RESUMO
Kaposi sarcoma originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi sarcoma-associated herpesvirus (KSHV) are endemic, Kaposi sarcoma is the most common cancer overall, but model systems for disease study are insufficient. Here, we report the development of a novel mouse model of Kaposi sarcoma, where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, and RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results show that mTOR inhibitors exert a direct anti-Kaposi sarcoma effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for Kaposi sarcoma and other cancers of endothelial origin.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Herpesvirus Humano 8/efeitos dos fármacos , Neovascularização Patológica/prevenção & controle , Sarcoma de Kaposi/prevenção & controle , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Proliferação de Células/efeitos dos fármacos , Hibridização Genômica Comparativa , DNA Viral/genética , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Imunofluorescência , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/crescimento & desenvolvimento , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos SCID , Fosforilação/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Sarcoma de Kaposi/irrigação sanguínea , Sarcoma de Kaposi/patologia , Sirolimo/administração & dosagem , Células Tumorais CultivadasRESUMO
KSHV inflammatory cytokine syndrome (KICS) is a newly described condition characterized by systemic illness as a result of systemic, lytic KSHV infection. We used Illumina sequencing to establish the DNA vironome of blood from such a patient. It identified concurrent high-level viremia of human herpesvirus (HHV) 8 and 6a. The HHV8 plasma viral load was 5,300,000 copies/ml, which is the highest reported to date; this despite less than five skin lesions and no HHV8 associated lymphoma. This is the first report of systemic HHV6a/KSHV co-infection in a patient. It is the first whole genome KSHV sequence to be determined directly from patient plasma rather than cultured or biopsied tumor material. This case supports KICS as a new clinical entity associated with KSHV.
Assuntos
Síndrome da Imunodeficiência Adquirida/virologia , Citocinas/sangue , DNA Viral/genética , Herpesvirus Humano 6/genética , Herpesvirus Humano 8/genética , Sarcoma de Kaposi/virologia , Síndrome de Resposta Inflamatória Sistêmica/virologia , Viremia/virologia , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/patologia , Adulto , Coinfecção , DNA Viral/isolamento & purificação , Herpesvirus Humano 6/isolamento & purificação , Herpesvirus Humano 8/isolamento & purificação , Humanos , Masculino , Filogenia , Sarcoma de Kaposi/etiologia , Sarcoma de Kaposi/metabolismo , Sarcoma de Kaposi/patologia , Análise de Sequência de DNA , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/patologia , Carga Viral/genética , Viremia/patologiaRESUMO
PURPOSE: A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC). EXPERIMENTAL DESIGN: Patients with advanced IRPTC with or without follicular elements and documented disease progression within the preceding 12 months were eligible to receive selumetinib at a dose of 100 mg twice daily. The primary endpoint was objective response rate using Response Evaluation Criteria in Solid Tumors. Secondary endpoints were safety, overall survival, and progression-free survival (PFS). Tumor genotype including mutations in BRAF, NRAS, and HRAS was assessed. RESULTS: Best responses in 32 evaluable patients out of 39 enrolled were 1 partial response (3%), 21 stable disease (54%), and 11 progressive disease (28%). Disease stability maintenance occurred for 16 weeks in 49%, 24 weeks in 36%. Median PFS was 32 weeks. BRAF V600E mutants (12 of 26 evaluated, 46%) had a longer median PFS compared with patients with BRAF wild-type (WT) tumors (33 versus 11 weeks, respectively, HR = 0.6, not significant, P = 0.3). The most common adverse events and grades 3 to 4 toxicities included rash, fatigue, diarrhea, and peripheral edema. Two pulmonary deaths occurred in the study and were judged unlikely to be related to the study drug. CONCLUSIONS: Selumetinib was well tolerated but the study was negative with regard to the primary outcome. Secondary analyses suggest that future studies of selumetinib and other mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) inhibitors in IRPTC should consider BRAF V600E mutation status in the trial design based on differential trends in outcome.
Assuntos
Adenocarcinoma Folicular/tratamento farmacológico , Benzimidazóis/uso terapêutico , Farmacogenética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzimidazóis/efeitos adversos , Carcinoma , Carcinoma Papilar , Diarreia/induzido quimicamente , Exantema/induzido quimicamente , Fadiga/induzido quimicamente , Feminino , Genótipo , Humanos , Radioisótopos do Iodo/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/radioterapia , Resultado do Tratamento , Proteínas ras/genéticaRESUMO
Over the past decade treatment for metastatic colorectal cancer (mCRC) has advanced beyond single-agent fluoropyrimidine use to include various cytotoxic combination regimens and novel targeted therapies. Despite the targeted therapy era, traditional cytotoxic agents remain the mainstay of therapy. Improvements in survival in mCRC can be attributed mostly to combination therapy, with enhanced efficacy due to optimization of fluoropyrimidine dosing and the addition of irinotecan and/or oxaliplatin. Despite the enormous progress, few patients with metastatic disease are cured. To realize that ambitious goal we need a better understanding of predictive molecular markers of response, mechanisms of drug toxicity, innate and acquired drug resistance as well as how to optimize cytotoxic agents in combination with newer targeted therapies.