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Background: As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Methods/design: In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). Results: Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1–13.8%) and 42.1% (16/38, 95% CI 26.3–59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4–99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9–3.7) and 10.3 months (95% CI 7.3–not evaluable [NE]), respectively. Conclusion: BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. Trial registration: Clinicaltrials.gov NCT02929290 (11/10/2016). [ABSTRACT FROM AUTHOR]

Background: Multiple primary malignant tumors (MPMT) refers to the presence of two or more primary cancers of different organs in the same patient. MPMT is a sparse disease in the past, but there has been a gradual increase in the morbidity. Since multiple primary malignant tumors treatment methods differ, it is essential for clinicians to be able to distinguish between separate primary lesions and metastasis.Case Presentation: We present the case of a 57-year-old woman with MPMT presenting with cancer in the left breast and synchronous double primary lung adenocarcinomas. We used IHC and epidermal growth factor receptor(EGFR)mutation to analyze genomic alteration profiles in the patient to validate the difference among the pathological assessments and the clinical differences between double primary lesions of lung and breast. EGFR gene analysis of breast cancer lesion revealed no mutations. The left and right lower lobe lung adenocarcinomas contained EGFR gene mutations: an L858R point mutation in exon 21 in the left lesion and a deletion mutation in exon 19 in the right lesion. The breast cancer and both lung adenocarcinomas were surgically resected. To date, the patient has remained disease-free.Conclusions: Both pathological and molecular assessment adapted in the current study appeared necessary. Mutational analysis of the EGFR gene provided important information not only in the diagnosis and but also in the treatment of MPMT. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs can be used in the prognosis of malignancies; however, their regulatory mechanisms are unknown, especially in pancreatic ductal adenocarcinoma (PDAC).Methods: In 120 PDAC specimens, miRNA levels were assessed by quantitative real time polymerase chain reaction (qRT-PCR). Then, the role of miR-29b-2-5p in cell proliferation was evaluated both in vitro (Trypan blue staining and cell cycle analysis in the two PDAC cell lines SW1990 and Capan-2) and in vivo using a xenograft mouse model. Next, bioinformatics methods, a luciferase reporter assay, Western blot, and immunohistochemistry (IHC) were applied to assess the biological effects of Cbl-b inhibition by miR-29b-2-5p. Moreover, the relationship between Cbl-b and p53 was evaluated by immunoprecipitation (IP), Western blot, and immunofluorescence.Results: From the 120 PDAC patients who underwent surgical resection, ten patients with longest survival and ten with shortest survival were selected. We found that high miR-29b-2-5p expression was associated with good prognosis (p = 0.02). The validation cohort confirmed miR-29b-2-5p as an independent prognostic factor in PDAC (n = 100, 95% CI = 0.305-0.756, p = 0.002). Furthermore, miR-29b-2-5p inhibited cell proliferation, induced cell cycle arrest, and promoted apoptosis both in vivo and in vitro. Interestingly, miR-29b-2-5p directly bound the Cbl-b gene, down-regulating its expression and reducing Cbl-b-mediated degradation of p53. Meanwhile, miR-29b-2-5p expression was negatively correlated with Cbl-b in PDAC tissues (r = - 0.33, p = 0.001).Conclusions: Taken together, these findings indicated that miR-29b-2-5p improves prognosis in PDAC by targeting Cbl-b to promote p53 expression, and would constitute an important prognostic factor in PDAC. [ABSTRACT FROM AUTHOR]

