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1.
Cancer Discov ; 10(1): 40-53, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732494

RESUMO

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor A2A de Adenosina/química , Terapia de Salvação , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma de Células Renais/patologia , Feminino , Seguimentos , Furanos/administração & dosagem , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Receptor A2A de Adenosina/metabolismo , Taxa de Sobrevida
2.
Appl Immunohistochem Mol Morphol ; 27(2): 92-100, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29346180

RESUMO

Cancer immunotherapies, such as atezolizumab, are proving to be a valuable therapeutic strategy across indications, including non-small cell lung cancer (NSCLC) and urothelial cancer (UC). Here, we describe a diagnostic assay that measures programmed-death ligand 1 (PD-L1) expression, via immunohistochemistry, to identify patients who will derive the most benefit from treatment with atezolizumab, a humanized monoclonal anti-PD-L1 antibody. We describe the performance of the VENTANA PD-L1 (SP142) Assay in terms of specificity, sensitivity, and the ability to stain both tumor cells (TC) and tumor-infiltrating immune cells (IC), in NSCLC and UC tissues. The reader precision, repeatability and intermediate precision, interlaboratory reproducibility, and the effectiveness of pathologist training on the assessment of PD-L1 staining on both TC and IC were evaluated. We detail the analytical validation of the VENTANA PD-L1 (SP142) Assay for PD-L1 expression in NSCLC and UC tissues and show that the assay reliably evaluated staining on both TC and IC across multiple expression levels/clinical cut-offs. The reader precision showed high overall agreement when compared with consensus scores. In addition, pathologists met the predefined training criteria (≥85.0% overall percent agreement) for the assessment of PD-L1 expression in NSCLC and UC tissues with an average overall percent agreement ≥95.0%. The assay evaluates PD-L1 staining on both cell types and is robust and precise. In addition, it can help to identify those patients who may benefit the most from treatment with atezolizumab, although treatment benefit has been demonstrated in an all-comer NSCLC and UC patient population.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/terapia , Imuno-Histoquímica/métodos , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Neoplasias da Bexiga Urinária/terapia , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/imunologia , Variações Dependentes do Observador , Seleção de Pacientes , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/imunologia
3.
Cancer Immunol Res ; 6(10): 1136-1149, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30131376

RESUMO

Adenosine signaling through A2A receptors (A2AR) expressed on immune cells suppresses antitumor immunity. CPI-444 is a potent, selective, oral A2AR antagonist. Blockade of A2AR with CPI-444 restored T-cell signaling, IL2, and IFNγ production that were suppressed by adenosine analogues in vitro CPI-444 treatment led to dose-dependent inhibition of tumor growth in multiple syngeneic mouse tumor models. Concentrations of extracellular adenosine in the tumor microenvironment, measured using microdialysis, were approximately 100-150 nmol/L and were higher than corresponding subcutaneous tissue. Combining CPI-444 with anti-PD-L1 or anti-CTLA-4 treatment eliminated tumors in up to 90% of treated mice, including restoration of immune responses in models that incompletely responded to anti-PD-L1 or anti-CTLA-4 monotherapy. Tumor growth was fully inhibited when mice with cleared tumors were later rechallenged, indicating that CPI-444 induced systemic antitumor immune memory. CD8+ T-cell depletion abrogated the efficacy of CPI-444 with and without anti-PD-L1 treatment, demonstrating a role for CD8+ T cells in mediating primary and secondary immune responses. The antitumor efficacy of CPI-444 with and without anti-PD-L1 was associated with increased T-cell activation, a compensatory increase in CD73 expression, and induction of a Th1 gene expression signature consistent with immune activation. These results suggest a broad role for adenosine-mediated immunosuppression in tumors and justify the further evaluation of CPI-444 as a therapeutic agent in patients with solid tumors. Cancer Immunol Res; 6(10); 1136-49. ©2018 AACR.


