Inhibition of Autotaxin with GLPG1690 Increases the Efficacy of Radiotherapy and Chemotherapy in a Mouse Model of Breast Cancer

Xiaoyun Tang,Yuanyuan Zhao,Melinda Wuest,Bertrand Heckmann,Jonathan M Curtis,Matthew G.K Benesch,Jennifer Dufour,David N Brindley,Frank Wuest,David Murray,Alain Monjardet

doi:10.1158/1535-7163.mct-19-0386

Abstract

Autotaxin catalyzes the formation of lysophosphatidic acid, which stimulates tumor growth and metastasis and decreases the effectiveness of cancer therapies. In breast cancer, autotaxin is secreted mainly by breast adipocytes, especially when stimulated by inflammatory cytokines produced by tumors. In this work, we studied the effects of an ATX inhibitor, GLPG1690, which is in phase III clinical trials for idiopathic pulmonary fibrosis, on responses to radiotherapy and chemotherapy in a syngeneic orthotopic mouse model of breast cancer. Tumors were treated with fractionated external beam irradiation, which was optimized to decrease tumor weight by approximately 80%. Mice were also dosed twice daily with GLPG1690 or vehicle beginning at 1 day before the radiation until 4 days after radiation was completed. GLPG1690 combined with irradiation did not decrease tumor growth further compared with radiation alone. However, GLPG1690 decreased the uptake of 3'-deoxy-3'-[18F]-fluorothymidine by tumors and the percentage of Ki67-positive cells. This was also associated with increased cleaved caspase-3 and decreased Bcl-2 levels in these tumors. GLPG1690 decreased irradiation-induced C-C motif chemokine ligand-11 in tumors and levels of IL9, IL12p40, macrophage colony-stimulating factor, and IFNγ in adipose tissue adjacent to the tumor. In other experiments, mice were treated with doxorubicin every 2 days after the tumors developed. GLPG1690 acted synergistically with doxorubicin to decrease tumor growth and the percentage of Ki67-positive cells. GLPG1690 also increased 4-hydroxynonenal-protein adducts in these tumors. These results indicate that inhibiting ATX provides a promising adjuvant to improve the outcomes of radiotherapy and chemotherapy for breast cancer.

Highlights

Radiotherapy (RT), chemotherapy, and surgery account for most of the first-line options for treating different stages of breast cancer
ATX inhibitors were developed over the last decade, and some have been studied for treating inflammatory diseases such as pulmonary fibrosis and chronic hepatitis [30]. One of these ATX inhibitors, GLPG1690 (Fig. 1A, IC50 $130–220 nmol/L; Ki $15 against human ATX), succeeded in halting the progression of idiopathic pulmonary fibrosis in phase IIa clinical trials [31, 32], and it is being tested in a phase III trial [33]
The present study investigated the effects of targeting ATX as a neoadjuvant therapy for breast cancer

Summary

Introduction

Radiotherapy (RT), chemotherapy, and surgery account for most of the first-line options for treating different stages of breast cancer This is done either alone or in combination with endocrine and/or targeted therapy, depending on the characteristics of the tumor [1]. The enhanced ATX-LPA– inflammatory cycle within the tumor microenvironment provides a supportive mechanism for cancer cell survival against RT or chemotherapy [3, 28, 29]. This inflammatory cycle can be broken by inhibiting ATX [13]. The values for choline obtained in the presence of excess GLPG1690 were

Materials and Methods

Results

Discussion

Disclosure of Potential Conflicts of Interest