Safety, tolerability, and pharmacokinetics of an anti-LAG-3 antibody SHR-1802 in patients with advanced solid tumors: a phase I dose-escalation and dose-expansion study.

Background: Lymphocyte-activation gene 3 (LAG-3), a checkpoint molecule contributing to immune suppressive microenvironment, is regarded as a promising target in cancer treatment. SHR-1802 is a novel anti-LAG-3 monoclonal antibody. Objectives: To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of SHR-1802. Design: A phase I dose-escalation and expansion trial of SHR-1802 in patients with advanced solid tumors. Methods: Patients with confirmed advanced solid tumors who failed previous standard-of-care or for whom no effective therapy was available were enrolled to receive SHR-1802 once every 21-day cycle. Dose escalation was performed in an accelerated titration design followed by a 3 + 3 scheme at escalating doses from 0.3 to 10 mg/kg. On the basis of results from dose-escalation phase, one or two dose levels were expanded to establish the recommended phase II dose (RP2D). The primary end points were dose-limiting toxicity (DLT) and RP2D. Results: Between 01 July 2020, and 07 September 2021, 28 patients were enrolled. No DLTs were observed, and all doses investigated were well tolerated. Treatment-related adverse events occurred in 20 patients (71.4%), all grade 1 or 2, with the most common ones being anemia (14.3%), asthenia (14.3%), electrocardiogram QT prolonged (14.3%), followed by increased blood fibrinogen (10.7%), infusion-related reaction (10.7%), and hypoalbuminemia (10.7%). No adverse event-related discontinuation occurred. Three patients died from adverse events, but none of the deaths were deemed related to study treatment. SHR-1802 exposure enhanced with the increasing doses in a greater than dose-proportional manner over the investigated dose range. The disease control rate was 32.0% (95% CI 14.9%-53.5%). The median progression-free survival was 2.0 months (95% CI 1.2-6.1). Conclusions: SHR-1802 demonstrated a tolerable safety profile and preliminary antitumor activity in patients with advanced solid tumors. Further studies with larger sample size and in combination forms are warranted for future clinical application. Registration ClinicalTrialsgov: NCT04414150.

Aberrant expression of WWOX and its association with cancer stem cell biomarker expression.

BACKGROUND: Nanog and CD133 are biomarkers of cancer stem cells (CSCs) that regulate cancer progression. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor protein that can inhibit tumor cell proliferation. The purpose of this study was to investigate the expression and clinical significance of Nanog, CD133, and WWOX in infiltrating breast cancer (IBC). METHODS: Expressions of Nanog, CD133, and WWOX in 204 IBC specimens and their corresponding control specimens were detected by immunohistochemistry. Patients' clinicopathologic and follow-up data were also collected. RESULTS: The rates of positive expression of Nanog and CD133 were significantly higher in IBC specimens than in control specimens, and their expression was positively associated with tumor size, grade, and tumor stages, lymph node metastasis (LNM), and tumor-node-metastasis (TNM) stage. The rate of positive expression of WWOX was significantly lower in IBC specimens than in control specimens, and its expression was inversely associated with tumor size, grade, and tumor stages, LNM, and TNM stage. Patients whose specimens expressed Nanog, CD133, or HER2 had a reduced overall survival (OS) when compared with patients not expressing these proteins. However, patients whose specimens expressed WWOX, ER, or PR had an increased OS when compared with patients who did not show expression. Multivariate analysis demonstrated that expression of Nanog, CD133, WWOX, ER, and HER2, and the TNM stage were independent prognostic factors for IBC patients. CONCLUSIONS: Therefore, Nanog, CD133, and WWOX should be considered as promising prognostic factors and therapeutic targets in IBC.

[Tumor metastasis in patients with non-small cell lung cancer is inversely correlated with the number of tumor-infiltrating CD8+ T cells].

