RESUMEN
Cancer is currently the second leading cause of death globally and is expected to be responsible for approximately 9.6 million deaths in 2018. With an unprecedented understanding of the molecular pathways that drive the development and progression of human cancers, novel targeted therapies have become an exciting new development for anti-cancer medicine. These targeted therapies, also known as biologic therapies, have become a major modality of medical treatment, by acting to block the growth of cancer cells by specifically targeting molecules required for cell growth and tumorigenesis. Due to their specificity, these new therapies are expected to have better efficacy and limited adverse side effects when compared with other treatment options, including hormonal and cytotoxic therapies. In this review, we explore the clinical development, successes and challenges facing targeted anti-cancer therapies, including both small molecule inhibitors and antibody targeted therapies. Herein, we introduce targeted therapies to epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), anaplastic lymphoma kinase (ALK), BRAF, and the inhibitors of the T-cell mediated immune response, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1)/ PD-1 ligand (PD-1 L).
Asunto(s)
Biomarcadores de Tumor , Inmunoterapia , Terapia Molecular Dirigida , Neoplasias/inmunología , Neoplasias/terapia , Animales , Ensayos Clínicos como Asunto , Terapia Combinada , Desarrollo de Medicamentos , Humanos , Inmunoterapia/métodos , Terapia Molecular Dirigida/métodos , Neoplasias/diagnóstico , Resultado del TratamientoRESUMEN
The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), is a stress response protein that is involved in the inhibition of multiple oncogenic signaling pathways. Initial studies have linked NDRG1 and the endoplasmic reticulum (ER) stress response. Considering this, we extensively examined the mechanism by which NDRG1 regulates the ER stress response in pancreatic and colon cancer cells. We also examined the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which induces NDRG1 expression and causes ER stress. The expression of NDRG1 was demonstrated to regulate the three main arms of the ER stress response by: (1) increasing the expression of three major ER chaperones, binding immunoglobulin protein (BiP), calreticulin, and calnexin; (2) suppressing the protein kinase, RNA-activated (PKR)-like ER kinase (PERK); (3) inhibiting the inositol-requiring kinase 1α (IRE1α) arm; and (4) increasing the cleavage of activating transcription factor 6 (ATF6). An important finding was that NDRG1 enhances the anti-proliferative and anti-migratory activity of Dp44mT. This increased efficacy could be related to the following effects in the presence of Dp44mT and NDRG1, namely: markedly increased activation of the PERK target, eukaryotic translation initiation factor 2α (eIF2α); the maintenance of activating transcription factor 4 (ATF4) expression; high cytosolic Ca+2 that increases the sensitivity of cells to apoptosis via activation of the calmodulin-dependent kinase II (CaMKII) signaling cascade; and increased pro-apoptotic C/EBP-homologous protein (CHOP) expression. Collectively, this investigation dissects the molecular mechanisms through which NDRG1 manipulates the ER stress response and its ability to potentiate the activity of the potent anti-cancer agent, Dp44mT.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Estrés del Retículo Endoplásmico , Retículo Endoplásmico/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Factor de Transcripción Activador 6/antagonistas & inhibidores , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/metabolismo , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Calnexina/genética , Calnexina/metabolismo , Calreticulina/genética , Calreticulina/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/genética , Línea Celular , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Endorribonucleasas/antagonistas & inhibidores , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/genética , Quelantes del Hierro/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , eIF-2 Quinasa/antagonistas & inhibidores , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismoRESUMEN
In this study we evaluated the antitumor efficacy of taxol in four solid tumor models derived from wap-ras line 69 transgenic mice. Taxol inhibited the growth of spontaneous salivary and mammary gland adenocarcinomas in wap-ras mice. In nude mice it was also effective against solid tumors caused by WR21 cells derived from a wap-ras salivary gland tumor. Taxol was not able to prevent tumor emergence in wap-ras/F mice, a subline of the wap-ras strain in which all males develop palpable mammary gland tumors between 1.5 and 3.0 months of age. Our data indicate the range of results that can be expected when this panel of related transgenic tumor models is used to study the antitumor effects of taxol and other therapeutic drugs that act by affecting tubulin polymerization. These models of ras-mediated neoplasia should prove useful for testing anticancer compounds with taxol-like mechanisms of action.