Current Cancer Drug Targets - Volume 24, Issue 7, 2024

Cholangiocarcinoma (CCA) is an epithelial cancer distinguished by bile duct cell differentiation and is also a fibroproliferative tumor. It is characterized by a dense mesenchyme and a complex tumor immune microenvironment (TME). The TME comprises both cellular and non-cellular components. The celluar component includes CCA cells, immune cells and mesenchymal cells represented by the cancer-associated fibroblasts (CAFs), while the non-cellular component is represented by mesenchymal elements such as the extracellular matrix (ECM). Recent studies have demonstrated the important role of the TME in the development, progression, and treatment resistance of CCA. These cell-associated prognostic markers as well as intercellular connections, may serve as potential therapeutic targets and could inspire new treatment approaches for CCA in the future. This paper aims to summarize the current understanding of CCA's immune microenvironment, focusing on immune cells, mesenchymal cells, ECM, intercellular interactions, and metabolism within the microenvironment.

Bladder cancer (BC) is a common malignant tumor of the urinary system. While current approaches involving adjuvant chemotherapy, radiotherapy, and immunotherapy have shown significant progress in BC treatment, challenges, such as recurrence and drug resistance, persist, especially in the case of muscle-invasive bladder cancer (MIBC). It is mainly due to the lack of pre-existing immune response cells in the tumor immune microenvironment. Micro-environmental changes (such as hypoxia and under-nutrition) can cause the aggregation of unfolded and misfolded proteins in the lumen, which induces endoplasmic reticulum (ER) stress. ER stress and its downstream signaling pathways are closely related to immunogenicity and tumor drug resistance. ER stress plays a pivotal role in a spectrum of processes within immune cells and the progression of BC cells, encompassing cell proliferation, autophagy, apoptosis, and resistance to therapies. Recent studies have increasingly recognized the potential of natural compounds to exhibit anti-BC properties through ER stress induction. Still, the efficacy of these natural compounds remains less than that of immune checkpoint inhibitors (ICIs). Currently, the ER stress-mediated immunogenic cell death (ICD) pathway is more encouraging, which can enhance ICI responses by mediating immune stemness. This article provides an overview of the recent developments in understanding how ER stress influences tumor immunity and its implications for BC. Targeting this pathway may soon emerge as a compelling therapeutic strategy for BC.

Background: CEACAM5 and CEACAM6 are glycosylphosphatidylinositol (GPI)- linked members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which are frequently upregulated in epithelial cancers where they contribute to invasion, metastasis, immune evasion, and resistance to anoikis. CT109 is a novel antibody with dual specificity to both CEACAM5 and 6. Objectives: In this study, we aimed to perform the preclinical characterization of CT109 and antibody- drug conjugate (ADCs) derivatives of CT109, focusing on CT109-SN-38. Methods: CT109’s cognate epitope was characterized by scanning mutagenesis. CT109 specificity and internalization kinetics were assessed by immunoblot and flow cytometry, respectively. Cognate antigen expression prevalence in colorectal cancer and normal tissue arrays was determined by immunohistochemistry. CT109 conjugations were generated by the reaction of reduced CT109 cysteines with maleimide-functionalized payload linkers. In vitro cytotoxic activity of CT109 ADCs was characterized on antigen-positive and negative pancreatic ductal adenocarcinoma cell (PDAC) lines using a luminometric viability assay. In vivo efficacy of CT109-SN-38 was assessed on a PDAC tumor xenograft model at 10 and 25 mg/kg concentrations. Results: CT109 was shown to bind a glycoepitope centered on N309. CT109 is internalized in the CEACAM5+/CEACAM6+ double-positive PDAC line, BxPC-3, with a t1/2 of 2.3 hours. CT109 ADCs elicit a dose and antigen-dependent cytotoxic effect, with CT109-SN-38 exhibiting an IC50 value of 21 nM in BxPC-3 cells. In a BxPC-3 tumor xenograft model, CT109-SN-38 reduced tumor growth and induced regression in 3/10 mice at a concentration 25 mg/kg. Conclusion: These data suggest that further preclinical and clinical development of CT109-SN-38 is warranted.