Assuntos
Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Neoplasias do Colo/tratamento farmacológico , Furanos/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Furanos/farmacologia , Humanos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Piridinas/farmacologia , Pirimidinas/farmacologia , Linfócitos T/efeitos dos fármacos
4.
JAMA Oncol ; 3(5): 620-627, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27918764

RESUMO

IMPORTANCE: Dysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC. OBJECTIVE: To determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, multicenter trial conducted from November 2012 to March 2014. Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy. Tumor samples were centrally tested for MET expression using Ventana anti-Total c-MET (SP44) rabbit monoclonal antibody, HER2 status, and Lauren histologic subtype. MET-positive tumors were defined as at least 50% of tumor cells showing weak, moderate, and/or strong staining intensity (MET 1+/2+/3+, respectively) by immunohistochemistry. INTERVENTIONS: Patients with HER2-negative, MET-positive GEC were enrolled and randomized 1:1 to receive mFOLFOX6 with or without onartuzumab (10 mg/kg). MAIN OUTCOMES AND MEASURES: Co-primary end points: overall survival in the intent-to-treat (ITT) population and in patients with MET 2+/3+ GEC. Secondary end points: progression-free survival (PFS), overall response rate (ORR), and safety. RESULTS: Enrollment was stopped early due to sponsor decision, which was agreed with an independent data monitoring committee. At the data cutoff (April 25, 2014) there were 562 patients in the ITT population (n = 283 placebo plus mFOLFOX6 [median age, 58 y; 65% male]; n = 279 onartuzumab plus mFOLFOX6 [median age, 60 y; 67% male]); 109 (38.5%) and 105 (37.6%) of the ITT population were MET 2+/3+, respectively. Addition of onartuzumab to mFOLFOX6 did not significantly improve OS, PFS, or ORR vs placebo plus mFOLFOX6 in the ITT (OS hazard ratio [HR], 0.82; 95% CI, 0.59-1.15; P = .24; PFS HR, 0.90; 95% CI, 0.71-1.16; P = .43; ORR, 46.1% vs 40.6%) or MET 2+/3+ populations (OS HR, 0.64; 95% CI, 0.40-1.03; P = .06; PFS HR, 0.79; 95% CI, 0.54-1.15; P = .22; ORR, 53.8% vs 44.6%). Safety was as expected for onartuzumab. CONCLUSIONS AND RELEVANCE: Addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3+ populations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01662869.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Junção Esofagogástrica , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/metabolismo , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/metabolismo , Método Duplo-Cego , Transição Epitelial-Mesenquimal , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Análise de Intenção de Tratamento/métodos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo
5.
J Thorac Oncol ; 12(2): 208-222, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27913228

RESUMO

INTRODUCTION: The Blueprint Programmed Death Ligand 1 (PD-L1) Immunohistochemistry (IHC) Assay Comparison Project is an industrial-academic collaborative partnership to provide information on the analytical and clinical comparability of four PD-L1 IHC assays used in clinical trials. METHODS: A total of 39 NSCLC tumors were stained with four PD-L1 IHC assays (22C3, 28-8, SP142, and SP263), as used in the clinical trials. Three experts in interpreting their respective assays independently evaluated the percentages of tumor and immune cells staining positive at any intensity. Clinical diagnostic performance was assessed through comparisons of patient classification above and below a selected expression cutoff and by agreement using various combinations of assays and cutoffs. RESULTS: Analytical comparison demonstrated that the percentage of PD-L1-stained tumor cells was comparable when the 22C3, 28-8, and SP263 assays were used, whereas the SP142 assay exhibited fewer stained tumor cells overall. The variability of immune cell staining across the four assays appears to be higher than for tumor cell staining. Of the 38 cases, 19 (50.0%) were classified above and five (13%) were classified below the selected cutoffs of all assays. For 14 of the 38 cases (37%), a different PD-L1 classification would be made depending on which assay/scoring system was used. CONCLUSIONS: The Blueprint PD-L1 IHC Assay Comparison Project revealed that three of the four assays were closely aligned on tumor cell staining whereas the fourth showed consistently fewer tumor cells stained. All of the assays demonstrated immune cell staining, but with greater variability than with tumor cell staining. By comparing assays and cutoffs, the study indicated that despite similar analytical performance of PD-L1 expression for three assays, interchanging assays and cutoffs would lead to "misclassification" of PD-L1 status for some patients. More data are required to inform on the use of alternative staining assays upon which to read different specific therapy-related PD-L1 cutoffs.


