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Targeting IL4/IL4R for the treatment of epithelial cancer metastasis

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Abstract

While progress has been made in treating primary epithelial tumors, metastatic tumors remain largely incurable and still account for 85–90 % of all cancer-related deaths. Interleukin-4 (IL4), a Th2 cytokine, and the IL4/IL4 receptor (IL4R) interaction have well defined roles in the immune system. Yet, IL4 receptors are over-expressed by many epithelial cancers and could be a promising target for metastatic tumor therapy. The IL4/IL4R signaling axis is a strong promoter of pro-metastatic phenotypes in epithelial cancer cells including enhanced migration, invasion, survival, and proliferation. The promotion of breast cancer growth specifically is also supported in part by IL4-induced glutamine metabolism, and we have shown that IL4 is also capable of inducing glucose metabolism in breast cancer cells. Importantly, there are several types of FDA approved medications for use in asthma patients that inhibit the IL4/IL4R signaling axis. However, these approved medications inhibit both the type I IL4 receptor found on immune cells, and the type II IL4 receptor that is predominantly expressed by some non-hematopoietic cells including epithelial cancer cells. This article reviews existing therapies targeting IL4, IL4R, or IL4/IL4R signaling, and recent findings guiding the creation of novel therapies that specifically inhibit the type II IL4R, while taking into consideration effects on immune cells within the tumor microenvironment. Some of these therapies are currently in clinical trials for cancer patients, and may be exploitable for the treatment of metastatic disease.

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Abbreviations

FDA:

Food and Drug Administration (U.S.A.)

γc:

Common gamma chain

IL4:

Interleukin 4

IL4R:

Interleukin 4 receptor

JAK:

Janus kinase

KO:

Knockout

MDSC:

Myeloid-derived suppressor cell

STAT:

Signal transducer and activator of transcription factor

TAM:

Tumor-associated macrophage

Th2:

T-helper type 2

TME:

Tumor microenvironment

Tc2:

Type 2 cytotoxic T cell

IRS:

Insuling receptor substrate protein

Tyk2:

Tyrosine kinase 2

mTOR:

Mammalian target of rapamycin

MAPK:

Mitogen-activated protein kinase

AKT:

Protein kinase B

PI3 K:

Phosphoinositide-3 kinase

ERK:

Extracellular signal-regulated kinase

pM:

Picomolar

Kd:

Dissociation constant

IL4-DM:

IL4 double mutein

NSCLC:

Non-small cell lung cancer

CML:

Chronic myeloid leukemia

AML:

Acute myeloid leukemia

GBM:

Glioblastoma multiforme

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Acknowledgments

This work was supported R01 CA157781 awarded to BF, and by F31 CA183539 awarded to KVB. Both awards were made by the U.S. National Institutes of Health/National Cancer Institute.

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  1. Department of Cancer Biology, Vanderbilt University, 771 PRB, 2220 Pierce Ave, Nashville, TN, 37233-6480, USA

    Katherine Venmar Bankaitis & Barbara Fingleton

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Bankaitis, K.V., Fingleton, B. Targeting IL4/IL4R for the treatment of epithelial cancer metastasis. Clin Exp Metastasis 32, 847–856 (2015). https://doi.org/10.1007/s10585-015-9747-9

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