of angiotensin-(1-7) peptide can be a potential therapy that delays such resistance.

14.
Int J Radiat Oncol Biol Phys ; 110(5): 1416-1422, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33636278

RESUMO

PURPOSE: Androgen deprivation therapy (ADT) is often used as adjuvant treatment with radiation therapy (RT) for intermediate-risk prostate cancer. ADT is associated with multiple side effects, including weight gain, loss of libido, and hot flashes. In contrast, antiandrogen monotherapy has been generally better tolerated. This study aimed to assess the effectiveness of enzalutamide (an antiandrogen) monotherapy with RT for the treatment of intermediate-risk prostate cancer. METHODS AND MATERIALS: This trial was an open-label, phase 2 study of 6 months of enzalutamide monotherapy with external beam RT for intermediate-risk prostate cancer. Enzalutamide was initiated 2 months before external beam RT. The primary endpoint was prostate-specific antigen (PSA) response measured at the end of enzalutamide administration at the 6-month timepoint. Secondary endpoints included assessment of toxicity and changes in anthropomorphic body measurement, sexual function, and metabolism. The sample size was 64 patients. The hypothesis was that if ≥60% of the patients did not achieve a PSA nadir of ≤0.2 ng/mL, the study results would be deemed negative. RESULTS: The results met the prespecified endpoint for efficacy in that PSA values ≤0.2 ng/mL were observed in 49 of 64 patients (77%), and 60 of 64 patients (94%) had PSA values ≤0.5ng/mL. The most frequent adverse events were hypertension and gynecomastia. There were no changes in anthropomorphic body measurements and only modest erectile dysfunction. CONCLUSIONS: Using PSA response as an endpoint, enzalutamide monotherapy may be as effective as ADT in combination with external beam RT for patients with intermediate-risk prostate cancer, and it is associated with fewer side effects. Randomized trials comparing enzalutamide with ADT are justified.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Benzamidas/uso terapêutico , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Antagonistas de Androgênios/efeitos adversos , Androgênios/sangue , Benzamidas/efeitos adversos , Composição Corporal/efeitos dos fármacos , Distribuição da Gordura Corporal , Ginecomastia/induzido quimicamente , Humanos , Hipertensão/induzido quimicamente , Masculino , Nitrilas/efeitos adversos , Feniltioidantoína/efeitos adversos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Risco , Testosterona/sangue , Fatores de Tempo
15.
Clin Cancer Res ; 27(12): 3397-3403, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33832947

RESUMO

PURPOSE: No circulating biomarkers are currently available to identify patients at highest risk of recurrence after nephrectomy for renal cell carcinoma (RCC). Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain circulates in plasma. We investigated whether plasma KIM-1 is a prognostic biomarker in patients with localized RCC after nephrectomy. EXPERIMENTAL DESIGN: The ECOG-ACRIN E2805 (ASSURE) trial evaluated adjuvant sunitinib, sorafenib, or placebo in resected high-risk RCC. KIM-1 levels were measured from banked plasma at trial enrollment 4-12 weeks after nephrectomy. Lognormal accelerated failure time models were used to test for association between KIM-1 and disease-free survival (DFS) as well as overall survival (OS). RESULTS: Plasma from 418 patients was analyzed. Higher post-nephrectomy KIM-1 was associated with worse DFS across all study arms after adjustment for Fuhrman grade, T stage, N stage, and tumor histology [survival time ratio 0.56 for 75th vs. 25th percentile of KIM-1; 95% confidence interval (CI), 0.42-0.73; P < 0.001]. The association between KIM-1 and DFS was stronger among patients with pathologic nodal involvement (P interaction = 0.0086). The addition of post-nephrectomy KIM-1 improved the concordance of clinical prognostic models [Stage, Size, Grade, and Necrosis (SSIGN) concordance 0.57 vs. 0.43, P = 0.05; UCLA International Staging System (UISS) concordance 0.60 vs. 0.40, P = 0.0005]. Higher post-nephrectomy KIM-1 was also associated with worse OS after multivariable adjustment (survival time ratio 0.71 for 75th vs. 25th percentile of KIM-1; 95% CI, 0.56-0.91; P < 0.001). CONCLUSIONS: Post-nephrectomy plasma KIM-1 is associated with DFS and OS in RCC, and may be a biomarker for microscopic residual disease.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Nefrectomia/efeitos adversos , Prognóstico , Sunitinibe/uso terapêutico
16.
Cancers (Basel) ; 13(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34439209

RESUMO

There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana-Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions.