Assuntos
Antígeno B7-H1/metabolismo , Bioensaio/métodos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/metabolismo , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Coortes , Humanos , Neoplasias Pulmonares/patologia , Prognóstico
6.
PLoS One ; 10(3): e0122149, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25807104

RESUMO

Several clinical trials in oncology have reported increased mortality or disease progression associated with erythropoiesis-stimulating agents. One hypothesis proposes that erythropoiesis-stimulating agents directly stimulate tumor proliferation and/or survival through cell-surface receptors. To test this hypothesis and examine if human tumors utilize the erythropoietin receptor pathway, the response of tumor cells to human recombinant erythropoietin was investigated in disaggregated tumor cells obtained from 186 patients with colorectal, breast, lung, ovarian, head and neck, and other tumors. A cocktail of well characterized tumor growth factors (EGF, HGF, and IGF-1) were analyzed in parallel as a positive control to determine whether freshly-isolated tumor cells were able to respond to growth factor activation ex vivo. Exposing tumor cells to the growth factor cocktail resulted in stimulation of survival and proliferation pathways as measured by an increase in phosphorylation of the downstream signaling proteins AKT and ERK. In contrast, no activation by human recombinant erythropoietin was observed in isolated tumor cells. Though tumor samples exhibited a broad range of cell-surface expression of EGFR, c-Met, and IGF-1R, no cell-surface erythropoietin receptor was detected in tumor cells from the 186 tumors examined (by flow cytometry or Western blot). Erythropoiesis-stimulating agents did not act directly upon isolated tumor cells to stimulate pathways known to promote proliferation or survival of human tumor cells isolated from primary and metastatic tumor tissues.


Assuntos
Epoetina alfa/farmacologia , Receptores da Eritropoetina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Células HT29 , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Masculino , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor IGF Tipo 1/metabolismo
7.
Clin Cancer Res ; 20(16): 4240-50, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24919569

RESUMO

PURPOSE: Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC. EXPERIMENTAL DESIGN: Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work. RESULTS: In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints. CONCLUSIONS: Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Panitumumabe , Prognóstico , Proteínas Proto-Oncogênicas p21(ras) , Taxa de Sobrevida , Adulto Jovem
8.
Clin Cancer Res ; 19(15): 4282-9, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23741071

