RESUMO
Cutaneous T-cell lymphoma is a heterogeneous group of lymphomas characterized by the accumulation of malignant T cells in the skin. The molecular and cellular etiology of this malignancy remains enigmatic, and what role antigenic stimulation plays in the initiation and/or progression of the disease remains to be elucidated. Deep sequencing of the tumor genome showed a highly heterogeneous landscape of genetic perturbations, and transcriptome analysis of transformed T cells further highlighted the heterogeneity of this disease. Nonetheless, using data harvested from high-throughput transcriptional profiling allowed us to develop a reliable signature of this malignancy. Focusing on a key cytokine signaling pathway previously implicated in cutaneous T-cell lymphoma pathogenesis, JAK/STAT signaling, we used conditional gene targeting to develop a fully penetrant small animal model of this disease that recapitulates many key features of mycosis fungoides, a common variant of cutaneous T-cell lymphoma. Using this mouse model, we show that T-cell receptor engagement is critical for malignant transformation of the T lymphocytes and that progression of the disease is dependent on microbiota.
Assuntos
Citocinas/fisiologia , Linfoma Cutâneo de Células T/etiologia , Transdução de Sinais/fisiologia , Neoplasias Cutâneas/etiologia , Animais , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/imunologia , Camundongos , Microbiota , Receptores de Antígenos de Linfócitos T/fisiologia , Fator de Transcrição STAT3/fisiologia , Síndrome de Sézary/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologiaRESUMO
PURPOSE: To conduct a first-in-human phase I study to determine the dose-limiting toxicities (DLT), characterize the pharmacokinetic profile, and document the antitumor activity of IPI-926, a new chemical entity that inhibits the Hedgehog pathway (HhP). EXPERIMENTAL DESIGN: Patients with solid tumors refractory to standard therapy were given IPI-926 once daily (QD) by mouth in 28-day cycles. The starting dose was 20 mg, and an accelerated titration schedule was used until standard 3 + 3 dose-escalation cohorts were implemented. Pharmacokinetics were evaluated on day -7 and day 22 of cycle 1. RESULTS: Ninety-four patients (32F, 62M; ages, 39-87) received doses ranging from 20 to 210 mg QD. Dose levels up to and including 160 mg administered QD were well tolerated. Toxicities consisted of reversible elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin, fatigue, nausea, alopecia, and muscle spasms. IPI-926 was not associated with hematologic toxicity. IPI-926 pharmacokinetics were characterized by a slow absorption (T(max) = 2-8 hours) and a terminal half-life (t(1/2)) between 20 and 40 hours, supporting QD dosing. Of those HhP inhibitor-naïve patients with basal cell carcinoma (BCC) who received more than one dose of IPI-926 and had a follow-up clinical or Response Evaluation Criteria in Solid Tumors (RECIST) assessment, nearly a third (8 of 28 patients) showed a response to IPI-926 at doses ≥130 mg. CONCLUSIONS: IPI-926 was well tolerated up to 160 mg QD within 28-day cycles, which was established as the recommended phase II dose and schedule for this agent. Single-agent activity of IPI-926 was observed in HhP inhibitor-naïve patients with BCC.
Assuntos
Proteínas Hedgehog/metabolismo , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Alcaloides de Veratrum/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/metabolismo , Alopecia/induzido quimicamente , Área Sob a Curva , Aspartato Aminotransferases/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Seguimentos , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/metabolismo , Neoplasias/patologia , Espasmo/induzido quimicamente , Resultado do Tratamento , Alcaloides de Veratrum/efeitos adversos , Alcaloides de Veratrum/farmacocinéticaRESUMO
Identification of safe, effective treatments to mitigate toxicity after extensive radiation exposure has proven challenging. Only a limited number of candidate approaches have emerged, and the U.S. Food and Drug Administration has yet to approve any agent for a mass-casualty radiation disaster. Because patients undergoing hematopoietic stem cell transplantation undergo radiation treatment that produces toxicities similar to radiation-disaster exposure, we studied patients early after such treatment to identify new approaches to this problem. Patients rapidly developed endotoxemia and reduced plasma bactericidal/permeability-increasing protein (BPI), a potent endotoxin-neutralizing protein, in association with neutropenia. We hypothesized that a treatment supplying similar endotoxin-neutralizing activity might replace the BPI deficit and mitigate radiation toxicity and tested this idea in mice. A single 7-Gy radiation dose, which killed 95% of the mice by 30 days, was followed 24 hours later by twice-daily, subcutaneous injections of the recombinant BPI fragment rBPI21 or vehicle alone for 14 or 30 days, with or without an oral fluoroquinolone antibiotic with broad-spectrum antibacterial activity, including that against endotoxin-bearing Gram-negative bacteria. Compared to either fluoroquinolone alone or vehicle plus fluoroquinolone, the combined rBPI21 plus fluoroquinolone treatment improved survival, accelerated hematopoietic recovery, and promoted expansion of stem and progenitor cells. The observed efficacy of rBPI21 plus fluoroquinolone initiated 24 hours after lethal irradiation, combined with their established favorable bioactivity and safety profiles in critically ill humans, suggests the potential clinical use of this radiation mitigation strategy and supports its further evaluation.
Assuntos
Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Proteínas Sanguíneas/uso terapêutico , Medula Óssea/patologia , Fluoroquinolonas/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Técnicas de Ablação , Animais , Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Peptídeos Catiônicos Antimicrobianos/farmacologia , Contagem de Células Sanguíneas , Proteínas Sanguíneas/administração & dosagem , Proteínas Sanguíneas/farmacologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos da radiação , Citocinas/sangue , Endotoxemia/sangue , Endotoxemia/complicações , Endotoxinas/metabolismo , Enrofloxacina , Fluoroquinolonas/administração & dosagem , Hematopoese/efeitos dos fármacos , Hematopoese/efeitos da radiação , Transplante de Células-Tronco Hematopoéticas , Humanos , Mediadores da Inflamação/sangue , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutropenia/sangue , Neutropenia/complicações , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/efeitos da radiação , Lesões por Radiação/sangue , Lesões por Radiação/complicações , Análise de Sobrevida , Irradiação Corporal TotalRESUMO
The critical clinical question in prostate cancer research is: How do we develop means of distinguishing aggressive disease from indolent disease? Using a combination of proteomic and expression array data, we identified a set of 36 genes with concordant dysregulation of protein products that could be evaluated in situ by quantitative immunohistochemistry. Another five prostate cancer biomarkers were included using linear discriminant analysis, we determined that the optimal model used to predict prostate cancer progression consisted of 12 proteins. Using a separate patient population, transcriptional levels of the 12 genes encoding for these proteins predicted prostate-specific antigen failure in 79 men following surgery for clinically localized prostate cancer (P = .0015). This study demonstrates that cross-platform models can lead to predictive models with the possible advantage of being more robust through this selection process.