Objective To analyze the relationship between the number of invasive T cells in in situ tumors and the clinical metastasis and prognosis in patients with non-small cell lung cancer (NSCLC). Methods A total of 140 lung cancer patients (including 43 cases with metastasis) were selected to observe the infiltration state of CD4+ T cells and CD8+ T cells in tumor tissues by immunohistochemical staining. The infiltration of CD4+ T cells and CD8+ T cells were compared between non-metastatic and metastatic patients. The effects of different infiltration levels of CD4+ T cells and CD8+ T cells on clinical prognosis were analyzed. Results The proportion of CD4+ T cells in the tumor tissues of the two groups was not significantly different. The number of CD8+ T cells in the metastatic group was significantly lower than that in the metastatic group, and the ratio of CD8/CD4 in the non-metastasis group was remarkably higher than that in the metastatic group. Patients with high CD8+ T cell infiltration level or high ratio of CD8/CD4 have a significantly better overall survival rate than the patients with low CD8+ T cell infiltration level or low ratio of CD8/CD4. Conclusion The number of CD8+ T cell infiltration and CD8/CD4 ratio in the tumor tissues of patients with metastatic NSCLC are significantly reduced, which is closely related to the poor prognosis of patients with NSCLC metastasis.

Correction: Let-7b attenuates cisplatin resistance and tumor growth in gastric cancer by targeting AURKB.

The original version of this Article neglected to indicate that the study was supported by Anhui Natural Science Foundation Project (1608085MH201). This has now been corrected in both the PDF and HTML versions of the Article.

Let-7b attenuates cisplatin resistance and tumor growth in gastric cancer by targeting AURKB.

Platinum-based chemotherapy is currently a standard treatment strategy for patients with gastric cancer. Eventhough it has been widely shown that microRNAs (miRNAs) are involved in tumor development, whether miRNAs have a role in chemosensitivity of gastric cancer cells to platinum-based treatment remain largely undefined. In this study, a cisplatin-resistant gastric cancer cell line (SGC7901/DDP) with stable enhanced expression or knockdown of let-7b was generated. MTT and TUNEL assays were carried out to assess whether miR-let-7 is crucial for cell viability and apoptosis, respectively. In vitro luciferase reporter assay was performed to explore target genes of let-7b. Further, a subcutaneously transplanted tumor model in BALB/c nude mice was used to determine the impacts of let-7b on tumor growth in vivo. We observed that the let-7b-expression level of SGC7901/DDP cells was significantly lower than for its parental SGC7901 cells. Transfection of let-7b mimics was found to increase the cytotoxicity of DDP to SGC7901/DDP cells by inducing apoptosis. However, reversed cytotoxicity of DDP was observed in SGC7901/DDP cells with knockdown of let-7b. Luciferase reporter assay indicated that let-7b targeted AURKB in SGC7901/DDP cells. Knockdown of AURKB imitated the effect of let-7b overexpression on the sensitivity of SGC7901/DDP cells to DDP. Further investigation demonstrated that the SGC7901/DDP primary tumor growth was significantly reduced by let-7b mimic transfection. These findings indicate that overexpression of let-7b might provide a potential strategic approach for attenuating DDP resistance in SGC7901/DDP human gastric cancer cells.

LncRNA CERNA2 is an independent predictor for clinical prognosis and is related to tumor development in gastric cancer.

Gastric cancer (GC) is the second most common cancer-related mortality worldwide. Mounting evidence has demonstrated that dysregulated long noncoding RNAs (lncRNAs) are involved in the development of GC. LncRNA CERNA2 (competing endogenous lncRNA 2 for microRNA let-7b) was previously found to be upregulated and play an oncogenic role in hepatocellular carcinoma, osteosarcoma and breast cancer. However, the clinical significance and biological functions of CERNA2 in GC remain largely unknown. In this study, we found that CERNA2 expression was significantly increased in GC tissues and cell lines compared to adjacent non-cancerous tissues and normal gastric epithelial cells, respectively. High levels of CERNA2 were correlated with poor clinical parameters and an unfavorable prognosis of GC patients. Moreover, silencing CERNA2 expression effectively inhibited gastric cancer cell growth and induced cell apoptosis in vitro. Collectively, our results demonstrate that the up-regulation of CERNA2 is associated with malignant status and poor prognosis in patients with GC, and silencing CERNA2 expression inhibits gastric cancer cell growth and promotes cell apoptosis, suggesting CERNA2 could possibly be a promising diagnostic and treatment target for GC.

