RESUMO
PURPOSE: Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened. EXPERIMENTAL DESIGN: In preclinical studies, we used a depilatory model to evaluate the ability of topical formulations of CUR61414 to repress Hh responsive cells found at the base of hair follicles in normal skin. We also tested the in vivo effects of topical CUR61414 on murine BCCs developed in Ptch1 (+/-) K14-CreER2 p53 fl/fl mice. In a phase I clinical study, we evaluated the safety, tolerability, and efficacy of a multidose regimen of CUR61414 (0.09%, 0.35%, 1.1%, and 3.1%) applied topically to human superficial or nodular BCCs for up to 28 days. RESULTS: In mice, topical CUR61414 significantly inhibited skin Hh signaling, blocked the induction of hair follicle anagen, and shrank existing BCCs. However, we observed no clinical activity of this formulation in human superficial or nodular BCCs in a phase I clinical study. CONCLUSIONS: Our data highlight some of the challenges of translating preclinical experience into successful human results for a topical anticancer agent.
Assuntos
Carcinoma Basocelular/tratamento farmacológico , Dioxóis/administração & dosagem , Piperazinas/administração & dosagem , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Administração Tópica , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Basocelular/genética , Dioxóis/efeitos adversos , Método Duplo-Cego , Sistemas de Liberação de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Piperazinas/efeitos adversos , Placebos , Neoplasias Cutâneas/genética , Bibliotecas de Moléculas Pequenas/análise , Receptor Smoothened , Resultado do TratamentoRESUMO
SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.
Assuntos
Amidas/química , Anilidas/química , Proteínas Hedgehog/metabolismo , Piridinas/química , Amidas/síntese química , Amidas/farmacologia , Anilidas/síntese química , Anilidas/farmacologia , Animais , Benzimidazóis/química , Carcinoma Basocelular/tratamento farmacológico , Linhagem Celular , Neoplasias Cerebelares/tratamento farmacológico , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Meduloblastoma/tratamento farmacológico , Camundongos , Camundongos Nus , Piridinas/síntese química , Piridinas/farmacologia , Transdução de Sinais , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues. Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours, Hh ligands fail to activate signalling in tumour epithelial cells. In contrast, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment. Specific inhibition of Hh signalling using small molecule inhibitors, a neutralizing anti-Hh antibody or genetic deletion of smoothened (Smo) in the mouse stroma results in growth inhibition in xenograft tumour models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signalling in the tumorigenesis of Hh-expressing cancers and have important implications for the development of Hh pathway antagonists in cancer.
Assuntos
Proteínas Hedgehog/metabolismo , Neoplasias/metabolismo , Comunicação Parácrina/fisiologia , Células Estromais/metabolismo , Animais , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias/genética , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptor SmoothenedRESUMO
BACKGROUND: The aim of this study was to characterize human embryonic stem (ES) cells at the molecular level by performing large-scale complementary DNA (cDNA) analysis using DNA micro-arrays. METHODS: The transcription profile of human ES cells was determined by comparing it to 2, 10 and 30-day old embryoid bodies (EBs) using Affymetrix Genechip human micro-arrays (U133). RESULTS: According to this analysis we demonstrate that two human ES cell lines are more close to each other than to their differentiated derivatives. We also show the spectrum of cytokine receptors that they express, and demonstrate the presence of five genes that are highly specific to human ES cells and to germ cells. Moreover, by profiling different stages in the differentiation of human embryoid bodies, we illustrate the clustering of five sets of temporally expressed genes, which could be related to the sequential stages of embryonic development. Among them are known genes that are involved in early pattern formation. CONCLUSIONS: The present study provides a molecular basis for the identity of human ES cells and demonstrates that during their in vitro differentiation they express embryonic specific genes in a stage specific manner.