Background: Hyperfibrinogenemia is a common problem associated with various carcinomas, and is accompanied by hypercoagulablity. In advanced non-small-cell lung cancer (NSCLC) it remains unclear whether or not chemotherapy-induced changes in fibrinogen level relate to chemotherapeutic response and prognosis. The purposes of this study were to: 1) analyze the association between chemotherapy-induced changes in plasmafibrinogen level and the chemotherapeutic response after the first two courses of standard first-line platinum-based chemotherapy; and 2) evaluate the prognostic significance of the basal plasma fibrinogen level in patients with advanced NSCLC.Methods: In this retrospective study, the data from 160 patients with advanced NSCLC were collected. The association between the changes in fibrinogen and the response to chemotherapy, or between the pre-and post-chemotherapy fibrinogen levels and patient clinical characteristics, were analyzed using SPSS software. In addition, the prognostic value of pre-chemotherapy fibrinogen levels was assessed.Results: The median pre-chemotherapy plasma fibrinogen level was 4.4 g/L. Pre-chemotherapy plasma fibrinogen levels correlated significantly with gender (p = 0.041). Post-chemotherapy plasma fibrinogen levels correlated with gender (p = 0.023), age (p = 0.018), ECOG (p = 0.002) and tumor response (p = 0.049). Plasma fibrinogen levels markedly decreased after chemotherapy in 98 (61.25 %) patients with pre-chemotherapy hyperfibrinogenemia (p = 0.008); and in this population there was a significant link between the decrease in fibrinogen level, and initial partial response (PR; p = 0.017) and stable disease (SD; p = 0.031). Univariate and multivariate analysis revealed thathigher levels of fibrinogen (≥4.4 g/L) and ECOG 1 were positively associated with shorter overall survival (OS). CEA and CA125 also decreased significantly (p =0.015, p =0.000) in DCR group after chemotherapy. Conclusions: This study showed that the reduction in plasma fibrinogen levels induced by chemotherapy might be as a promising biomarker as CEA and CA125 for evaluating the efficacy of chemotherapy in advanced NSCLC. In addition, basal plasma fibrinogen levels could be used as an independent prognostic parameter for the OS of patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background: The epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer has been successfully treated with tyrosine kinase inhibitors (TKIs). Acquired resistance becomes a tough issue when patients fail to respond to the third-generation TKI osimertinib. This study aimed to report a case baring acquired EGFR L858R/L718Q mutation in the central nervous system induced by osimertinib, which was successfully overcome using afatinib.Case Presentation: A 65-year-old female patient was diagnosed with stage IV non-small-cell lung adenocarcinoma with synchronic brain metastasis in February 2015. Before and during treatment, 416 tumor-related genes were monitored dynamically by liquid biopsies using next-generation sequencing, and the treatment strategy was decided according to the gene status. At baseline, an EGFR L858R mutation in exon 21 was detected, so treatment with icotinib was started. After 8 months, she experienced disease progression with leptomeningeal metastasis and switched to osimertinib based on an acquired EGFR T790 M mutation. After 9 months, her disease progressed and an EGFR L718Q mutation was found in the cerebrospinal fluid. The patient was then challenged with afatinib, and her disease was under control for 4 months. In January 2017, the patient passed away, with an overall survival time of 23 months, 15 months after leptomeningeal metastasis.Conclusion: The acquired EGFR L718Q mutation in the cerebrospinal fluid resulted in subsequent resistance to osimertinib and could be partly overcome using afatinib, indicating a promising treatment option in the clinic. [ABSTRACT FROM AUTHOR]

Background: Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance.Methods: MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth.Results: MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression.Conclusions: Our results suggested that c-Cbl can reverse tamoxifen resistance in HER2-overexpressing breast cancer cells by inhibiting the formation of the ER-c-Src-HER2 complex. [ABSTRACT FROM AUTHOR]

Background: Programmed death-ligand 1 (PD-L1) is an immunosuppressor that plays an important role in cancer treatments. Although majority of the studies demonstrated that PD-L1 expression was regulated by cellular intrinsic and extrinsic controls, and IFN-γ was a key molecule of extrinsic control, other studies imply that other cytokines play important roles in PD-L1 expression. In this study, we investigated the regulation of PD-L1 by chemokine signaling pathway in gastric cancer (GC) cells.Methods: Bioinformatics was used to explore the PD-L1-related genes in GC and propose a hypothesis. PD-L1 and CXCR3 expression were detected by western blot in SGC7901 and MKN74 cell lines. Meanwhile, PD-L1 and CXCR3 expressions were immunohistochemically assessed for their relevance. Moreover, PD-L1, pSTAT3 and pAkt were detected after treatment with CXCL9/10/11. Furthermore,PD-L1, pSTAT3 and pAkt were evaluated after blocking chemokine signaling in SGC7901 cells.Results: Based on online database analysis, CXCL9/10/11-CXCR3 is proposed to upregulate PD-L1 expression by activating the STAT and PI3K-Akt pathways. This hypothesis was confirmed by in vitro and vivo experiments. CXCR3 and PD-L1 were expressed in GC cell lines and tissues, and the expression of CXCR3 and PD-L1 was positively related. PD-L1 was upregulated after treatment with CXCL9/10/11, accompanied by activation of STAT3 and Akt. After blocking chemokine signaling, upregulation of PD-L1 and activation of STAT3 and Akt were diminished.Conclusions: CXCL9/10/11-CXCR3 upregulated the expression of PD-L1 by activating the STAT and PI3K-Akt signaling pathways in GC cells. There was a significant positive correlation between the expression of PD-L1 and CXCR3 in gastric cancer patient tissues. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the safety of sorafenib for the treatment of unresectable hepatocellular carcinoma in Chinese patients.Methods: A subgroup of 345 Chinese patients from the international database of the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study was included in this analysis. Safety assessment measures were adverse events (AEs) and serious adverse events (SAEs) graded using the National Cancer Institute Common Terminology Criteria version 3.0.Results: Of 331 evaluable patients, 98% started sorafenib at 800 mg/day. The median treatment duration was 22 weeks (range, 0.1-116 weeks), and median overall survival (OS) was 322 days (10.7 months). Approximately 50% of patients had at least one adverse event, and 6% had grade 3-4 adverse events. Drug-related adverse events were experienced by 29% of patients, and 3.6% had grade 3-4 drug-related adverse events. Overall, 23% of patients (n = 77) experienced serious adverse events, among which only 1 event was drug-related (0.3%). No differences in overall adverse events, serious adverse events, and deaths were observed between Child-Pugh A and Child-Pugh B patients. The most frequent drug-related adverse events were dermatological/skin (24%), hand-foot skin reaction (20%), gastrointestinal (11%), and diarrhea (11%). The majority of adverse events occurred within 30 days of beginning sorafenib.Conclusion: Sorafenib has satisfactory efficacy and safety in Chinese Child-Pugh A and B patients with unresectable HCC using the recommended dosage of 800 mg/day, and the safety of sorafenib is not affected by liver function. Prophylaxis for gastrointestinal adverse events may help to decrease dose interruptions or discontinuation.Trial Registration: ClinicalTrials.gov ; Identifier: NCT00812175. Date of registration: December 19, 2008. [ABSTRACT FROM AUTHOR]

