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

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Inhibition of Autotaxin with GLPG1690 Increases the Efficacy of Radiotherapy and Chemotherapy in a Mouse Model of Breast Cancer Published OnlineFirst September 23, 2019; DOI: 10.1158/1535-7163.MCT-19-0386 MOLECULAR CANCER THERAPEUTICS | SMALL MOLECULE THERAPEUTICS Inhibition of Autotaxin with GLPG1690 Increases the Efficacy of Radiotherapy and Chemotherapy in a Mouse Model of Breast Cancer Xiaoyun Tang1,2, Melinda Wuest2,3, Matthew G.K. Benesch1,2,4, Jennifer Dufour3, YuanYuan Zhao5, Jonathan M. Curtis5, Alain Monjardet6, Bertrand Heckmann6, David Murray2,7, Frank Wuest2,3, and David N. Brindley1,2 ABSTRACT ◥ Autotaxin catalyzes the formation of lysophosphatidic acid, However, GLPG1690 decreased the uptake of 30-deoxy-30-[18F]- whichstimulatestumorgrowthandmetastasisanddecreasesthe fluorothymidinebytumorsandthepercentageofKi67-positive effectiveness of cancer therapies. In breast cancer, autotaxin is cells. This was also associated with increased cleaved caspase-3 secreted mainly by breast adipocytes, especially when stimulated and decreased Bcl-2 levels in these tumors. GLPG1690 decreased by inflammatory cytokines produced by tumors. In this work, we irradiation-induced C-C motif chemokine ligand-11 in tumors studied the effects of an ATX inhibitor, GLPG1690, which is in and levels of IL9, IL12p40, macrophage colony-stimulating phase III clinical trials for idiopathic pulmonary fibrosis, on factor, and IFNg in adipose tissue adjacent to the tumor. In responses to radiotherapy and chemotherapy in a syngeneic other experiments, mice were treated with doxorubicin every orthotopic mouse model of breast cancer. Tumors were treated 2 days after the tumors developed. GLPG1690 acted synergisti- with fractionated external beam irradiation, which was opti- cally with doxorubicin to decrease tumor growth and the per- mizedtodecreasetumorweightby approximately 80%. Mice centage of Ki67-positive cells. GLPG1690 also increased were also dosed twice daily with GLPG1690 or vehicle beginning 4-hydroxynonenal-protein adducts in these tumors. These at 1 day before the radiation until 4 days after radiation was results indicate that inhibiting ATX provides a promising adju- completed. GLPG1690 combined with irradiation did not vant to improve the outcomes of radiotherapy and chemotherapy decrease tumor growth further compared with radiation alone. for breast cancer. Introduction lipid in human plasma (>200 mmol/L; ref. 3). LPA is a lipid growth factor, which signals through six G protein–coupled receptors. LPA Radiotherapy (RT), chemotherapy, and surgery account for most of promotes cell proliferation, survival, migration, and angiogenesis, and the first-line options for treating different stages of breast cancer. This generates inflammation (4, 5). The effects constitute the hallmarks of is done either alone or in combination with endocrine and/or targeted cancer progression (6, 7). therapy, depending on the characteristics of the tumor (1). However, ATX is secreted directly by melanoma, glioblastoma, and thyroid some tumors develop resistance and become refractory to RT and cancer cells (8, 9). However, breast cancer cells express very little chemotherapy. A critical barrier in dealing with this situation is the ATX (9, 10). The adjacent adipose tissue produces the major part of lack of drugs that reverse this resistance or block the survival signals ATX in human and mouse 4T1 breast tumors, which acts on the tumor from the tumor microenvironment (2). microenvironment in a paracrine manner to increase the levels of Autotaxin (ATX) is a secreted lysophospholipase D–like enzyme proinflammatory cytokines (11, 12). Inflammatory cytokines pro- that generates most of the extracellular lysophosphatidic acid (LPA) duced by tumors increase ATX secretion by breast adipocytes further from lysophosphatidylcholine (LPC), the most abundant phospho- and thus establish a vicious loop of inflammation-driven ATX pro- duction because the subsequent LPA stimulates the production of fl 1Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada. more in ammatory cytokines (13, 14). 2Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Increasing evidence has identified enhanced ATX-LPA signaling as Alberta, Canada. 3Division of Oncologic Imaging, Department of Oncology, a major promoter of therapy resistance in cancers (15–17). ENPP2 University of Alberta, Edmonton, Alberta, Canada. 4Discipline of Surgery, (ATX) is the second most upregulated gene in breast cancer stem cells Faculty of Medicine, Memorial University of Newfoundland, St. John's, New- that are resistant to chemotherapy (18). We showed that LPA 5 foundland and Labrador, Canada. Department of Agricultural, Food and Nutri- decreases the cytotoxic effects of taxanes (19), tamoxifen (20), and tional Science, University of Alberta, Edmonton, Alberta, Canada. 