Aberrant expression of ALDH1, MMP9, Integrin αvß3, and KiSS-1 in invasive ductal carcinoma and their clinical significance.

BACKGROUND: Aldehyde dehydrogenase 1 (ALDH1, a biomarker of cancer stem cells), matrix metalloproteinase 9 (MMP9, known as a matrilysin), Integrin αvß3 (known as a biomarker of cell-matrix adhesion) and KiSS-1 (suppressor gene of tumor metastasis) are all related to cancer invasion and metastasis in many cancers. The purpose of this study was to investigate the expression of ALDH1, MMP9, Integrin αvß3, and KiSS-1 in invasive ductal carcinoma (IDC), and their respective associations with clinical characteristics and survival in IDC. METHODS: Immunohistochemical staining was used to detect the expression of ALDH1, MMP9, Integrin αvß3, and KiSS-1 in 227 whole IDC tissue specimens. Patients' clinical and demographic data were both collected. RESULTS: The expression of ALDH1, MMP9, and Integrin αvß3 were significantly higher in IDC tissues than in the control tissues. The positive expressions of ALDH1, MMP9, and Integrin αvß3 were positively associated with tumor grades, lymph node metastasis (LNM), tumor stages, and tumor node metastasis (TNM) stages, and inversely with overall survival (OS) and recurrence-free survival (RFS). Positive expression of KiSS-1 was negatively associated with tumor grades, LNM, tumor stages, and TNM stages, but positively with OS and RFS. A multivariate analysis demonstrated that the positive expression of ALDH1, MMP9, Integrin αvß3, KiSS-1, ER, and HER-2, as well as TNM stages were independent prognostic factors for OS and RFS in IDC. CONCLUSIONS: The expression of ALDH1, MMP9, Integrin αvß3, and KiSS-11 should represent promising biomarkers in predicting metastasis and prognosis, as well as being potential therapeutic targets for IDC.

Metformin induces apoptosis via a mitochondria-mediated pathway in human breast cancer cells in vitro.

Breast cancer is the most commonly occurring cancer and second leading cause of mortality in women. Metformin is a widely prescribed anti-hyperglycemic drug, which is emerging as a potential cancer preventative and treatment agent. However, the mechanisms underlying the suppressive effects of metformin on cancer cell growth and the induction of cancer cell apoptosis are not fully elucidated. The present study aimed to identify the pathways regulated by metformin in two breast cancer cell lines, MDA-MB-231 and MDA-MB-435. Cells were treated with various concentrations of metformin and then evaluated with respect to viability, proliferation, adenosine triphosphate (ATP) and reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆ψm), and the expression of anti- and pro-apoptotic proteins. Metformin caused apoptosis in a concentration- and time-dependent manner, and decreased cell viability and ATP production. Furthermore, metformin induced the generation of ROS and decreased the ∆ψm. Moreover, metformin downregulated the expression of the anti-apoptotic proteins B-cell lymphoma 2 (BCL-2) and myeloid cell leukemia-1, and upregulated the expression of the pro-apoptotic BCL-2-associated X protein in MDA-MB-231 cells. These results demonstrate that the apoptotic and cytotoxic effects of metformin on breast cancer cells are mediated by the intrinsic mitochondria-mediated apoptosis pathway.

Baicalein inhibits hepatocellular carcinoma cells through suppressing the expression of CD24.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death and is the most common type of liver cancer. Current therapies for hepatocellular carcinoma are still rather limited and novel therapeutic strategies are required. Baicalein, extracted from Scutellaria baicalensis, has anticancer effects on HCC in vitro and vivo. However, the detailed mechanisms are not well studied yet. In the present study, we evaluated anticancer effects of purified botanical extracts on HCC cells using high-throughput screening and investigated the effects of baicalein on HCC cells using proliferation and apoptosis assays, RT-PCR, and Western blot. Transfection was used to explore the underlying mechanisms of these effects. Our results showed that baicalein is the most efficient botanical extract in a HCC cell line as compared with the other 13 extracts. Baicalein significantly decreased the expression of c-Myc, a crucial regulator of cell proliferation, apoptosis and cellular transformation, in dose- and time-dependent manners in HCC cells. Moreover, baicalein inhibited HCC cell proliferation and induced apoptosis. The mRNA and protein expressions of CD24 were downregulated by baicalein in HCC cells and ectopic overexpression of CD24 reversed baicalein-induced inhibition of cell proliferation and survival. Taken together, our results demonstrate efficient anticancer effects of baicalein on HCC cells and indicate that baicalein suppresses cell growth and cell survival through downregulation of CD24.

