Project description:BackgroundEffective therapeutic options are limited for patients with advanced esophageal squamous cell carcinoma (ESCC). The incorporation of an immune checkpoint inhibitor and a molecular anti-angiogenic agent into the commonly adopted chemotherapy may produce synergistic effects. Therefore, we aimed to investigate the efficacy and safety of camrelizumab plus apatinib combined with chemotherapy as the first-line treatment of advanced ESCC.MethodsIn this single-arm prospective phase II trial, patients with unresectable locally advanced or recurrent/metastatic ESCC received camrelizumab 200 mg, liposomal paclitaxel 150 mg/m2 , and nedaplatin 50 mg/m2 on day 1, and apatinib 250 mg on days 1-14. The treatments were repeated every 14 days for up to 9 cycles, followed by maintenance therapy with camrelizumab and apatinib. The primary endpoint was objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.ResultsWe enrolled 30 patients between August 7, 2018 and February 23, 2019. The median follow-up was 24.98 months (95% confidence interval [CI]: 23.05-26.16 months). The centrally assessed ORR was 80.0% (95% CI: 61.4%-92.3%), with a median duration of response of 9.77 months (range: 1.54 to 24.82+ months). The DCR reached 96.7% (95% CI: 82.8%-99.9%). The median PFS was 6.85 months (95% CI: 4.46-14.20 months), and the median OS was 19.43 months (95% CI: 9.93 months - not reached). The most common grade 3-4 treatment-related adverse events (AEs) were leukopenia (83.3%), neutropenia (60.0%), and increased aspartate aminotransferase level (26.7%). Treatment-related serious AEs included febrile neutropenia, leukopenia, and anorexia in one patient (3.3%), and single cases of increased blood bilirubin level (3.3%) and toxic epidermal necrolysis (3.3%). No treatment-related deaths occurred.ConclusionsCamrelizumab plus apatinib combined with liposomal paclitaxel and nedaplatin as first-line treatment demonstrated feasible anti-tumor activity and manageable safety in patients with advanced ESCC. Randomized trials to evaluate this new combination strategy are warranted.Trial registrationThis trial was registered on July 27, 2018, at ClinicalTrials.gov (identifier: NCT03603756).

Project description:Purpose: Primary retroperitoneal liposarcomas (RLPSs) are rare heterogeneous tumors for which there are few effective therapies. Certain anti-angiogenic tyrosine kinase inhibitors have demonstrated efficacy against various solid tumors. The aims of this study were to investigate the effect of Apatinib against retroperitoneal liposarcoma cells and its underlying mechanism and to explore the anti-tumor efficacy of a combination of Apatinib and Epirubicin. Methods: SW872 cells were treated with Apatinib(18μM) for 24 h. The RNAs of the control group and experimental group were stored in TRIzol reagent at -80 ℃. Then mRNA extraction and RNA sequencing were performed by Beijing Mygenostics Co. Ltd., Beijing, China. A Bioanalyzer 2100 System (Agilent Technologies, Santa Clara, CA, USA) was used to assay RNA integrity. An AMPureXP system (BeckmanCoulter, Brea, CA, USA) was used to perform PCR on the products. Quality-tested library preparations were sequenced on the Illumina Novaseq platform (Illumina, San Diego, CA, USA). There were three biological replicates per condition. Differential expression analysis of both groups was performed using DESeq2R v. 1.20.0. The Benjamini-Hochberg multiple hypothesis test correction was performed to obtain the false discovery rate (FDR). The criteria used to select the DEGs were |log2(FoldChange)| > 0.5 and FDR < 0.05. When log2(FoldChange) > 0, the gene was considered upregulated. When log2(FoldChange) < 0, the gene was considered downregulated. profiler package in R (R Core Team, Vienna, Austria) was used for GO function and KEGG pathway enrichment analyses of the DEGs. Histograms and bubble graphs were plotted with the ggplot2 package in R v. 3.4.3. Results:To elucidate the mechanisms by which Apatinib inhibited liposarcoma cells, we used RNA-seq to evaluate relative genetic changes in the SW872 cells after being treated with Apatinib for 24 hs, and found 2,038 DEGs, including 1,059 significantly downregulated genes and 979 significantly upregulated genes. The output of the KEGG pathway enrichment analysis suggests that Apatinib might inhibit SW872 cell proliferation through p53, DNA replication, and other important signaling pathways. GO enrichment analysis was performed on the genes that were significantly altered after Apatinib application.High-throughput RNA sequencing showed that Apatinib downregulated the expression of TYMS and RRM2. Conclusions: Apatinib showed strong efficacy against liposarcoma both in vitro and in vivo. Apatinib might inhibit liposarcoma cell proliferation through the RRM2/PI3K/AKT/mTOR signaling pathway and downregulate PD-L1 via the TYMS/STAT3 signaling pathway.

