Endometrioid Endometrial RNA Index Predicts Recurrence in Stage I Patients.

PURPOSE: Risk prediction with genomic and transcriptomic data has the potential to improve patient outcomes by enabling clinicians to identify patients requiring adjuvant treatment approaches, while sparing low-risk patients from unnecessary interventions. Endometrioid endometrial carcinoma (EEC) is the most common cancer in women in developed countries, and rates of endometrial cancer are increasing. EXPERIMENTAL DESIGN: We collected a 105-patient case-control cohort of stage I EEC comprising 45 patients who experienced recurrence less than 6 years after excision, and 60 Fédération Internationale de Gynécologie et d'Obstétrique grade-matched controls without recurrence. We first utilized two RNA-based, previously validated machine learning approaches, namely, EcoTyper and Complexity Index in Sarcoma (CINSARC). We developed Endometrioid Endometrial RNA Index (EERI), which uses RNA expression data from 46 genes to generate a personalized risk score for each patient. EERI was trained on our 105-patient cohort and tested on a publicly available cohort of 263 patients with stage I EEC. RESULTS: EERI was able to predict recurrences with 94% accuracy in the training set and 81% accuracy in the test set. In the test set, patients assigned as EERI high-risk were significantly more likely to experience recurrence (30%) than the EERI low-risk group (1%) with a hazard ratio of 9.9 (95% CI, 4.1-23.8; P < 0.001). CONCLUSIONS: Tumors with high-risk genetic features may require additional treatment or closer monitoring and are not readily identified using traditional clinicopathologic and molecular features. EERI performs with high sensitivity and modest specificity, which may benefit from further optimization and validation in larger independent cohorts.

Characterization of Aminobenzylphenols as Protein Disulfide Isomerase Inhibitors in Glioblastoma Cell Lines.

Disulfide bond formation is a critical post-translational modification of newly synthesized polypeptides in the oxidizing environment of the endoplasmic reticulum and is mediated by protein disulfide isomerase (PDIA1). In this study, we report a series of α-aminobenzylphenol analogues as potent PDI inhibitors. The lead compound, AS15, is a covalent nanomolar inhibitor of PDI, and the combination of AS15 analogues with glutathione synthesis inhibitor buthionine sulfoximine (BSO) leads to synergistic cell growth inhibition. Using nascent RNA sequencing, we show that an AS15 analogue triggers the unfolded protein response in glioblastoma cells. A BODIPY-labeled analogue binds proteins including PDIA1, suggesting that the compounds are cell-permeable and reach the intended target. Taken together, these findings demonstrate an extensive biochemical characterization of a novel series of highly potent reactive small molecules that covalently bind to PDI.