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IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma.

ABSTRACT: Inflammation mediated by activation of JAK/STAT signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL6 receptor (IL6R) as a strategy to inhibit IL6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with PDAC was assessed for its ability to activate STAT3/SOCS3 in human monocytes using immunofluorescence microscopy and quantitative gene expression assays. KPC mice and syngeneic mice (wild type and IL6-/-) implanted with KPC-derived cell lines were treated with an IL6R-blocking antibody (anti-IL6R). The impact of treatment on tumor growth in KPC mice and mice with KPC-derived tumor implants was monitored using ultrasonography and calipers, respectively. Tumors were analyzed by IHC to detect changes in STAT activation, tumor viability, and proliferation. We found that STAT3 was the most activated STAT protein in PDAC tumors from KPC mice. Plasma from patients with advanced PDAC stimulated STAT3/SOCS3 activation in human monocytes. In mice, anti-IL6R antibodies targeted Ly6Chi monocytes, inhibited STAT3 activation in tumor cells, and decreased tumor cell proliferation in vivo IL6R blockade in combination with chemotherapy induced tumor cell apoptosis, tumor regressions, and improved overall survival. Overall, we show that IL6 signaling drives STAT3 activation in tumor cells and mediates chemoresistance in PDAC. Thus, disrupting IL6 signaling using anti-IL6R antibodies holds promise for improving chemotherapy efficacy in PDAC. Mol Cancer Ther; 16(9); 1898-908. ©2017 AACR.

SUBMITTER: Long KB

PROVIDER: S-EPMC5587413 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma.

Long Kristen B KB Tooker Graham G Tooker Evan E Luque Santiago Lombo SL Lee Jae W JW Pan Xiaoqing X Beatty Gregory L GL

Molecular cancer therapeutics 20170613 9

Inflammation mediated by activation of JAK/STAT signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL6 receptor (IL6R) as a strategy to inhibit IL6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with ...[more]

PMID: 28611107

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating and painful cancers. It is often highly resistant to therapy owing to inherent chemoresistance and the desmoplastic response that creates a barrier of fibrous tissue preventing transport of chemotherapeutics into the tumor. The growth of the tumor in pancreatic cancer often leads to invasion of other organs and partial or complete biliary obstruction, inducing intense pain for patients and necessitating tumor resection or repeated stenting. Here, we have developed a delivery device to provide enhanced palliative therapy for pancreatic cancer patients by providing high concentrations of chemotherapeutic compounds locally at the tumor site. This treatment could reduce the need for repeated procedures in advanced PDAC patients to debulk the tumor mass or stent the obstructed bile duct. To facilitate clinical translation, we created the device out of currently approved materials and drugs. We engineered an implantable poly(lactic-co-glycolic)-based biodegradable device that is able to linearly release high doses of chemotherapeutic drugs for up to 60 days. We created five patient-derived PDAC cell lines and tested their sensitivity to approved chemotherapeutic compounds. These in vitro experiments showed that paclitaxel was the most effective single agent across all cell lines. We compared the efficacy of systemic and local paclitaxel therapy on the patient-derived cell lines in an orthotopic xenograft model in mice (PDX). In this model, we found up to a 12-fold increase in suppression of tumor growth by local therapy in comparison to systemic administration and reduce retention into off-target organs. Herein, we highlight the efficacy of a local therapeutic approach to overcome PDAC chemoresistance and reduce the need for repeated interventions and biliary obstruction by preventing local tumor growth. Our results underscore the urgent need for an implantable drug-eluting platform to deliver cytotoxic agents directly within the tumor mass as a novel therapeutic strategy for patients with pancreatic cancer.

Dataset Information

IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma.

Publications

IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma.

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