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.