Background: This study investigated the effect of poly(ADP-ribose) polymerase inhibitors (PARPi) as maintenance therapy after first- and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). Methods: This study retrospectively analyzed 172 patients with rHGSOC treated at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital between January 2017 and December 2021. The 1st-PARPi group comprised patients who received a PARPi as maintenance therapy after first-line chemotherapy (n=23), and the 1st-control group comprised those who did not (n = 105). Similarly, the 2nd-PARPi group comprised patients not given a PARPi in their first-line treatment (n = 30), and the 2nd-control group comprised those who were given a PARPi (n = 89). Results: Among the 23 patients in the 1st-PARPi group and the 105 patients in the 1st-control group, nine and 99 were platinum-sensitive, and 14 and six were platinum-resistant, respectively (hazard ratio [HR]: 14.46, P < 0.0001). Among the 30 patients in the 2nd-PARPi group and 89 patients in the 2nd-control group, 10 and 71 were platinum-sensitive, and 20 and 18 were platinumresistant, respectively (HR: 4.37, P < 0.0001). Age, stage, residual tumor, the courses of platinumbased chemotherapy, and breast cancer susceptibility gene mutations were not associated with platinum sensitivity when using a PARPi as maintenance therapy after first- and second-line chemotherapy. Conclusion: Patients with rHGSOC using a PARPi were more likely to be platinum-sensitive and develop platinum resistance independent of PARPi duration. Care should be taken when using a PARPi as maintenance therapy after first- and second-line chemotherapy.

Introduction: The purpose of this research was to settle the role of brucine in pancreatic ductal adenocarcinoma (PDAC) and the mechanisms involved. Methods: The findings of this study suggest that brucine exerts inhibitory effects on cell growth, clonogenicity, and invasive potential of Panc02 and Mia Paca-2 cells. These effects may be linked to an increase in apoptotic-prone cell population. Results: Gene sequencing data suggests that these effects are mediated through the induction of apoptosis. Experimental evidence further supports the notion that brucine reduces mitochondrial membrane potential and upregulates Bax expression while downregulating Bcl-2 expression. These effects are believed to be a result of brucine-mediated suppression of PI3K/Akt activity, which serves as a regulatory factor of mTOR, Bax, and Bcl-2. Suppression of PI3K activity enhances the tumor-suppressing effects of brucine. Conclusion: Overall, these findings suggest that brucine has therapeutic potential as a remedy option for PDAC.

Background: Ovarian cancer (OC) is one of the malignant diseases of the reproductive system in elderly women. Aging-related genes (ARGs) were involved in tumor malignancy and cellular senescence, but the specifics of these mechanisms in OC remain unknown. Methods: ARGs expression and survival data of OC patients were collected from TCGA and CPTAC databases. Subtype classification was used to identify the roles of hub ARGs in OC progression, including function enrichment, immune infiltration, and drug sensitivity. LASSO regression was utilized to confirm the prognosis significance for these hub ARGs. MTT, EdU, Transwell, and wounding healing analysis confirmed the effect of IGFBP5 on the proliferation and migration ability of OC cells. Results: ARGs were ectopically expressed in OC tissues compared to normal ovary tissues. Three molecular subtypes were divided by ARGs for OC patients. There were significant differences in ferroptosis, m6A methylation, prognosis, immune infiltration, angiogenesis, differentiation level, and drug sensitivity among the three groups. LASSO regression indicated that 4 signatures, FOXO4, IGFBP5, OGG1 and TYMS, had important prognosis significance. Moreover, IGFBP5 was significantly correlated with immune infiltration. The hub ARG, IGFBP5, expression was significantly decreased in OC patients compared to normal women. IGFBP5 could also reduce the migration and proliferation ability of OC cells compared to vector and NC groups. Conclusion: IGFBP5 was correlated with OC prognosis and associated with OC migration and proliferation. This gene may serve as potential prognostic biomarkers and therapeutic targets for OC patients.