6Galapagos RMV, Parc Biocitech, Romainville, France. 7Division of Experimental Oncology, doxorubicin (21) on breast cancer cells. This LPA effect depends on the Department of Oncology, University of Alberta, Edmonton, Alberta, Canada. upregulation of antioxidant proteins and multidrug resistance trans- porters (21), which protects cancer cells by decreasing oxidative Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). damage and by exporting chemotherapeutic drugs and toxic oxidation products (22). About 60% of breast cancer patients receive lumpec- Corresponding Author: David N. Brindley, University of Alberta, 357 Heritage – Medical Research Centre, Edmonton, Alberta T6G 2S2, Canada. Phone: 780-492- tomy followed by RT to the affected breast. The post RT-induced 2078; Fax: 780-492-3383; E-mail: [email protected] cytokine surge (23) produces fatigue in patients (24). We showed that the expressions of ATX, LPA , and LPA receptors, cyclooxygenase-2, Mol Cancer Ther 2020;XX:XX–XX 1 2 and multiple inflammatory cytokines are increased after irradiation of doi: 10.1158/1535-7163.MCT-19-0386 human breast adipose tissue (25). Ionizing radiation also induced ATX Ó2019 American Association for Cancer Research. and LPA2 receptor expression in rat small intestine epithelial cells (26), AACRJournals.org | OF1 Downloaded from mct.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst September 23, 2019; DOI: 10.1158/1535-7163.MCT-19-0386 Tang et al. which attenuated radiation-induced apoptosis by the subsequent rather than a supersaturating concentration of 4 mmol/L. This was activation of LPA signaling (27). Thus, the enhanced ATX-LPA– because the supraphysiologic concentrations of LPC would displace inflammatory cycle within the tumor microenvironment provides a GLPG1690 bound in vivo from ATX and artificially decrease the supportive mechanism for cancer cell survival against RT or chemo- estimated extent of inhibition. Briefly, 17 mL of plasma or 17 mLof therapy (3, 28, 29). This inflammatory cycle can be broken by buffer A (100 mmol/L Tris-HCl, pH 9.0; 500 mmol/L NaCl; 5 mmol/L inhibiting ATX (13). MgCl2; and 0.05% v/v Triton X-100) with 20% DMSO or 20% ATX inhibitors were developed over the last decade, and some DMSO containing 8 mmol/L GLPG1690 were mixed with 8 mLof have been studied for treating inflammatory diseases such as buffer A and preincubated at 37C for 30 minutes. Samples were then pulmonary fibrosis and chronic hepatitis (30). One of these ATX mixed with 25 mL of 600 mmol/L C14:0-LPC in buffer A and incubated inhibitors, GLPG1690 (Fig. 1A,IC50 130–220 nmol/L; Ki 15 for a further 2 hours at 37 C. After this, 20 mL samples of these against human ATX), succeeded in halting the progression of incubation mixtures were pipetted in duplicate into a 96-well plate idiopathic pulmonary fibrosis in phase IIa clinical trials (31, 32), and mixed with 90 mL/well of buffer C [88.3 mL Buffer B (100 mmol/L fi and it is now being tested in a phase III trial (33). Signi cantly, Tris-HCl, pH 8.5, and 5 mmol/L CaCl2), 0.58 mL of 10 mmol/L many therapeutics that are effective against fibrosis are also used Amplex Red, 0.12 mL of 1,000 U/mL horseradish peroxidase, 1 mL to improve cancer treatments (34). It was, therefore, important to of 50 U/mL choline oxidase]. Fluorescence was measured at Excitation establishifanATXinhibitorthatisinclinicaltrialsforfibrosis 544 nm/Emission 590 nm, and choline concentrations were calcu- has positive effects on the treatment of cancers. lated from a choline standard curve. The samples containing the This study tested GLPG1690 in combination with RT or chemo- excess of GLPG1690 in the assay served as a control to determine therapy in a syngeneic orthotopic 4T1 mouse model of breast cancer. ATX-dependent choline formation and account for any free choline This study provides novel information about how targeting ATX in in the plasma. The values for choline obtained in the presence of the tumor microenvironment can improve the efficacy of breast excess GLPG1690 were <5% of the values where no GLPG was cancer treatments. added, which validates the assay. Measurement of LPA and sphingosine 1-phosphate Materials and Methods concentrations in mouse plasma Cell lines and reagents Plasma LPA and sphingosine 1-phosphate concentrations were Mouse 4T1 breast cancer cells, human Hs578T breast cancer measured as described previously (10). Briefly, plasma was treated fi 13 cells, and patient matching Hs578Bst stromal broblasts were from with labeled internal standards including C17:0-LPA and [ C2D2] the American Type Culture Collection. Cells were within 10 pas- S1P. Lipid phosphates were extracted into butan-1-ol.
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