RESUMO

PURPOSE: This planned exploratory analysis assessed the predictive nature of baseline circulating factors of the insulin-like growth factor (IGF) axis on the treatment effect of ganitumab (monoclonal antibody inhibitor of IGF-1 receptor) plus gemcitabine in a randomized phase II study in metastatic pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Baseline levels of IGFs/IGF binding proteins (IGFBP) were analyzed in serum or plasma. Mutations and gene expression were analyzed in archival samples. Treatment effects between biomarker subgroups were compared for overall survival (OS). Associations of tumor markers with OS were evaluated. RESULTS: For patients with evaluable samples, ganitumab was associated with improved OS versus placebo (HR, 0.49; 95% CI: 0.28-0.87). The treatment effect on improved OS was strong in the patient subset with higher levels of IGF-1, IGF-2, or IGFBP-3, or lower levels of IGFBP-2, but not so on the other corresponding subset. Median OS of ganitumab versus placebo in patients with higher levels of IGF-1, IGF-2, and IGFBP-3 was 16 versus 6.8 months (HR, 0.25; 95% CI: 0.09-0.67), 16 versus 5.9 months (HR, 0.24; 95% CI: 0.09-0.68), and 16 versus 6.8 months (HR, 0.28; 95% CI: 0.11-0.73), and in patients with lower IGFBP-2 levels was 12.7 versus 6.6 months (HR, 0.19; 95% CI: 0.07-0.55). Interaction between treatment and IGFs/IGFBPs in multivariate analyses suggested predictive potential for IGF-2 (P = 0.002) and IGFBP-2 (P = 0.02). KRAS mutation status and PTEN expression were not associated with OS. CONCLUSIONS: Baseline circulating factors of the IGF axis may predict OS benefit from ganitumab plus gemcitabine in metastatic pancreatic adenocarcinoma.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Receptor IGF Tipo 1/imunologia , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/patologia , Anticorpos Monoclonais Humanizados , Biomarcadores Tumorais/sangue , Desoxicitidina/administração & dosagem , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , PTEN Fosfo-Hidrolase/genética , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Receptor IGF Tipo 1/genética , Análise de Sobrevida , Proteínas ras/genética , Gencitabina
9.
Lancet Oncol ; 14(3): 228-35, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23414585

RESUMO

BACKGROUND: Insulin-like growth factors (IGF-1 and IGF-2) bind to the IGF-1 receptor (IGF-1R), increasing cell proliferation and survival. Ganitumab is a monoclonal IgG1 antibody that blocks IGF-1R. We tested the efficacy and safety of adding ganitumab to endocrine treatment for patients with hormone-receptor-positive breast cancer. METHODS: We did this phase 2 trial in outpatient clinics and hospitals. We enrolled postmenopausal women with hormone-receptor-positive, locally advanced or metastatic breast cancer previously treated with endocrine treatment. They were randomly assigned (2:1) with a central randomisation schedule to receive intravenous ganitumab 12 mg per kg bodyweight or placebo in combination with open-label intramuscular fulvestrant (500 mg on day 1, then 250 mg on days 15, 29, and every 28 days) or oral exemestane (25 mg once daily) on a 28-day cycle. Patients, investigators, study monitors, and the sponsor staff were masked to treatment allocation. Response was assessed every 8 weeks. The primary endpoint was median progression-free survival in the intention-to-treat population. We analysed overall survival as one of our secondary endpoints. The study is registered at ClinicalTrials.gov, number NCT00626106. FINDINGS: We screened 189 patients and enrolled 156 (106 in the ganitumab group and 50 in the placebo group). Median progression-free survival did not differ significantly between the ganitumab and placebo groups (3·9 months, 80% CI 3·6-5·3 vs 5·7 months, 4·4-7·4; hazard ratio [HR] 1·17, 80% CI 0·91-1·50; p=0·44). However, overall survival was worse in the the ganitumab group than in the placebo group (HR 1·78, 80% CI 1·27-2·50; p=0·025). With the exception of hyperglycaemia, adverse events were generally similar between groups. The most common grade 3 or higher adverse event was neutropenia-reported by six of 106 (6%) patients in the ganitumab group and one of 49 (2%) in the placebo group. Hyperglycaemia was reported by 12 of 106 (11%) patients in the ganitumab group (with six patients having grade 3 or 4 hyperglycaemia) and none of 49 in the placebo group. Serious adverse events were reported by 27 of 106 (25%) patients in the ganitumab group and nine of 49 (18%) patients in the placebo group. INTERPRETATION: Addition of ganitumab to endocrine treatment in women with previously treated hormone-receptor-positive locally advanced or metastatic breast cancer did not improve outcomes. Our results do not support further study of ganitumab in this subgroup of patients. FUNDING: Amgen.


