Li Xiao

Background/Objectives: Reducing corticosteroid exposure has become an important objective in the management of chemotherapy-induced nausea and vomiting (CINV), given the dose-related toxicity of dexamethasone (DEX). This prospective phase III randomized (LD-NEPA: low-dose dexamethasone plus netupitant/palonosetron) study evaluated whether a reduced dose of 5 mg DEX could maintain antiemetic efficacy when combined with NEPA in patients receiving highly or moderately emetogenic chemotherapy (HEC/MEC). Methods: Adult patients were randomly assigned (1:1) to receive NEPA with either 5 mg DEX (5D group) or 8 mg DEX (8D group). Among 186 randomized patients, 180 were included in the analysis (89 in the 5D group and 91 in the 8D group). The primary endpoint was the complete response rate (CRR; no emesis and no rescue medication use) during the 0–168 h period. Secondary endpoints included phase-specific CRR, total control rate (TCR), complete control rate (CCR), daily incidence of nausea and vomiting, and safety outcomes. Results: The overall CRR was 78.7% in the 5D group and 70.3% in the 8D group. The between-group difference was 8.4% (95% CI: −1.5% to 19.0%), demonstrating the reduced-dose regimen was non-inferior, with the lower bound exceeding the prespecified −15% margin. Consistent results were observed across secondary endpoints. Treatment-related adverse events were mostly grade 1–2 and occurred with broadly comparable frequencies between the two groups. Conclusions: A single lower dose of 5 mg DEX is noninferior to an 8 mg dose combined with NEPA for preventing 168 h nausea and vomiting of diverse HEC/MEC, offering comparable efficacy while reducing corticosteroid exposure.

Colorectal cancer is a malignant disease with high morbidity and mortality. In recent years, immune checkpoint inhibitors have emerged as a promising therapeutic strategy; however, patients with proficient mismatch repair/microsatellite-stable (pMMR/MSS) colorectal cancer derive limited benefit from immunotherapy. We conducted a single-arm, exploratory clinical study to evaluate the efficacy of camrelizumab combined with apatinib in patients with advanced metastatic colorectal cancer who had received third-line or later treatment. This trial is registered with ClinicalTrials.gov (NCT04067986; registered August 20, 2019). Our results demonstrated that apatinib significantly enhanced the therapeutic efficacy of immunotherapy in patients with pMMR/MSS colorectal cancer. Mechanistically, apatinib improved immunotherapy outcomes by modulating the tumor microenvironment in vivo. Further in vitro experiments revealed that apatinib reduced levels of exosomal PD-L1 in the tumor microenvironment by inhibiting tumor-derived exosome secretion. This inhibitory effect was mediated through the regulation of Exo70. Collectively, our findings indicate that apatinib enhances the efficacy of camrelizumab in pMMR/MSS colorectal cancer and provide a theoretical rationale for the combined use of camrelizumab and apatinib in this patient population.

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPis) like niraparib represents a major therapeutic challenge in ovarian cancer (OC). This study elucidates a novel resistance mechanism driven by the minichromosome maintenance proteins 2 and 5 (MCM2/5). In niraparib-resistant (NirR) OC cells, RNA-seq revealed upregulation of MCM2 and MCM5, which was functionally linked to enhanced proliferation and homologous recombination repair. Co-immunoprecipitation confirmed strengthened MCM2/5 interaction in NirR cells. Genetic knockdown of MCM2/5 resensitized NirR cells to niraparib, while their overexpression conferred resistance in parental cells. Mechanistically, the upregulation of MCM2/5 was transcriptionally regulated by the E2F1 transcription factor, activated via the CDK4/6-RB pathway. Consequently, pharmacological inhibition of CDK4/6 downregulated MCM2/5 expression and, when combined with niraparib, synergistically suppressed NirR tumor growth both in vitro and in vivo. Our findings identify the MCM2/5 complex as a critical mediator of PARPi resistance and establish the therapeutic potential of combining PARPis with CDK4/6 inhibitors to overcome this resistance in ovarian cancer.

Pooled analysis of the SPOTLIGHT and GLOW phase III trials, involving 1072 patients with locally advanced or metastatic gastric/gastroesophageal junction (GC/GEJ) adenocarcinoma positive for claudin18.2 (CLDN18.2) and negative for HER2, showed that zolbetuximab combined with chemotherapy significantly improved progression-free survival (PFS) compared to placebo (HR = 0.72; 95% CI, 0.61–0.84). Subgroup analyses revealed better outcomes in Asian patients, those with gastric cancer, and those with intestinal-type GC. In a cohort of 92 GC patients (immunohistochemical detection based on a CLDN18.2 subtype-specific antibody), CLDN18.2 positivity was associated with lymph node metastasis, advanced cancer stages (III–IV), and shorter overall survival (OS) (HR = 1.728; 95% CI, 1.003–2.977; P = 0.0404). In our study, knockdown of CLDN18.2 inhibited tumor growth in vivo and in vitro. Additionally, CLDN18.2 knockdown down-regulated minichromosome maintenance (MCM) proteins, particularly MCM2 and MCM5, and decreased phosphorylation of ERK, CDK, and MCM2 in GC cells. These findings provide a theoretical basis for the future selection of advantageous populations for CLDN18.2-targeted therapy and combination therapy strategies.

