Limited fibrosis accompanies triple-negative breast cancer metastasis in multiple model systems and is not a preventive target

// Danielle Brooks 1 , Alexandra Zimmer 1 , Lalage Wakefield 2 , L. Tiffany Lyle 3 , Simone Difilippantonio 4 , Fabio C. Tucci 5 , Stephane Illiano 6 , Christina M. Annunziata 1 and Patricia S. Steeg 1 1 Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA 2 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA 3 Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA 4 Laboratory Animal Sciences Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA 5 Epigen Biosciences, Inc., San Diego, CA, USA 6 Sanofi, Chilly Mazarin, France Correspondence to: Patricia S. Steeg, email: steegp@mail.nih.gov Keywords: breast cancer; ovarian cancer; fibrosis; lysophosphatidic acid receptor; metastasis Received: December 29, 2017      Accepted: April 04, 2018      Published: May 04, 2018 ABSTRACT The lysophosphatidic acid receptor 1 (LPAR1) is mechanistically implicated in both tumor metastasis and tissue fibrosis. Previously, metastasis was increased when fulminant fibrosis was first induced in mice, suggesting a direct connection between these processes. The current report examined the extent of metastasis-induced fibrosis in breast cancer model systems, and tested the metastasis preventive efficacy and fibrosis attenuation of antagonists for LPAR1 and Idiopathic Pulmonary Fibrosis (IPF) in breast and ovarian cancer models. Staining analysis demonstrated only focal, low-moderate levels of fibrosis in lungs from eleven metastasis model systems. Two orally available LPAR1 antagonists, SAR100842 and EPGN9878, significantly inhibited breast cancer motility to LPA in vitro . Both compounds were negative for metastasis prevention and failed to reduce fibrosis in the experimental MDA-MB-231T and spontaneous murine 4T1 in vivo breast cancer metastasis models. SAR100842 demonstrated only occasional reductions in invasive metastases in the SKOV3 and OVCAR5 ovarian cancer experimental metastasis models. Two approved drugs for IPF, nintedanib and pirfenidone, were investigated. Both were ineffective at preventing MDA-MB-231T metastasis, with no attenuation of fibrosis. In summary, metastasis-induced fibrosis is only a minor component of metastasis in untreated progressive breast cancer. LPAR1 antagonists, despite in vitro evidence of specificity and efficacy, were ineffective in vivo as oral agents, as were approved IPF drugs. The data argue against LPAR1 and fibrosis as monotherapy targets for metastasis prevention in triple-negative breast cancer and ovarian cancer.