Assuntos
Androstadienos , Anticorpos Monoclonais , Neoplasias da Mama/tratamento farmacológico , Estradiol/análogos & derivados , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Idoso , Androstadienos/administração & dosagem , Androstadienos/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Estradiol/administração & dosagem , Estradiol/efeitos adversos , Feminino , Fulvestranto , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/patologia , Pós-Menopausa , Receptor ErbB-2/genética
10.
Clin Pharmacol Drug Dev ; 2(4): 367-78, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27121941

RESUMO

Ganitumab is an investigational, fully human monoclonal antibody antagonist of the insulin-like growth factor-1 receptor (IGF1R) that has shown trends towards improved progression-free survival and overall survival in a phase 2 pancreatic cancer clinical trial. To characterize ganitumab pharmacokinetics (PK) and identify factors affecting PK, ganitumab serum concentration data from three clinical trials were analyzed. The PK of ganitumab as monotherapy and in combination with gemcitabine in patients with pancreatic or non-pancreatic cancer were assessed with a non-linear mixed-effect model. We found that ganitumab exhibited linear and time-invariant kinetics. A two-compartment model adequately described data over a dose range of 1-20 mg/kg with good predictive capability. Typical clearance and central volume of distribution values were 1.7- and 1.3-fold higher, respectively, in patients with pancreatic cancer than in patients with other advanced solid cancers, resulting in lower ganitumab exposure. Covariate analysis was used to evaluate effects of cancer type, gemcitabine coadministration, clinical study, demographics, and laboratory values on ganitumab PK. Pancreatic cancer type was the most significant covariate on clearance along with weight, albumin, and serum creatinine. Gemcitabine coadministration did not affect ganitumab clearance. Thus, disease state can significantly affect PK and should be considered when selecting the clinically effective dose.

11.
J Clin Oncol ; 30(15): 1849-56, 2012 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-22508822

RESUMO

PURPOSE: Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). PATIENTS AND METHODS: Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. RESULTS: Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. CONCLUSION: Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Tumor Desmoplásico de Pequenas Células Redondas/tratamento farmacológico , Receptor IGF Tipo 1/antagonistas & inibidores , Sarcoma de Ewing/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Neoplasias Ósseas/sangue , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Tumor Desmoplásico de Pequenas Células Redondas/sangue , Tumor Desmoplásico de Pequenas Células Redondas/imunologia , Tumor Desmoplásico de Pequenas Células Redondas/mortalidade , Tumor Desmoplásico de Pequenas Células Redondas/secundário , Feminino , Humanos , Hibridização in Situ Fluorescente , Fator de Crescimento Insulin-Like I/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Receptor IGF Tipo 1/imunologia , Sarcoma de Ewing/sangue , Sarcoma de Ewing/genética , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/secundário , Análise de Sequência de RNA , Fatores de Tempo , Translocação Genética , Resultado do Tratamento , Adulto Jovem
12.
Clin Cancer Res ; 18(12): 3414-27, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22510349

RESUMO

PURPOSE: This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab. RESULTS: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses. CONCLUSIONS: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/efeitos adversos , Biomarcadores Tumorais , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Panitumumabe , Compostos de Fenilureia , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/uso terapêutico , Receptor IGF Tipo 1/antagonistas & inibidores , Sorafenibe , Gencitabina
13.
Nephrol Dial Transplant ; 27(7): 2733-45, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22167585

