Chuanxi Lai's research while affiliated with Sir Run Run Shaw Hospital and other places

Background Exportin‐1 (XPO1), a crucial protein regulating nuclear‐cytoplasmic transport, is frequently overexpressed in various cancers, driving tumor progression and drug resistance. This makes XPO1 an attractive therapeutic target. Over the past few decades, the number of available nuclear export‐selective inhibitors has been increasing. Only KPT‐330 (selinexor) has been successfully used for treating haematological malignancies, and KPT‐8602 (eltanexor) has been used for treating haematologic tumours in clinical trials. However, the use of nuclear export‐selective inhibitors for the inhibition of XPO1 expression has yet to be thoroughly investigated in clinical studies and therapeutic outcomes for solid tumours. Methods We collected numerous literatures to explain the efficacy of XPO1 Inhibitors in preclinical and clinical studies of a wide range of solid tumours. Results In this review, we focus on the nuclear export function of XPO1 and results from clinical trials of its inhibitors in solid malignant tumours. We summarized the mechanism of action and therapeutic potential of XPO1 inhibitors, as well as adverse effects and response biomarkers. Conclusion XPO1 inhibition has emerged as a promising therapeutic strategy in the fight against cancer, offering a novel approach to targeting tumorigenic processes and overcoming drug resistance. SINE compounds have demonstrated efficacy in a wide range of solid tumours, and ongoing research is focused on optimizing their use, identifying response biomarkers, and developing effective combination therapies. Key Points Exportin‐1 (XPO1) plays a critical role in mediating nucleocytoplasmic transport and cell cycle. XPO1 dysfunction promotes tumourigenesis and drug resistance within solid tumours. The therapeutic potential and ongoing researches on XPO1 inhibitors in the treatment of solid tumours. Additional researches are essential to address safety concerns and identify biomarkers for predicting patient response to XPO1 inhibitors.

134 Background: Chemoradiation is the standard neoadjuvant treatment for locally advanced rectal cancer. Microsatellite stable (MSS)/ mismatch repair proficient (pMMR) rectal cancer rarely responds to immune checkpoint inhibitor monotherapy, but combination with chemoradiation may improve sensitivity of MSS/pMMR tumors by inducing immune-stimulatory effects. Therefore, we aimed to investigate the efficacy and safety of patients treated with neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX for MSS/pMMR locally advanced rectal cancer. Methods: This is an open-label, single-center, phase ¢ò study. Patients (pts) with locally advanced rectal adenocarcinoma with MSS/pMMR were eligible. MMR protein expression was tested by immunohistochemistry (IHC) £¬and MSI status was confirmed by NGS (next generation sequencing). All pts included in this study underwent neoadjuvant short-course radiation (total dose of 5¡Á5Gy) in the first week after enrollment, then followed by 6 cycles of envafolimab (anti-PD-L1 inhibitor,150mg, d1, subcutaneous injection, QW) plus 2 cycles of CAPEOX in the next six weeks, and subsequently underwent total mesorectal excision (TME) in the ninth week. The primary endpoint is pathological complete response rate. Secondary endpoints include tumor regression grade (TRG), 3 year disease free survival, overall survival, toxicity, and quality of life (QoL). Results: This study intends to recruit 32 pts, and a total of 21 pts were enrolled from January 2022 to September 2022. Overall median age was 67 (42-79) years. 12 pts completed study designed treatment protocol (envafolimab plus CAPOX) followed with TME procedures, and 9 pts are still undergoing neoadjuvant treatment. All 12 pts achieved major partial response (MPR) evaluated by diffusion-weighted magnetic resonance imaging (DW-MRI), and 8 pts (8/12,76.6%) achieved pCR. During neoadjuvant treatment period, 20 pts (20/21, 95.2%) presented with treatment-related AEs (TRAEs) of any grade, 18 pts (18/21, 85.7%) had grade 1-2 and one each pts had grade 3 and 4 thrombocytopenia (2/21, 9.5%). The most common TRAEs were sensation of rectal tenesmus. Conclusions: Neoadjuvant preoperative short-course radiation followed by envafolimab plus CAPEOX in MSS/pMMR locally advanced rectal cancer achieved a promising pathologic response. Meanwhile, this combination neoadjuvant therapy is safe and worthy of application to clinical practice. (Funded by Sir Run Run Shaw Hospital Zhejiang University School of Medicine.) Clinical trial information: NCT05216653 .