Safety and Efficacy Study of Chemotherapy Plus Apatinib as Second-line Therapy in Metastatic Colorectal Cancer
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ABSTRACT:
DISEASE(S): Angiogenesis,Chemotherapy,Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2247501 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Bevacizumab, as an antibody of vascular endothelial generated factor (VEGF), combined with the fluorouracil-based chemotherapy regimens for metastatic colorectal cancer, has become the classical first-line treatment. However, vast majority of patients eventually will suffer progression disease. The second-line treatment includes replacing chemotherapy regimens whistle continuing bevacizumab or other anti-VEGF antibodies, such as Aflibercept and Ramucirumab. Apatinib is a small molecule tyrosine kinase inhibitor (TKI), which can highly selectively bind to and strongly block VEGF receptor 2 (VEGFR - 2), also potently suppress the activities of Ret, c-kit and c-src, resulting in reduced cell migration, proliferation, and tumor microvascular density mediated by VEGF .There are already robust data showing that antibodies aimed at blocking VEGF signaling pathways combined with chemotherapy to treat advanced colorectal cancer is superior as compared to chemotherapy alone. Thus, we hypothesize that the effect of using the second-line chemotherapy regimens combined with apatinib may be superior to those combined with bevacizumab. In this study,the patients who have progressed following or on first-line oxaliplatin and 5-FU combined with bevacizumab are randomised into two arms. Patients in the experimental arm receive second-line FOLFIRI combined with apatinib and those in the control arm receive second-line FOLFIRI combined with bevacizumab. To compare the efficacy and safety of the two arms, progression-free survival(PFS) is the primary end point.If apatinib is superior to bevacizumab in the second-line setting,it is one possible option of anti-angiogenic therapy in combination with second-line FOLFIRI for treatment of advanced colorectal cancer.
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Project description:(1) Evaluate the efficacy of apatinib in combination with standard second-line chemotherapy for advanced colorectal cancer. Whether it can prolong Progression Free Survival (PFS), overall survival (OS) in patients with advanced colorectal cancer and reduce symptoms and improve quality of life compared with standard second-line chemotherapy; (2) Observe the safety of apatinib for the treatment of advanced colorectal cancer.
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Project description:Regorafenib has been proved to improved survival in patients with metastatic colorectal cancer who have been failed to all of known standard chemotherapy (The CORRECT study). The phase Ib study of regorafenib plus FOLFOX or FOLFIRI was performed and the dose of regorafenib was fixed; 160 mg/day on days 4 to 10 (7 days per cycle when combined with FOLFOX or FOLFIRI). Regorafenib plus FOLFOX as second-line chemotherapy in mCRC patients who progressed after first-line irinotecan-based chemotherapy has not been studied yet, and because there have been unmet needs for the discovery of valid targeted agent combination for the second-line FOLFOX as above reasons, the investigators planned this study of regorafenib plus FOLFOX as second-line chemotherapy in mCRC patients who progressed after first-line irinotecan-based chemotherapy.
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Project description:Targeted therapy for patients with EGFR mutations by tyrosine kinase inhibitors (TKIs) has provided a significant benefit to patients. However, gradually developed resistance to the therapy becomes a major challenge in clinical practice. Herein, we report that Apatinib, an anti-angiogenic drug, strongly and specifically inhibits Gefitinib-resistant cancer cells but not their parental sensitive cells. Gefitinib-resistant lung cancer cell line (PC9GR) was established from its parental sensitive line (PC9) with a traditional EGFR mutation after long time exposure to Gefitinib. The established PC9GR cells had over 250 fold increased resistance to Gefitinib than its sensitive parental PC9 cells. Apatinib demonstrated much stronger (~5 fold) growth inhibition on PC9GR cells than on PC9 and other lung cancer cell lines. This inhibition was mostly achieved through cell cycle rest in G1 phase as demonstrated by transcriptome and protein expression data. Oral intake of Apatinib in mouse model significantly inhibited establishment and growth of PC9GR implanted tumors. VEGFR2 phosphorylation in PC9GR tumors after Apatinib treatment was significantly reduced along with less micro-vessel formation. Apatinib may provide a benefit to patients with acquired resistance to TKI treatment.
2019-05-15 | GSE129221 | GEO
Project description:This experiment is aimed at studying the effect of two different chemotherapies (FOLFOX and FOLFIRI) and their interaction with a ULK1 inhibitor on HCT116 colorectal cancer cell line.
2023-09-01 | E-MTAB-12947 | biostudies-arrayexpress
Project description:We report that previously described molecular subtypes of colorectal cancer are associated with the response to therapy in patients with metastatic disease. We also identified a patient population with high FOLFIRI sensitivity, as indicated by their 2.7-fold longer overall survival when treated with FOLFIRI, as first-line regimen, instead of FOLFOX. Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer.
2017-08-17 | GSE72969 | GEO
Project description:We report that previously described molecular subtypes of colorectal cancer are associated with the response to therapy in patients with metastatic disease. We also identified a patient population with high FOLFIRI sensitivity, as indicated by their 2.7-fold longer overall survival when treated with FOLFIRI, as first-line regimen, instead of FOLFOX. Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer.
2017-08-17 | GSE72968 | GEO
Project description:BackgroundLimited data are available for the combination regimen of anti-programmed cell death protein 1 (PD-1) inhibitor and anti-angiogenic agents as second-line therapy for the treatment of patients with advanced non-small cell lung cancer (NSCLC), especially in patients with squamous NSCLC. This study assessed the efficacy and safety of camrelizumab plus apatinib (a vascular endothelial growth factor receptor 2 inhibitor) as second-line treatment in patients with advanced squamous NSCLC.MethodsIn the Cohort 3 from a phase II dose-expansion trial, patients with advanced non-central squamous NSCLC who were immunotherapy naïve and had failed prior first-line platinum-based chemotherapy received 200 mg of camrelizumab intravenously every 2 weeks plus oral apatinib at the recommended dose of 250 mg once daily. The primary endpoint was objective response rate (ORR) assessed by the investigators as per the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1.ResultsCohort 3 was prematurely terminated because of slow accrual after 25 patients with advanced squamous NSCLC had been enrolled between 10 October 2018, and 3 March 2019. At the data cutoff date of 12 June 2020, the median follow-up was 13.3 (range, 1.6 to 19.2) months. Among all 25 participants, the ORR was 32.0% (95% CI: 14.9% to 53.5%), the clinical benefit rate was 44.0% (95% CI: 24.4% to 65.1%), and the disease control rate (DCR) was 84.0% (95% CI: 63.9% to 95.5%). Median progression-free survival (PFS) was 6.0 (95% CI: 3.5 to 8.1) months, and median overall survival (OS) was 13.3 (95% CI: 6.4 to 18.8) months. Furthermore, clinical benefits from this combination regimen were evident across all tumor PD ligand 1 (PD-L1) expression subgroups. The most common treatment-related adverse events (TRAEs) of grade 3 or higher were hypertension (44.0%) and palmar-plantar erythrodysesthesia (16.0%). As reported by the investigators, 3 participants (12.0%) died due to TRAEs (interstitial pneumonia, hemorrhage, and unknown reason; n=1 each, 4%).ConclusionsCamrelizumab plus apatinib as second-line therapy showed satisfactory antitumor activity in patients with non-central squamous NSCLC, regardless of tumor PD-L1 expression. Camrelizumab plus apatinib had a manageable safety profile in this patient population, and the toxic reactions observed were generally consistent with those in previously reported studies. Interstitial pneumonia and hemorrhage are important risks requiring careful monitoring and prompt intervention.
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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.
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