RESUMO

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) stimulate formation of red blood cells by binding to and activating Epo receptors (EpoR) on erythroid progenitor cells. Beyond successful treatment of anemia, ESAs have been reported to reduce damage following insult to organs, including the kidney, possibly via direct activation of EpoR. However, data on ESA effects outside hematopoietic functions are conflicting. Furthermore, limited use of appropriate EpoR-positive and EpoR-negative controls and lack of specific anti-EpoR antibodies make interpretation of data difficult. Recently positive and negative control cell types were validated and a sensitive and specific anti-EpoR antibody (A82) that detects low levels of EpoR protein was described. METHODS: A82 was used to measure EpoR protein levels in tissues, human renal cells and human cell lines by western blot analysis. Surface EpoR was examined on renal cells by measuring binding of [125I]-rHuEpo or antibodies. Renal cells and cell lines were treated with rHuEpo to see if phosphorylation of signaling proteins or proliferation/survival could be induced. Small inhibitory RNA (siRNA) were used to determine if EpoR knockdown affected cell viability. RESULTS: Total EpoR protein was low to undetectable in tissues and renal cells with no detectable EpoR on cell surfaces. EpoR knockdown had no effect on viability of renal cell lines. RHuEpo had no detectable effect on intracellular signaling on renal cell lines with no growth-promoting or survival effect on primary human renal cells. CONCLUSIONS: These results suggest that functional EpoR protein is absent on renal cells and that non-EpoR mechanisms should be explored to explain non-hematopoietic effects of ESAs.


Assuntos
Eritropoetina/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , Megacariócitos/metabolismo , Receptores da Eritropoetina/metabolismo , Transdução de Sinais , Western Blotting , Proliferação de Células , Sobrevivência Celular , Ensaio de Imunoadsorção Enzimática , Eritropoetina/genética , Citometria de Fluxo , Humanos , Rim/citologia , Nefropatias/genética , Nefropatias/patologia , Megacariócitos/citologia , Fosforilação , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores da Eritropoetina/antagonistas & inibidores , Receptores da Eritropoetina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
J Clin Pharmacol ; 51(6): 830-41, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20663992

RESUMO

Inhibition of 11ß-HSD1 is hypothesized to improve measures of insulin sensitivity and hepatic glucose output in patients with type II diabetes. AMG 221 is a potent, small molecule inhibitor of 11ß-HSD1. The objective of this analysis is to describe the pharmacokinetic/pharmacodynamic (PK/PD) relationship between AMG 221 and 11ß-HSD1 inhibition in ex vivo adipose tissue samples. Healthy, obese subjects were administered a single dose of 3, 30, or 100 mg of oral AMG 221 (n = 44) or placebo (n = 11). Serial blood samples were collected over 24 hours. Subcutaneous adipose tissue samples were collected by open biopsy. Population PK/PD analysis was conducted using NONMEM. The inhibitory effects (mean ± standard error of the estimate) of AMG 221 on 11ß-HSD1 activity were directly related to adipose concentrations with I(max) (the maximal inhibition of 11ß-HSD1 activity) and IC50 (the plasma AMG 221 concentration associated with 50% inhibition of enzyme activity) of 0.975 ± 0.003 and 1.19 ± 0.12 ng/mL, respectively. The estimated baseline 11ß-HSD1 enzyme activity was 755 ± 61 pmol/mg. An equilibration rate constant (k(eo)) of 0.220 ± 0.021 h⁻¹ described the delay between plasma and adipose tissue AMG 221 concentrations. AMG 221 potently blocked 11ß-HSD1 activity, producing sustained inhibition for the 24-hour study duration as measured in ex vivo adipose samples. Early characterization of concentration-response relationships can support rational selection of dose and regimen for future studies.


Assuntos
Obesidade/tratamento farmacológico , Gordura Subcutânea Abdominal/enzimologia , Tiazóis/farmacologia , Tiazóis/farmacocinética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Administração Oral , Adulto , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Modelos Biológicos , Obesidade/sangue , Obesidade/enzimologia , Tiazóis/administração & dosagem , Tiazóis/sangue
15.
Blood ; 115(21): 4264-72, 2010 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-20124513

