RESUMEN
Macina et al. (2023) recently reported mixed results on the German translation of the Self and Interpersonal Functioning Scale (SIFS). By focusing on suboptimal indices of structural validity, they recommended choosing other available instruments over the SIFS in future research on personality impairment. Reflecting on Macina et al.'s overall conclusions inspired us to consider broader issues in the field of personality impairment assessment. In this commentary, we discuss some issues regarding test translation and validity raised by Macina et al.'s article. We advise against assuming equivalence between original and translated versions of a test and discuss some caveats regarding comparison between different instruments based on structural validity. We also call into question whether the latter should be the litmus test for judging the quality of a measure. Finally, we discuss how the proliferation of personality impairment measures can benefit the broader field. Notably, this would allow moving toward a "what works for whom" approach that considers the match between psychometric property, desired use of the instrument, and characteristics of the target population.
RESUMEN
Recurrent somatic mutations in the BRG1/BRM-associated factor (BAF) chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial, endometrial, and ovarian clear cell carcinomas, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has been previously identified as targetable vulnerability in the context of ARID1A mutations. In this study, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor, and it elucidates the aspects of its application potential in ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression, in addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 patients with cancer correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, these data suggest that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents, and may be beneficial in various indications with recurrent ARID1A mutations. Significance: The EZH2 inhibitor tulmimetostat achieves comprehensive target inhibition in ARID1A mutant solid tumor models and cancer patients that can be assessed with a pharmacodynamic gene signature in peripheral blood.
