Alessia Ciarrocchi

An Innovative Drug Repurposing Approach to Restrain Endometrial Cancer Metastatization

Background: Endometrial cancer (EC) is the most common gynecologic tumor and the world’s fourth most common cancer in women. Most patients respond to first-line treatments and have a low risk of recurrence, but refractory patients, and those with metastatic cancer at diagnosis, remain with no treatment options. Drug repurposing aims to discover new clinical indications for existing drugs with known safety profiles. It provides ready-to-use new therapeutic options for highly aggressive tumors for which standard protocols are ineffective, such as high-risk EC. Methods: Here, we aimed at defining new therapeutic opportunities for high-risk EC using an innovative and integrated computational drug repurposing approach. Results: We compared gene-expression profiles, from publicly available databases, of metastatic and non-metastatic EC patients being metastatization the most severe feature of EC aggressiveness. A comprehensive analysis of transcriptomic data through a two-arm approach was applied to obtain a robust prediction of drug candidates. Conclusions: Some of the identified therapeutic agents are already successfully used in clinical practice to treat other types of tumors. This highlights the potential to repurpose them for EC and, therefore, the reliability of the proposed approach.

Endometrial carcinoma and immune escape: prognostic relevance of HLA class I loss in NSMP subtype

Aims This study aims to define and characterize human leukocyte antigen class I (HLA‐I) expression in a consecutive series of molecularly classified endometrial carcinomas (ECs), and to evaluate its association with clinicopathologic features, spatial cancer–immune phenotypes and patient prognosis, with a focus on the NSMP (no specific molecular profile) subtype. Methods and results HLA‐I expression was assessed by immunohistochemistry on whole tissue sections from 208 ECs, classified into POLE ‐mutated, MMR‐deficient (MMRd), p53‐abnormal (p53abn) and NSMP subtypes. Loss of HLA‐I was identified in 31% of cases and was associated with adverse features including high‐grade, aggressive histotypes, deep myometrial invasion, substantial lymphovascular space invasion (LVSI), extensive tumour necrosis and an ‘excluded’ immune phenotype. While HLA‐I loss showed no significant prognostic impact in POLE , MMRd or p53abn tumours, it significantly correlated with worse disease‐free survival in NSMP tumours ( P  < 0.001). Multivariate analysis confirmed HLA‐I loss as an independent prognostic factor in early‐stage NSMP ECs, in addition to substantial LVSI, presence of lymph node metastases and spatial cancer–immune phenotypes. Integration of HLA‐I status improved the performance of predictive models over time. Conclusions HLA‐I loss defines a biologically aggressive subgroup within NSMP ECs and is associated with adverse clinicopathologic and immune features. Assessment of HLA‐I expression could refine risk stratification in NSMP ECs, a group traditionally lacking robust prognostic markers and may help identify patients who could benefit from intensified clinical surveillance and future immunomodulatory treatment strategies.