Effect of chemotherapy alone or combined with immunotherapy for locally advanced or metastatic genitourinary small cell carcinoma: a real-world retrospective study.

BACKGROUND: Genitourinary small cell carcinoma is rare, and has a poor prognosis. However, effective treatment options for this disease are limited. We present a study to assess the efficacy of chemotherapy alone or combined with immunotherapy for locally advanced or metastatic genitourinary small cell carcinoma (GSCC). METHODS: We performed a retrospective analysis of patients with locally advanced or metastatic GSCC from Jan 2013 to September 2022 at Sun Yat-sen University Cancer Center. The survival and safety profiles were analyzed. RESULTS: Forty-two GSCC patients were enrolled, which included 20 with chemotherapy plus immunotherapy and 22 with chemotherapy alone. The median follow-up time was 15.13 months (95% CI, 8.84-21.42). The addition of immunotherapy to chemotherapy demonstrated no significant difference in median progression-free survival (p = 0.37). However, the median overall survival (OS) was 22.97 and 14.03 months with immunotherapy plus chemotherapy and chemotherapy alone, respectively (HR = 0.69, 95%CI 0.08-0.55, p = 0.017). Two patients with immunotherapy plus chemotherapy achieved clinical complete remission. The overall response rate for patients receiving chemotherapy combined with immunotherapy was 65%, which was higher in comparison to those treated with chemotherapy alone (50%). Univariate and multivariate analyses demonstrated that chemotherapy combined with immunotherapy independently achieved favorable OS. Four patients experienced immunotherapy-related adverse events, with one developing grade 3 hypothyroidism. CONCLUSIONS: Among patients with locally advanced or metastatic GSCC, immunotherapy combined with chemotherapy might be thought of as a potentially effective treatment option for patients with GSCC.

Ulinastatin inhibits the metastasis of nasopharyngeal carcinoma by involving uPA/uPAR signaling.

Distant metastasis is the primary reason for treatment failure in patients with nasopharyngeal carcinoma (NPC). In this study, we investigated the effect of ulinastatin (UTI) on NPC metastasis and its underlying mechanism. Highly-metastatic NPC cell lines S18 and 58F were treated with UTI and the effect on cell proliferation, migration, and invasion were determined by MTS and Transwell assays. S18 cells with luciferase-expressing (S18-1C3) were injected into the left hind footpad of nude mice to establish a model of spontaneous metastasis from the footpad to popliteal lymph node (LN). The luciferase messenger RNA (mRNA) was measured by quantitative polymerase chain reaction (qPCR), and the metastasis inhibition rate was calculated. Key molecular members of the UTI-related uPA, uPAR, and JAT/STAT3 signaling pathways were detected by qPCR and immunoblotting. UTI suppressed the migration and infiltration of S18 and 5-8F cells and suppressed the metastasis of S18 cells in vivo without affecting cell proliferation. uPAR expression decreased from 24 to 48 h after UTI treatment. The antimetastatic effect of UTI is partly due to the suppression of uPA and uPAR. UTI partially suppresses NPC metastasis by downregulating the expression of uPA and uPAR.

Potential inhibitors for blocking the interaction of the coronavirus SARS-CoV-2 spike protein and its host cell receptor ACE2.

BACKGROUND: The outbreak of SARS-CoV-2 continues to pose a serious threat to human health and social. The ongoing pandemic of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made a serious threat to public health and economic stability worldwide. Given the urgency of the situation, researchers are attempting to repurpose existing drugs for treating COVID-19. METHODS: We first established an anti-coronavirus drug screening platform based on the Homogeneous Time Resolved Fluorescence (HTRF) technology and the interaction between the coronavirus spike protein and its host receptor ACE2. Two compound libraries of 2,864 molecules were screened with this platform. Selected candidate compounds were validated by SARS-CoV-2_S pseudotyped lentivirus and ACE2-overexpressing cell system. Molecular docking was used to analyze the interaction between S protein and compounds. RESULTS: We identified three potential anti-coronavirus compounds: tannic acid (TA), TS-1276 (anthraquinone), and TS-984 (9-Methoxycanthin-6-one). Our in vitro validation experiments indicated that TS-984 strongly inhibits the interaction of the coronavirus S protein and the human cell ACE2 receptor. Additionally, tannic acid showed moderate inhibitory effect on the interaction of S protein and ACE2. CONCLUSION: This platform is a rapid, sensitive, specific, and high throughput system, and available for screening large compound libraries. TS-984 is a potent blocker of the interaction between the S-protein and ACE2, which might have the potential to be developed into an effective anti-coronavirus drug.