Background: Claudin-18.2 (CLDN18.2) has emerged as a promising therapeutic target for gastric cancer due to its frequent and specific expression in malignant lesions. Dendritic cell (DC)-based vaccines represent a potent strategy for inducing antitumor immunity; however, their efficacy against solid tumors, such as gastric cancer, remains challenging. Methods: We developed a lentiviral vector encoding human CLDN18.2 (Lv-CLDN18.2) to generate antigen-loaded DC vaccines. In vitro, human monocyte-derived DCs were transduced and co-cultured with autologous T cells to induce cytotoxic T lymphocytes (CTLs). CTL function was assessed by flow cytometry, cytokine ELISA, and cytotoxicity assays against CLDN18.2-positive gastric cancer cells. In vivo, the therapeutic efficacy of the DC vaccine was evaluated in a syngeneic mouse model subcutaneously inoculated with MFC-CLDN18.2 cells. Results: We successfully produced high-titer Lv-CLDN18.2 and established stable CLDN18.2-positive gastric cancer cell lines. Lv-CLDN18.2-transduced DCs exhibited a mature phenotype with upregulated co-stimulatory (CD80/CD86) and antigen-presenting molecules (HLA-ABC/DR). These DCs potently stimulated CTLs, leading to a significantly higher proportion of activated CD8⁺CD25⁺ T cells, enhanced secretion of IFN-γ and TNF-α, and potent, specific lysis of CLDN18.2-positive target cells in vitro. In mouse models, vaccination with Lv-CLDN18.2-DCs significantly suppressed tumor growth, which was associated with robust CD8⁺ T cell infiltration, reduced tumor cell proliferation (Ki-67), and decreased CLDN18.2-positive tumor cells in vivo. Conclusions: Our study demonstrates that a CLDN18.2-targeting DC vaccine can effectively induce potent antigen-specific CTL responses and elicit significant antitumor immunity in a preclinical model. These findings provide a strong rationale for the clinical development of CLDN18.2-directed DC-based immunotherapy for gastric cancer.

Background: Dexamethasone (DEX) can cause various side effects, particularly when used over several consecutive days to prevent chemotherapy-induced nausea and vomiting (CINV). Efforts to minimize the dose and frequency of DEX present challenges in managing CINV.Methods: This single-center, retrospective study included 100 patients with solid tumors undergoing moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC). Each patient received a single low-dose DEX (8 mg) and NEPA prior to each chemotherapy cycle. The primary efficacy endpoint was the complete response (CR: no emesis, no rescue medication) within 0–168 h post-chemotherapy initiation in cycle 1. The main secondary endpoints were CR during the acute (0–24 h), delayed (24–120 h), and long-delayed (120–168 h) phases.Results: Between August 2023 and April 2024, a total of 100 patients received 230 chemotherapy cycles, consisting of 67.4% MEC and 32.6% HEC. CR rates rose from 85% in cycle 1–93.1% in cycle 4, with a slight decline during the delayed phase compared to the acute phase. Better outcomes appeared to be associated with fewer risk factors. Treatment was well-tolerated, with only Grade 1 or 2 adverse events reported; constipation and hyperglycemia were the most common. Regression analysis indicated a significant association between diabetes and CR rates (OR 0.09, 95% CI 0.02–0.40, p = 0.002).Conclusion: Single low-dose DEX (8 mg) with NEPA safely prevents CINV in high-risk patients during MEC/HEC cycles, offering an alternative to minimize the dose and frequency of DEX.

Gastric cancer (GC) has a high global incidence and mortality rate

Background: For most colorectal cancer (CRC) patients, expanding the benefits of immunotherapy, particularly through blocking programmed cell death-1 (PD-1) and its ligand (PD-L1), is crucial, especially in cases with limited response to neoadjuvant therapy. This study investigates the role of Myoferlin (MYOF) as a novel target in CRC immunotherapy. Methods: Human CRC cell lines (RKO, HCT116), normal intestinal epithelial cells (HIEC-6), and the murine CRC cell line MC38 were used to study the effects of apatinib and MYOF in CRC cells. RNA sequencing, the CPTAC and TCGA databases, and other molecular and cellular methods were applied to disclose the mechanisms involved. A series of mouse models were established to assess the effects of apatinib and MYOF knockdown on tumor progression, immune cell infiltration, and immune checkpoint protein response. Results: We found that MYOF is overexpressed in CRC and linked to immune cell infiltration and checkpoint expression. Suppression of MYOF expression significantly inhibited CRC cell proliferation and migration, as well as reduced PD-L1 protein levels. Integrative analysis showed that apatinib modulates MYOF expression via VEGFR2, resulting in decreased PD-L1 expression, increased CD8+ T cell infiltration, and reduced pro-tumor M2 macrophages. Animal experiments further revealed that apatinib treatment or MYOF knockdown enhanced the efficacy of immune checkpoint blockade (ICB) in CRC. Conclusions: These findings highlight novel antitumor mechanisms of MYOF and suggest that combining apatinib with ICB therapy may improve CRC treatment outcomes, offering a promising strategy to enhance immune responses.

Pancreatic cancer (PC) is an aggressive and fatal malignant tumor, and exosomes have been reported to be closely related to PC invasion and metastasis. Here we found that Exo70, a key subunit of the exocyst complex, promoted PC metastasis by regulating the secretion of tumor exosomes. Clinical sample studies showed that Exo70 was highly expressed in PC and negatively correlated with patients’ survival. Exo70 promoted PC cell lines’ invasion and migration. Interestingly, knockdown of Exo70, or using an Exo70 inhibitor (ES2) inhibited the secretion of tumor exosomes and increased the accumulation of cellular vesicles. Furthermore, Exo70 was found to accumulate in the exosomes, which then fused with neighboring PC cells and promoted their invasion. Moreover, Exo70 increased the expression of exosomal PD-L1, leading to the immune escape of PC cells. In vivo, knockdown of Exo70 or treatment with ES2 both decreased the tumor metastasis of PC cells in mice. This study provides new insight into the mechanism of invasion and metastasis in PC and identifies Exo70 as a potential prognostic factor and therapeutic target for PC.