SRPX2 promotes cell migration and invasion via FAK dependent pathway in pancreatic cancer.

Sushi repeat-containing protein, X-linked 2, abbreviated as SRPX2, is a candidate downstream target protein for E2A-HLF and involved in disorders of language cortex and cognition. Recent studies have demonstrated that elevated SRPX2 exhibits crucial roles in gastric cancer, however, underlying clinical significance and biological function of SRPX2 in pancreatic ductal adenocarcinoma (PDAC), remains unclear. Data from Oncomine database showed that higher SRPX2 expression is more commonly observed in PDAC compared with normal pancreatic duct, similar results were also found in 12 matched PDAC tissue samples, 7 PDAC cell lines and a tissue microarray containing 81 PDAC specimens as demonstrated by real-time quantitative PCR and immunohistochemistry, respectively. Besides, higher SRPX2 expression was closely correlated with advanced TNM stage. Silencing of endogenous SRPX2 expression reduced abilities of cell migration and invasion of PDAC cells. Further studies revealed that SRPX2 expression in PDAC tissues significantly correlated with the phosphorylation levels of FAK, indicating that FAK dependent pathway may be account for the effect of SRPX2 on cell migration and invasion in PDAC. Collectively, this study reveals that frequently elevated SRPX2 contributes to cell migration and invasion in PDAC and SRPX2-related pathways might be a potential therapeutic target for PDAC.

Clinicopathological significance of CD133 and CD44 expression in infiltrating ductal carcinoma and their relationship to angiogenesis.

BACKGROUND: Breast cancer is the leading cause of cancer death in females worldwide, and the majority type is infiltrating ductal carcinoma (IDC). Most of IDC patients died of metastasis and recurrence. Cancer stem cells (CSCs) are defined with the ability to be self-renewal and potentially promote proliferation and formation of tumors. CSCs are related to angiogenesis and are important targets in new cancer treatment strategies. In this study, we purposed to investigate on expression and clinical significances of CSCs marked by CD133 and CD44 in IDC and their relationship to angiogenesis. METHODS: The specimens of IDC from 325 Chinese patients with follow-up were analyzed for CD133, CD44, CD82, and CD34 protein expression by immunohistochemical staining. The Pearson chi-square test and t test were used to assess the associations among the positive staining of these markers and clinicopathological characteristics. Postoperative overall survival time in these patients with IDC was analyzed by univariate and multivariate analyses. RESULTS: In IDC tissues, positive rates of 48.6%, 53.8%, and 42.2% were obtained for CD133, CD44, and CD82 protein, respectively; the mean score of microvessel density (MVD) was 20.5 ± 7.0 in IDC group. And there was a significant difference between the two groups. There was a positive relationship between the expression of CD133, CD44, and the score of MVD and the grades of tumor, lymph node metastasis, tumor-node-metastasis (TNM) stages (all P < 0.05); and the expression of CD82 was negatively related to grades of tumor, lymph node metastasis, and TNM stages (all P < 0.05). The overall mean survival time of the patients with CD133, CD44, and the score of MVD (≥21) positive expression was lower than that of patients with negative expression. The overall mean survival time of patients of CD82-positive expression was longer than that of patients of the negative expression group. The positive expression of CD133 and CD82, and TNM stages were independent prognostic factors of IDC (P < 0.05). CONCLUSIONS: CSCs, angiogenesis, and aberrant expression of CD82 may be involved in the initiation, development, metastasis, and recurrence. It is suggested that CSCs, angiogenesis, and CD82 be possible as a therapeutic marker for anti-tumor therapy.