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Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy.

ABSTRACT: Weekly gemcitabine therapy is the major treatment offered for patients with pancreatic adenocarcinoma cancer; however, relative resistance of tumor cells to chemotherapy, rapid regrowth, and metastasis are the main causes of death within a year. Recently, the daily continuous administration of chemotherapy in low doses--called metronomic chemotherapy (MC)--has been shown to inhibit primary tumor growth and delay metastases in several tumor types; however, its use as a single therapy is still in question due to its moderate therapeutic benefit. Here, we show that the combination of weekly gemcitabine with MC of the same drug delays tumor regrowth and inhibits metastasis in mice implanted orthotopically with pancreatic tumors. We further demonstrate that weekly gemcitabine, but not continuous MC gemcitabine or the combination of the two drug regimens, promotes rebound myeloid-derived suppressor cell (MDSC) mobilization and increases angiogenesis in this tumor model. Furthermore, Bv8 is highly expressed in MDSCs colonizing pancreatic tumors in mice treated with weekly gemcitabine compared to MC gemcitabine or the combination of the two regimens. Blocking Bv8 with antibodies in weekly gemcitabine-treated mice results in a significant reduction in tumor regrowth, angiogenesis, and metastasis. Overall, our results suggest that pro-tumorigenic effects induced by weekly gemcitabine are mediated in part by MDSCs expressing Bv8. Therefore, both Bv8 inhibition and MC can be used as legitimate 'add-on' treatments for preventing post-chemotherapy pancreatic cancer recurrence, progression, and metastasis following weekly gemcitabine therapy.

SUBMITTER: Hasnis E

PROVIDER: S-EPMC4198746 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy.

Hasnis Erez E Alishekevitz Dror D Gingis-Veltski Svetlana S Bril Rotem R Fremder Ella E Voloshin Tali T Raviv Ziv Z Karban Amir A Shaked Yuval Y

Neoplasia (New York, N.Y.) 20140620 6

Weekly gemcitabine therapy is the major treatment offered for patients with pancreatic adenocarcinoma cancer; however, relative resistance of tumor cells to chemotherapy, rapid regrowth, and metastasis are the main causes of death within a year. Recently, the daily continuous administration of chemotherapy in low doses--called metronomic chemotherapy (MC)--has been shown to inhibit primary tumor growth and delay metastases in several tumor types; however, its use as a single therapy is still in ...[more]

PMID: 24957319

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Project description:Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with an extremely low 5-year survival rate. Accumulating evidence has unveiled that inflammatory response promotes tumor progression, enhances angiogenesis, and causes local immunosuppression. Herein, we aim to develop an inflammatory related prognostic signature, and found it could be used to predict gemcitabine response in PDAC. Methods: PDAC cohorts with mRNA expression profiles and clinical information were systematically collected from the four public databases. An inflammatory response related genes (IRRGs) prognostic signature was constructed by LASSO regression analysis. Kaplan-Meier survival analysis, receiver operating characteristic analysis, principal component analysis, and univariate and multivariate Cox analyses were carried out to evaluate effectiveness, and reliability of the signature. The correlation between gemcitabine response and risk score was evaluated in the TCGA-PAAD cohort. The GDSC database, pRRophetic algorithm, and connectivity map analysis were used to predict gemcitabine sensitivity and identify potential drugs for the treatment of PDAC. Finally, we analyzed differences in frequencies of gene mutations, infiltration of immune cells, as well as biological functions between different subgroups divided by the prognostic signature. Results: We established a seven IRRGs (ADM, DCBLD2, EREG, ITGA5, MIF, TREM1, and BTG2) signature which divided the PDAC patients into low- and high-risk groups. Prognostic value of the signature was validated in 11 PDAC cohorts consisting of 1337 PDAC patients from 6 countries. A nomogram that integrated the IRRGs signature and clinicopathologic factors of PDAC patients was constructed. The risk score showed positive correlation with gemcitabine resistance. Two drugs (BMS-536924 and dasatinib) might have potential therapeutic implications in high-risk PDAC patients. We found that the high-risk group had higher frequencies of KRAS, TP53, and CDKN2A mutations, increased infiltration of macrophages M0, neutrophils, and macrophages M2 cells, as well as upregulated hypoxia and glycolysis pathways, while the low-risk group had increased infiltration of CD8+ T, naïve B, and plasma and macrophages M1 cells. Conclusion: We constructed and validated an IRRGs signature that could be used to predict the prognosis and gemcitabine response of patients with PDAC, as well as two drugs (BMS-536924 and dasatinib) may contribute to PDAC treatment.

Dataset Information

Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy.

Publications

Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy.

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