17.
Sci Transl Med ; 13(577)2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33472951

RESUMO

Angiotensin converting enzyme 2 (ACE2) is an enzyme that belongs to the renin-angiotensin system (RAS) and antagonizes the classical angiotensin (Ang) II/angiotensin II receptor type 1 (AT1) receptor pathway. Here, we report that higher ACE2 expression correlates with better overall survival in patients with clear cell renal cell carcinoma (ccRCC). Moreover, ACE2 has inhibitory effects on tumor proliferation in ccRCC in vitro and in preclinical animal models of ccRCC. We further show that Ang-(1-7), a heptapeptide generated by ACE2, is the likely mediator of this effect. Vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) treatment of ccRCC xenografts decreased ACE2 expression, and combination treatment with VEGFR-TKI and Ang-(1-7) generated additive suppression of tumor growth and improved survival outcomes. Last, the addition of Ang-(1-7) to programmed death-ligand 1 (PD-L1) pathway inhibitor and VEGFR-TKI showed further growth suppression in an immunocompetent RCC model. Together, these results suggest that targeting the ACE2/Ang-(1-7) axis is a promising therapeutic strategy against ccRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Angiotensina I , Angiotensina II , Enzima de Conversão de Angiotensina 2 , Animais , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Fragmentos de Peptídeos , Peptidil Dipeptidase A , Inibidores de Proteínas Quinases , Fator A de Crescimento do Endotélio Vascular
18.
Clin Cancer Res ; 27(13): 3610-3619, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33849963

RESUMO

PURPOSE: Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance. PATIENTS AND METHODS: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole-exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing. RESULTS: A total of 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes (PTEN, RB1, and TP53), which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression vs. 53.9% at baseline) and BRCA2 alterations (64.7% at progression vs. 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR-regulated genes, and neuroendocrine markers at progression. CONCLUSIONS: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide, highlighting the importance of serial tumor sampling in CRPC.


Assuntos
Benzamidas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Humanos , Masculino , Metástase Neoplásica , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/patologia
19.
Cancer Immunol Res ; 9(2): 156-169, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33229411

RESUMO

Blockade of the PD1 pathway is a broadly effective cancer therapy, but additional immune-inhibitory pathways contribute to tumor immune evasion. HERV-H LTR-associating 2 (HHLA2; also known as B7H5 and B7H7) is a member of the B7 family of immunoregulatory ligands that mediates costimulatory effects through its interaction with the CD28 family member transmembrane and immunoglobulin domain containing 2 (TMIGD2). However, HHLA2 has also been known to have inhibitory effects on T cells. Here, we report that we have identified killer cell immunoglobulin-like receptor, three immunoglobulin domains and long cytoplasmic tail 3 (KIR3DL3) as an inhibitory receptor for HHLA2 in T cells and natural killer (NK) cells and have generated HHLA2 and KIR3DL3 antibodies that block the immune-inhibitory activity of HHLA2, preserving the costimulatory signal. It is known that HHLA2 is frequently expressed in several tumor types, including clear cell renal cell carcinoma (ccRCC). We found that HHLA2 expression was nonoverlapping with PDL1 expression in ccRCC, suggesting that HHLA2 mediates a mechanism of tumor immune evasion that is independent from PDL1. Blockade of both the PD1 and KIR3DL3 pathways may be a more effective way to reverse tumor immune evasion.See related Spotlight on p. 128.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma de Células Renais/imunologia , Imunoglobulinas/metabolismo , Neoplasias Renais/imunologia , Receptores KIR/metabolismo , Animais , Antígeno B7-H1/imunologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Humanos , Imunoglobulinas/imunologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Receptores KIR/imunologia , Linfócitos T/imunologia
20.
J Clin Invest ; 130(6): 3287-3298, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32478682

RESUMO

Despite widespread use of taxanes, mechanisms of action and resistance in vivo remain to be established, and there is no way of predicting who will respond to therapy. This study examined prostate cancer (PCa) xenografts and patient samples to identify in vivo mechanisms of taxane action and resistance. Docetaxel drug-target engagement was assessed by confocal anti-tubulin immunofluorescence to quantify microtubule bundling in interphase cells and aberrant mitoses. Tumor biopsies from metastatic PCa patients obtained 2 to 5 days after their first dose of docetaxel or cabazitaxel were processed to assess microtubule bundling, which correlated with clinical response. Microtubule bundling was evident in PCa xenografts 2 to 3 days after docetaxel treatment but was decreased or lost with acquired resistance. Biopsies after treatment with leuprolide plus docetaxel showed extensive microtubule bundling as did biopsies obtained 2 to 3 days after initiation of docetaxel or cabazitaxel in 2 patients with castration-resistant PCa with clinical responses. In contrast, microtubule bundling in biopsies 2 to 3 days after the first dose of docetaxel was markedly lower in 4 nonresponding patients. These findings indicate that taxanes target both mitotic and interphase cells in vivo and that resistance is through mechanisms that impair drug-target engagement. Moreover, the findings suggest that microtubule bundling after initial taxane treatment may be a predictive biomarker for clinical response.


Assuntos
Hidrocarbonetos Aromáticos com Pontes , Resistencia a Medicamentos Antineoplásicos , Microtúbulos/metabolismo , Neoplasias da Próstata/metabolismo , Taxoides , Animais , Hidrocarbonetos Aromáticos com Pontes/farmacocinética , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular Tumoral , Docetaxel/farmacocinética , Docetaxel/farmacologia , Humanos , Masculino , Camundongos , Camundongos Nus , Microtúbulos/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Taxoides/farmacocinética , Taxoides/farmacologia
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