Patient-Derived Organoids Can Guide Personalized-Therapies for Patients with Advanced Breast Cancer.

Most breast cancers at an advanced stage exhibit an aggressive nature, and there is a lack of effective anticancer options. Herein, the development of patient-derived organoids (PDOs) is described as a real-time platform to explore the feasibility of tailored treatment for refractory breast cancers. PDOs are successfully generated from breast cancer tissues, including heavily treated specimens. The microtubule-targeting drug-sensitive response signatures of PDOs predict improved distant relapse-free survival for invasive breast cancers treated with adjuvant chemotherapy. It is further demonstrated that PDO pharmaco-phenotyping reflects the previous treatment responses of the corresponding patients. Finally, as clinical case studies, all patients who receive at least one drug predicate to be sensitive by PDOs achieve good responses. Altogether, the PDO model is developed as an effective platform for evaluating patient-specific drug sensitivity in vitro, which can guide personal treatment decisions for breast cancer patients at terminal stage.

LACTB promotes metastasis of nasopharyngeal carcinoma via activation of ERBB3/EGFR-ERK signaling resulting in unfavorable patient survival.

Nasopharyngeal carcinoma (NPC) originates in the nasopharyngeal epithelium and has the highest metastatic rate among head and neck cancers. Distant metastasis is the main reason for treatment failure with the underlying mechanisms remaining unclear. By comparing the expression profiling of NPCs versus non-cancerous nasopharyngeal tissues, we found LACTB was highly expressed in the tumor tissues. We found that elevated expression of the LACTB protein in primary NPCs correlated with poorer patient survival. LACTB is known to be a serine protease and a ubiquitous mitochondrial protein localized in the intermembrane space. Its role in tumor biology remains controversial. We found that the different methylation pattern of LACTB promoter led to its differential expression in NPC cells. Overexpressing LACTB in NPC cells promoted their motility in vitro and metastasis in vivo. While knocking down LACTB reduced the metastasis capability of NPC cells. However, LACTB did not influence cellular proliferation. We further found the role of LACTB in promoting NPC metastasis depended on the activation of ERBB3/EGFR-ERK signaling, which in turn, affected the stability and the following acetylation of histone H3. These findings may shed light on unveiling the mechanisms of NPC metastasis.

S100A14 suppresses metastasis of nasopharyngeal carcinoma by inhibition of NF-kB signaling through degradation of IRAK1.

Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with highly aggressive and metastatic potential in which distant metastasis is the main reason for treatment failure. Till present, the underlying molecular mechanisms of NPC metastasis remains poorly understood. Here, we identified S100 calcium-binding protein A14 (S100A14) as a functional regulator suppressing NPC metastasis by inhibiting the NF-kB signaling pathway and reversing the epithelial-mesenchymal transition (EMT). S100A14 was found to be downregulated in highly metastatic NPC cells and tissues. Immunohistochemical staining of 202 NPC samples revealed that lower S100A14 expression was significantly correlated with shorter patient overall survival (OS) and distant metastasis-free survival (DMFS). S100A14 was also found as an independent prognostic factor for favorable survival. Gain- and loss-of-function studies confirmed that S100A14 suppressed the in vitro and in vivo motility of NPC cells. Mechanistically, S100A14 promoted the ubiquitin-proteasome-mediated degradation of interleukin-1 receptor-associated kinase 1 (IRAK1) to suppress NPC cellular migration. Moreover, S100A14 and IRAK1 established a feedback loop that could be disrupted by the IRAK1 inhibitor T2457. Overall, our findings showed that the S100A14-IRAK1 feedback loop could be a promising therapeutic target for NPC metastasis.

Antioxidants suppress radiation-induced apoptosis via inhibiting MAPK pathway in nasopharyngeal carcinoma cells.

Nasopharyngeal carcinoma (NPC) is relatively sensitive to ionizing radiation, and radiotherapy is the main treatment modality for non-metastatic NPC. Radiation therapy generates overproduction of reactive oxygen species (ROS), which can cause DNA damage and induce apoptosis in tumors, thereby killing the malignant cells. Although dietary antioxidant supplementation reduces oxidative stress and promotes tumor progression, the effects of antioxidants on the NPC cells upon radiation have not been reported. In the present study, we showed that antioxidants (ß-Carotene, NAC, GSH) played an anti-apoptotic role in response to radiation via decreasing ROS production and inhibiting MAPK pathway in NPC cells. Based on that, we conclude that the use of supplemental antioxidants during radiotherapy should be avoided because of the possibility of tumor protection and reduced treatment efficacy.