Abstract
After a decade of intense preclinical investigations, the first in-class autotaxin inhibitor, GLPG1690, has entered Phase III clinical trials for idiopathic pulmonary fibrosis. In the intervening time, a deeper understanding of the role of the autotaxin–lysophosphatidate (LPA)–lipid phosphate phosphatase axis in breast cancer progression and treatment resistance has emerged. Concordantly, appreciation of the tumor microenvironment and chronic inflammation in cancer biology has matured. The role of LPA as a central mediator behind these concepts has been exemplified within the breast cancer field. In this review, we will summarize current challenges in breast cancer therapy and delineate how blocking LPA signaling could provide novel adjuvant therapeutic options for overcoming therapy resistance and adverse side effects, including radiation-induced fibrosis. The advent of autotaxin inhibitors in clinical practice could herald their applications as adjuvant therapies to improve the therapeutic indexes of existing treatments for breast and other cancers.
Highlights
History of Breast Cancer, Current Management, and Remaining ChallengesBreast cancer is believed to be the oldest documented cancer, described in an Egyptian scroll dating to 1700 BCE as a bulging mass for which no cure was possible [1]
The 20th century saw cancer treatment develop into a trimodal entity—surgery, the “cold knife”, the remove the cancer with a margin of healthy tissue; radiotherapy, “the hot knife”, to eradicate any remaining cells within the surgical field; and chemotherapy, to both eliminate any circulating cancer cells and prevent local reoccurrence
Tumor Microenvironment understand the genomic alterations in ATX expression and post-transcriptional regulation
Summary
D that that generates generates most most of of the the extracellular extracellular Autotaxin (ATX) is lysophosphatidate (LPA). 3. Maladaptive Effects of Excessive ATX Secretion and LPA Signaling in Inflammation, Fibrosis, and the Tumor Microenvironment. If inflammation is not resolved, chronic activation of ATX-LPA-inflammatory signaling and the wound healing response becomes maladaptive [30,32] in diseases such as pulmonary fibrosis, cirrhosis, rheumatoid arthritis, inflammatory bowel disease, and cancers [24,48]. More recent studies demonstrate that ATX produced by platelets provides LPA for seeding, further enhanced by niche additional signalingcancer mediated by ATXfurther binding to cell surface integrins at establishing a hospitable for metastatic cell seeding, enhanced by additional the sites of metastases signaling mediated[84,85]. By ATX binding to cell surface integrins at the sites of metastases [84,85]
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