RESUMEN
Extrinsic pathway agonists have failed repeatedly in the clinic for three core reasons: Inefficient ligand-induced receptor multimerization, poor pharmacokinetic properties, and tumor intrinsic resistance. Here, we address these factors by (i) using a highly potent death receptor agonist (DRA), (ii) developing an injectable depot for sustained DRA delivery, and (iii) leveraging a CRISPR-Cas9 knockout screen in DRA-resistant colorectal cancer (CRC) cells to identify functional drivers of resistance. Pharmacological blockade of XIAP and BCL-XL by targeted small-molecule drugs strongly enhanced the antitumor activity of DRA in CRC cell lines. Recombinant fusion of the DRA to a thermally responsive elastin-like polypeptide (ELP) creates a gel-like depot upon subcutaneous injection that abolishes tumors in DRA-sensitive Colo205 mouse xenografts. Combination of ELPdepot-DRA with BCL-XL and/or XIAP inhibitors led to tumor growth inhibition and extended survival in DRA-resistant patient-derived xenografts. This strategy provides a precision medicine approach to overcome similar challenges with other protein-based cancer therapies.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Proteína bcl-X/antagonistas & inhibidores , Animales , Antineoplásicos/química , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Resistencia a Antineoplásicos/genética , Células HCT116 , Células HT29 , Humanos , Ratones , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
The Clock Drawing Test is a cognitive screening tool gaining popularity in the perioperative setting. We compared 3 common scoring systems: (1) the Montreal Cognitive Assessment; (2) the Mini-Cog; and (3) the Libon scale. Three novice raters acquired interrater and intrarater reliability for each scoring system and then scored 738 preoperative clock drawings with each scoring system. Final scores correlated with each other but with notable discrepancies, indicating the need to attend to interrater and intrarater reliability when implementing any scoring approach in a clinical setting.
