Dataset Information

Efficacy of Combined VEGFR1-3, PDGFα/β, and FGFR1-3 Blockade Using Nintedanib for Esophagogastric Cancer.

ABSTRACT:

Purpose

VEGFR2-directed therapy is commonly used to treat metastatic esophagogastric cancer, but disease progresses in most patients within months. Therapeutic resistance is likely mediated in part by co-occurring amplifications of the genes for multiple oncogenic receptor tyrosine kinases (RTK). We therefore tested the efficacy of combined inhibition of VEGFR1-3, PDGFα/β, and FGFR1-3 using nintedanib.

Patients and methods

Patients with metastatic esophagogastric adenocarcinoma and disease progression on first-line chemotherapy were treated with nintedanib 200 mg twice daily. The primary endpoint was progression-free survival (PFS) at 6 months; secondary endpoints included tumor response and safety. Tumor biopsies were profiled by targeted capture next-generation sequencing (NGS) to identify molecular predictors of drug response.

Results

The study achieved its primary endpoint; 6 of 32 patients (19%) were progression-free at 6 months. With a median follow-up of 14.5 months among survivors, median overall survival (OS) was 14.2 months [95% confidence interval (CI), 10.8 months-NR]. Nintedanib was well tolerated; grade ≥ 3 toxicities were uncommon and included grade 3 hypertension (15%) and liver enzyme elevation (4%). FGFR2 alterations were identified in 18% of patients but were not predictive of clinical outcome on nintedanib therapy. Alterations in cell-cycle pathway genes were associated with worse median PFS (1.61 months for patients with cell-cycle pathway alterations vs. 2.66 months for patients without, P = 0.019).

Conclusions

Nintedanib treatment resulted in modest disease stabilization in patients with metastatic esophagogastric cancer. Alterations in cell-cycle pathway genes and increased global copy-number alteration (CNA) burden warrant further study as prognostic or predictive biomarkers.

SUBMITTER: Won E

PROVIDER: S-EPMC6606369 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Efficacy of Combined VEGFR1-3, PDGFα/β, and FGFR1-3 Blockade Using Nintedanib for Esophagogastric Cancer.

Won Elizabeth E Basunia Azfar A Chatila Walid K WK Hechtman Jaclyn F JF Chou Joanne F JF Ku Geoffrey Y GY Chalasani Sree B SB Boyar Michelle S MS Goldberg Zoe Z Desai Avni M AM Tuvy Yaelle Y Berger Michael F MF Tang Laura L Kelsen David P DP Schattner Mark M Ilson David H DH Capanu Marinela M Solit David B DB Schultz Nikolaus N Janjigian Yelena Y YY

Clinical cancer research : an official journal of the American Association for Cancer Research 20190405 13

<h4>Purpose</h4>VEGFR2-directed therapy is commonly used to treat metastatic esophagogastric cancer, but disease progresses in most patients within months. Therapeutic resistance is likely mediated in part by co-occurring amplifications of the genes for multiple oncogenic receptor tyrosine kinases (RTK). We therefore tested the efficacy of combined inhibition of VEGFR1-3, PDGFα/β, and FGFR1-3 using nintedanib.<h4>Patients and methods</h4>Patients with metastatic esophagogastric adenocarcinoma an ...[more]

PMID: 30952642

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Project description:The role and therapeutic promise of poly-ADP ribose polymerase (PARP) inhibitors in anticancer chemotherapy are increasingly being explored, particularly in adjuvant or maintenance therapy, considering their low efficacy as monotherapy agents and their potentiating effects on concurrently administered contemporary chemotherapeutics. Against the background of increasing acquired resistance to FGFR1 inhibitors and our previous work, which partially demonstrated the caspase-3/PARP-mediated antitumor and antimetastatic efficacy of PD173074, a selective FGFR1 inhibitor, against ALDH-high/FGFR1-rich pancreatic ductal adenocarcinoma (PDAC) cells, we investigated the probable synthetic lethality and therapeutic efficacy of targeted PARP inhibition combined with FGFR1 blockade in patients with PDAC. Using bioinformatics-based analyses of gene expression profiles, co-occurrence and mutual exclusivity, molecular docking, immunofluorescence staining, clonogenicity, Western blotting, cell viability or cytotoxicity screening, and tumorsphere formation assays, we demonstrated that FGFR1 and PARP co-occur, form a complex, and reduce survival in patients with PDAC. Furthermore, FGFR1 and PARP expression was upregulated in FGFR1 inhibitor (dasatinib)-resistant PDAC cell lines SU8686, MiaPaCa2, and PANC-1 compared with that in sensitive cell lines Panc0403, Panc0504, Panc1005, and SUIT-2. Compared with the limited effect of single-agent olaparib (PARP inhibitor) or PD173074 on PANC-1 and SUIT-2 cells, low-dose combination (olaparib + PD173074) treatment significantly, dose-dependently, and synergistically reduced cell viability, upregulated cleaved PARP, pro-caspase (CASP)-9, cleaved-CASP9, and cleaved-CASP3 protein expression, and downregulated Bcl-xL protein expression. Furthermore, combination treatment markedly suppressed the clonogenicity and tumorsphere formation efficiency of PDAC cells regardless of FGFR1 inhibitor-resistance status and enhanced RAD51 and γ-H2AX immunoreactivity. In vivo studies have shown that both early and late initiation of combination therapy markedly suppressed tumor xenograft growth and increase in weight, although the effect was more pronounced in the early initiation group. In conclusion, FGFR1 inhibitor-resistant PDAC cells exhibited sensitivity to PD173074 after olaparib-mediated loss of PARP signaling. The present FGFR1/PARP-mediated synthetic lethality proof-of-concept study provided preclinical evidence of the feasibility and therapeutic efficacy of combinatorial FGFR1/PARP1 inhibition in human PDAC cell lines.

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Dataset Information

Efficacy of Combined VEGFR1-3, PDGFα/β, and FGFR1-3 Blockade Using Nintedanib for Esophagogastric Cancer.

Purpose

Patients and methods

Results

Conclusions

Publications

Efficacy of Combined VEGFR1-3, PDGFα/β, and FGFR1-3 Blockade Using Nintedanib for Esophagogastric Cancer.

Similar Datasets

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