Project description:Immunotherapy by immune checkpoint inhibitors (ICIs) has showed outstanding efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). The combination of immunotherapy with anti-angiogenic therapy exhibited enhanced efficacy in multiline treatment. However, the potential biomarkers for predicting and monitoring the therapeutic response of the combined therapy remain undefined. In this study, we performed a pilot study by prospectively recruiting 22 advanced NSCLC patients who failed to previous lines of chemotherapy, chemoradiotherapy, TKI therapy, surgery, or any combination of the therapies, and investigated the prognostic factors for patients who received anti-PD-1 (Camrelizumab) and anti-angiogenic (Apatinib) combined therapy. The objective response rate (ORR) assessed by an independent radiology review was 22.7%, and the median progression-free survival (PFS) was 5.25 months. We found that high concentration of circulating-free DNA (cfDNA) (HR = 27.75, P = 0.003), MIKI67 mutation (HR = 114.11, P = 0.009) and gene variations related to hyper-progressive disease (HPD) (HR = 36.85, P = 0.004) were independent risk factors and exhibited significant correlation with PFS. Circulating tumor DNA (ctDNA) mutational status was also a predicting indicator for PFS. In contrast, the blood tumor mutational burden (bTMB) could not stratify the clinical benefit in this combined therapy (HR = 0.81, P = 0.137). Furthermore, we found that the variant allele fraction (VAF) of mutations in ctDNA was sensitive indicators of therapeutic response and therefore can be used to monitor the tumor relief or progression. In conclusion, cfDNA concentration, MIKI67 mutations and HPD-related mutations were independent risk factors and PFS predictors for multiline combined anti-angiogenic/ICI combined therapy. ctDNA may be a novel monitoring biomarker for therapeutic response and predicting biomarker for prognosis in future combined therapy involving PD-1 blockade.

Project description:Gastric cancer (GC), one of the types of tumor most prone to malignancy, is characterized by high lethality. Numerous molecular mediators of GC have been identified, including transcription factors, signaling molecules and non-coding RNAs. Recently, inhibition of angiogenesis has emerged as a potential strategy for GC therapy. In the present study, the levels of vascular endothelial growth factor (VEGF), peroxisome proliferator-activated receptor-? (PPAR?) and miR-21 in GC patients and individuals without cancer, and the correlation between VEGF and miR-21, and PPAR? and miR-21 expression were analyzed. In addition, the GC MKN45 cell line was treated with apatinib (a tyrosine kinase inhibitor) and aspirin (an activator of the transcription factor, PPAR?) to investigate the effects of these compounds on tumorigenesis. Furthermore, the present study attempted to elucidate the molecular mechanisms of alteration of GC tumorigenesis by aspirin and apatinib. The results of the current study demonstrated that there was a higher expression of VEGF and miR-21 in GC tissues compared with that in morphologically adjacent normal tissues whereas PPAR? expression was decreased. These results were confirmed in vitro, as treatment of MKN45 cells with VEGF resulted in a significant increase in miR-21 expression and a significant reduction in PPAR? protein expression. Furthermore, the inhibitory effects of VEGF on PPAR? mRNA and protein expression were demonstrated to be mediated by miR-21. Suppression of PPAR? protein expression attenuated the inhibitory effects of miR-21 on the level of PPAR? mRNA, thereby enhancing tumorigenesis in gastric cancer. Treatment of MKN45 cells with aspirin reduced the levels of phosphorylated AKT by activating PPAR?, whereas treatment with apatinib inhibited the phosphorylation of vascular endothelial growth factor receptor 2 and phosphoinositide-3 kinase in MKN45 cells. Finally, treatment of MKN45 cells with apatinib and aspirin suppressed tumorigenesis by inhibiting cell proliferation, migration, invasion and colony formation. Taken together, the results of the present study indicate that treatment with a combination of aspirin and apatinib may be a potential therapeutic strategy for GC treatment.

Project description:BackgroundPerioperative therapy can improve the low survival benefit of surgery alone for locally advanced gastric cancer. The introduction of immunotherapy and its combination with chemotherapy and/or targeted therapy has created more opportunities for optimal treatment. The aim of the present study was to compare the efficacy and safety of S-1 plus oxaliplatin (SOX) combined with apatinib (SOXA) or SOX combined with apatinib and camrelizumab (SOXAP) versus SOX as the perioperative therapy for resectable, locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.MethodsThe study was a multicenter, randomized, open-label, parallel-controlled trial conducted in China. Eligible participants were randomized to the SOX, SOXA, and SOXAP groups. Patients received three pre-operative and three postoperative 3-week cycles of SOX or SOXA or SOXAP, followed by apatinib (SOXA group) or apatinib combined with camrelizumab (SOXAP group) for 3 cycles, which could be continued at the investigator's choice. Overall treatment is up to 1 year of apatinib and up to 17 cycles of camrelizumab. SOX is 130 mg/m2 oxaliplatin on day 1 plus S-1 orally twice daily on days 1 to 14. Apatinib is orally administered at a dose of 500 mg (SOXA group) or 250 mg (SOXAP group) on days 1 to 21, and camrelizumab 200 mg is given intravenously once every 3 weeks. The primary endpoint was major pathological response assessed by blinded independent review committee. The secondary endpoints included pathological complete response, lymph node status after neoadjuvant therapy, margin-free resection rate, progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), and safety.DiscussionThe trial provides important data regarding the use of perioperative SOXAP and SOXA for patients with resectable, locally advanced gastric or GEJ adenocarcinoma. The results will contribute to optimal perioperative disease treatment.Trial registrationClinicalTrials.gov (no. NCT04208347). First posted on December 23, 2019.

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Camrelizumab Combined With Apatinib in the Treatment of Patients With Advanced Gastric Cancer and Colorectal Cancer

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