RESUMEN
The molecular landscape of squamous cell carcinoma of the head and the neck (SCCHN) has been characterized and actionable or targetable genomic alterations have been identified. However, targeted therapies have very limited activity in unselected SCCHN, and the current treatment strategy is still based on tumor location and disease stage and not on tumor biology. Trying to select upfront the patients who will benefit from a specific treatment might be a way to improve patients' outcome. With the objective of optimizing the activity of targeted therapies and immunotherapy, we have designed an umbrella biomarker-driven study dedicated to recurrent and/or metastatic SCCHN patients (EORTC-1559-HNCG, NCT03088059). In this article, we review not only the different trial designs for biomarker-driven studies with their respective advantages and opportunities but also the potential pitfalls that led to the design of the EORTC-1559-HNCG protocol. We also discuss the scientific and logistic challenges of biomarker-driven trials.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Antineoplásicos/farmacología , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Biopsia , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Europa (Continente) , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Terapia Molecular Dirigida/métodos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Selección de Paciente , Medicina de Precisión/métodos , Supervivencia sin Progresión , Proyectos de Investigación , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
The effect of solution conditions on the conformation of the peptide corresponding to residues 129-141 of the mouse prion protein has been examined by experimental and theoretical tools including circular dichroism, secondary structure predictions, and Molecular Dynamics simulations. The conformational properties of the peptide observed by CD confirm the prediction results: the peptide is chiefly random coil in water. The conformational sampling performed by Molecular Dynamics simulations in water also corroborates the flexibility of the peptide, in particular for the N-terminal part. We show, however, that the peptide samples hairpin conformations in one of several approximately 1-ns Molecular Dynamics simulations in water. Interestingly, the analysis of the CD spectra obtained in this study suggests the presence of beta-structure which, given the length of the peptide, can only consist in beta-hairpin. The peptide can also be induced to form a modest percentage of helical structure in the presence of organic cosolvents such as trifluoroethanol, or detergents such as sodium dodecyl sulfate and lysophosphatidylcholine. This result is different from that obtained for a homologous hamster fragment, which differs from the mouse sequence by the single substitution of Ile 139 to Met. Interestingly, this substitution is crucial for the barrier in the transmission of the prion disease between hamsters and mice.