RESUMO

Erythropoiesis stimulating agents (ESAs) have been reported to activate erythropoietin receptors (EpoR) on cell types, including endothelial, neuronal, renal tubule, and cardiac cells. ESAs have also been reported to promote angiogenesis. However, those findings are controversial and confounded by methodologic issues. We show that EpoR mRNA was detected in essentially all cell types examined, including primary human endothelial, renal, cardiac, and neuronal cells but 10- to 100-fold lower than Epo-responsive cells using quantitative reverse-transcribed polymerase chain reaction. Total endothelial EpoR protein examined using a new monoclonal antibody was low to undetectable. Surface EpoR on endothelial cells was not detected using [(125)I]-rHuEpo surface-binding studies. There was no evidence of ESA-induced intracellular signaling in endothelial cells. There was a similar lack of EpoR expression and signaling in other cell types examined. Experiments were performed examining ESA function on these cells. An in vivo rat corneal angiogenesis assay demonstrated neo-vessel formation in response to recombinant human vascular endothelial growth factor (rHuVEGF). However, recombinant mouse Epo did not induce vessel formation. Similarly, ESAs did not reproducibly provide cytoprotection to neuronal, renal, or cardiac cells. Taken together, our data challenge the notion of presence or function of EpoR on nonhematopoietic cells, and call into question the preclinical basis for clinical studies exploring direct, "pleiotropic" actions of ESAs.


Assuntos
Células Endoteliais/metabolismo , Túbulos Renais Proximais/metabolismo , Miócitos Cardíacos/metabolismo , Neurônios/metabolismo , Receptores da Eritropoetina/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Células Cultivadas , Primers do DNA/genética , Células Endoteliais/efeitos dos fármacos , Eritropoetina/metabolismo , Eritropoetina/farmacologia , Hematínicos/farmacologia , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Células PC12 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores da Eritropoetina/genética , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Fatores de Crescimento do Endotélio Vascular/farmacologia
16.
Blood ; 115(21): 4254-63, 2010 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-20124514

RESUMO

Certain oncology trials showed worse clinical outcomes in the erythropoiesis-stimulating agent (ESA) arm. A potential explanation was that ESA-activated erythropoietin (Epo) receptors (EpoRs) promoted tumor cell growth. Although there were supportive data from preclinical studies, those findings often used invalidated reagents and methodologies and were in conflict with other studies. Here, we further investigate the expression and function of EpoR in tumor cell lines. EpoR mRNA levels in 209 human cell lines representing 16 tumor types were low compared with ESA-responsive positive controls. EpoR protein production was evaluated in a subset of 66 cell lines using a novel anti-EpoR antibody. EpoR(+) control cells had an estimated 10 000 to 100 000 EpoR dimers/cell. In contrast, 54 of 61 lines had EpoR protein levels lower than 100 dimers/cell. Cell lines with the highest EpoR protein levels (400-3200 dimers/cell) were studied further, and, although one line, NCI-H661, bound detectable levels of [(125)I]-recombinant human Epo (rHuEpo), none showed evidence of ESA-induced EpoR activation. There was no increased phosphorylation of STAT5, AKT, ERK, or S6RP with rHuEpo. In addition, EpoR knockdown with siRNAs did not affect viability in 2 cell lines previously reported to express functional EpoR (A2780 and SK-OV-3). These results conflict with the hypothesis that EpoR is functionally expressed in tumors.


Assuntos
Neoplasias/genética , Neoplasias/metabolismo , Receptores da Eritropoetina/genética , Receptores da Eritropoetina/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular , Primers do DNA/genética , Eritropoetina/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Hematínicos/farmacologia , Humanos , Masculino , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , RNA Interferente Pequeno/genética , Receptores da Eritropoetina/antagonistas & inibidores , Proteínas Recombinantes , Transdução de Sinais
17.
J Immunol Methods ; 352(1-2): 126-39, 2010 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-19887071