Background: β-Elemene, a compound found in an herb used in traditional Chinese medicine, has shown promising anti-cancer effects against a broad spectrum of tumors. The mechanism by which β-elemene kills cells remains unclear. The aim of the present study is to investigate the anti-tumor effect of β-elemene on human gastric cancer cells and the molecular mechanism involved.Results: β-Elemene inhibited the viability of human gastric cancer MGC803 and SGC7901 cells in a dose-dependent manner. The suppression of cell viability was due to the induction of apoptosis. A robust autophagy was observed in the cells treated with β-elemene; it was characterized by the increase of punctate LC3 dots, the cellular morphology, and the increased levels of LC3-II protein. Further study showed that β-elemene treatment up-regulated Atg5-Atg12 conjugated protein but had little effect on other autophagy-related proteins. PI3K/Akt/mTOR/p70S6K1 activity was inhibited by β-elemene. Knockdown of Beclin 1 with small interfering RNA, or co-treatment with the autophagy inhibitor, 3-methyladenine or chlorochine enhanced significantly the antitumor effects of β-elemene.Conclusions: Our data provides the first evidence that β-elemene induces protective autophagy and prevents human gastric cancer cells from undergoing apoptosis. A combination of β-elemene with autophagy inhibitor might thus be a useful therapeutic option for advanced gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Stable disease (SD) has ambiguous clinical significance for patients according to the dominant Response Evaluation Criteria in Solid Tumours (RECIST). The primary aims of the study were: (1) to clarify the clinical significance of SD by comparing the progression-free survival (PFS) of response and SD patients with advanced non-small cell lung cancer (NSCLC) after the first two courses of the standard first-line platinum-based chemotherapy; (2) to explore the relationship between the percentage change in tumour size and PFS among initial SD patients, in order to provide some guidance for clinicians in deciding continuation/termination of the current treatment at a relative early time.Methods: A total of 179 advanced NSCLC patients whose baseline CT image was available for review were included in the study. Another CT image was taken in the initial assessment after chemotherapy. A comparison of PFS between initial partial response (PR) and SD was used to determine whether significant differences exist. The relationship between the early percentage of change in tumour size of initial SD patients and their PFS was investigated. In addition, overall survival (OS), the secondary endpoint in this study, was investigated as well.Results: Patients with initial PR are not significantly distinguished from those with initial SD when their PFS is concerned (median PFS 249 days [95% confidence interval, 187-310 days] versus 220 days [95% confidence interval, 191-248 days], p > 0.05). Their median OS was 364 days (95% confidence interval, 275-452 days) for the initial PR patients versus 350 days (95% confidence interval, 293-406 days) for the initial SD patients, which suggests no significant difference as well p > 0.05). In addition, all the initial SD patients enjoyed similar PFS and OS.Conclusions: Initial PR and SD enjoy similar PFS and OS for patients with advanced NSCLC. Within the initial SD subgroup, different percentages of tumour shrinkage or increase undergo similar PFS and OS. RECIST remains a reliable norm in assessing the effectiveness of chemotherapy for patients with advanced NSCLC before functional assessment has been integrated into the criteria. [ABSTRACT FROM AUTHOR]