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

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 0 -deoxy-3 0 -[ 18 F]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 IFNg 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.

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…These compounds will not reach the clinic, but GLPG1690 is in Phase III trials. We showed that GLPG1690 decreases the proliferation of breast cancer cells in irradiated tumors [120], which supports the case for blocking LPA signaling to improve the efficacy of RT. In addition, blocking LPA signaling should decrease the co-morbidity of fibrosis.…”

“…LPA decreases the killing of breast cancer cells by paclitaxel [78], tamoxifen [117], and doxorubicin [118], which are major therapeutics for different types of breast cancer. Axiomatically, ATX inhibition increased the efficacy of doxorubicin in decreasing breast tumor growth and metastases in mice [119,120]. This LPA effect depends on the activation of LPAR1, which stabilizes the transcription factor, Nrf2 (Figure 6).…”

Cancer-associated adipocytes: emerging supporters in breast cancer

“…In a vitro assay, Bochet et al showed that BC cells exhibited enhanced IL-6 expression, Chk1 phosphorylation, and a radioresistant phenotype in the presence of adipocytes, revealing a new role of tumor-surrounding adipocytes in fostering a radioresistant phenotype in BC [ 109 ]. Tang et al reported that the mammary adipocyte-derived ATX secretion was promoted by BC-produced inflammatory cytokines, leading to enhanced resisting effects in radiotherapy or chemotherapy [ 110 , 111 ]. Thus, inhibiting adipocyte-derived ATX provided a promising adjuvant to improve BC outcomes of radiotherapy and chemotherapy.…”

Autotaxin Implication in Cancer Metastasis and Autoimunne Disorders: Functional Implication of Binding Autotaxin to the Cell Surface

“…More recently, another ATX/lysoPLD inhibitor, GLPG1690, succeeded in halting the progression of idiopathic pulmonary fibrosis in Phase 2a clinical trials and it is now being tested in a Phase 3 trial [51]. In the breast cancer context, this compound has also been shown to increase radiotherapy efficiency and chemotherapy in the 4T1 mouse model [52]. However, although these inhibitors are really promising, they only partially block metastatic spread and new approaches will therefore have to be considered.…”