RESUMO

Erythropoietin (Epo) binds and activates the Epo receptor (EpoR) on the surface of erythroid progenitor cells resulting in formation of erythrocytes. Recently, EpoR was reported to be expressed on non-erythroid cells suggesting a role for Epo outside of erythropoiesis. However those studies employed antibodies with questionable specificity and the significance of the observations are controversial. In order to accurately determine the expression of EpoR proteins in cells, we have generated a panel of novel anti-human EpoR monoclonal antibodies. One of these antibodies (A82) was particularly sensitive and it detected the EpoR protein on intact cells by flow cytometry and by western blot analysis with cell lysates. Both methods were optimized and using them, EpoR protein was detected by western immunoblotting with lysates from fewer than 200 EpoR positive control cells and the positive signals were proportional to EpoR protein expression level with a minimal signal in EpoR negative cells. The proteins detected by western blot analysis using A82 included full-length EpoR ( approximately 59kDa) as well as smaller EpoR fragments derived from the EPOR gene. These results indicate that A82 can be used to examine low level EpoR expression in cells by western and flow cytometry allowing an improved understanding of EpoR expression and metabolism.


Assuntos
Anticorpos Monoclonais , Células Precursoras Eritroides/metabolismo , Fragmentos de Peptídeos/biossíntese , Receptores da Eritropoetina/biossíntese , Animais , Western Blotting , Extratos Celulares , Separação Celular , Ensaio de Imunoadsorção Enzimática , Células Precursoras Eritroides/citologia , Células Precursoras Eritroides/imunologia , Citometria de Fluxo , Células HeLa , Humanos , Imunização , Camundongos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Coelhos , Receptores da Eritropoetina/genética , Receptores da Eritropoetina/imunologia
18.
J Clin Oncol ; 27(34): 5800-7, 2009 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19786654

RESUMO

PURPOSE: To determine the maximum-tolerated dose (MTD) and to assess the safety, pharmacokinetics, and evidence of antitumor activity of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1 (IGF-1R). PATIENTS AND METHODS: Patients with advanced solid malignancies or non-Hodgkin's lymphoma received escalating doses of AMG 479 intravenously (IV) every 2 weeks (Q2W). Blood samples were assayed to determine pharmacokinetic parameters and IGF-1R occupancy on neutrophils; fluorodeoxyglucose-positron emission tomography scans were used to assess tumor metabolic effects. RESULTS: Fifty-three patients received 312 infusions of AMG 479 Q2W. Overall, the most common grades 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. One dose-limiting toxicity (ie, grade 3 thrombocytopenia) occurred in a patient at 20 mg/kg during course 1; grade 3 thrombocytopenia (n = 8) and grade 3 transaminitis elevations (n = 1) also were reported but not in the escalation phase. The maximum-planned dose of 20 mg/kg was safely administered; thus, an MTD was not reached. High levels of neutrophil IGF-1R binding and increases from baseline in serum IGF-1 levels were observed in the 12- and 20-mg/kg cohorts. Tumor responses included one durable complete response (CR) and one unconfirmed partial response (PR) in two patients with Ewing/primitive neuroectodermal tumors and included one PR and one minor response in two patients with neuroendocrine tumors. The patients with Ewing/PNET who had a CR have remained disease free on therapy after 28 months. CONCLUSION: AMG 479 can be administered safely at 20 mg/kg IV Q2W. The absence of severe toxicities, attainment of serum concentrations associated with high levels of IGF-1R binding on neutrophils, and provocative antitumor activity warrant additional studies of this agent.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias/tratamento farmacológico , Receptor IGF Tipo 1/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Receptor IGF Tipo 1/metabolismo , Adulto Jovem
19.
Biotechniques ; 46(5): 358-60, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19480632

RESUMO

Significant advances in biological knowledge have been made through the application of genomic, proteomic, and metabolomic technologies to the interrogation of static samples in model systems of human disease. The integration of the results of these technologies under the banner of systems biology holds much promise. In this forward-looking essay, we posit that to fully understand human biology, such measurements not only need to be integrated, but conducted in humans in real time through the merging of molecular biology and imaging technologies.


Assuntos
Biologia Computacional/métodos , Biologia Molecular/métodos , Biologia Computacional/tendências , Diagnóstico , Diagnóstico por Imagem , Tratamento Farmacológico , Humanos
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