Anti-vascular effects of the cytosolic phospholipase A2 inhibitor AVX235 in a patient-derived basal-like breast cancer model

• Published in: BMC cancer Vol. 16; no. 190; p. 191
• Main Authors: Kim, Eugene, Tunset, Hanna Maja, Cebulla, Jana, Vettukattil, Riyas, Helgesen, Heidi, Feuerherm, Astrid Jullumstrø, Engebråten, Olav, Mælandsmo, Gunhild Mari, Johansen, Berit, Moestue, Siver Andreas
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 07-03-2016; BioMed Central
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic Agents - pharmacology; Breast cancer; Breast Neoplasms - diagnosis; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Care and treatment; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Choline metabolism; Complications and side effects; Cytosolic phospholipase A2; Development and progression; Dinoprostone - metabolism; Disease Models, Animal; Drug dosages; Dynamic contrast enhanced MRI; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Enzymes; Estrogens; Female; Growth factors; Humans; Kinases; Klinisk medisinske fag: 750; Magnetic Resonance Imaging; Medisinske Fag: 700; Metabolites; Mice; Micro-CT; Neoplasms, Basal Cell - drug therapy; Neoplasms, Basal Cell - metabolism; Neoplasms, Basal Cell - pathology; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Nuclear magnetic resonance spectroscopy; Onkologi: 762; Phospholipase A2 Inhibitors - pharmacology; Phospholipases; Phospholipases A2, Cytosolic - metabolism; Prostaglandin E2; Spectrum analysis; Targeted therapy; Triple Negative Breast Neoplasms - diagnosis; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Tumor Burden - drug effects; Tumors; VDP; X-Ray Microtomography; Xenograft Model Antitumor Assays; United States; United States > US
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-016-2225-1

Group IVA cytosolic phospholipase A2 (cPLA2α) plays an important role in tumorigenesis and angiogenesis. It is overexpressed in basal-like breast cancer (BLBC), which is aggressive and usually triple-negative, making it unresponsive to current targeted therapies. Here, we evaluated the anti-angiogenic effects of a specific cPLA2α inhibitor, AVX235, in a patient-derived triple-negative BLBC model.
Mice bearing orthotopic xenografts received i.p. injections of AVX235 or DMSO vehicle daily for 1 week and then every other day for up to 19 days. Six treated and six control mice were terminated after 2 days of treatment, and the tumors excised for high resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) and prostaglandin E2 (PGE2) enzyme immunoassay (EIA) analysis. A 1-week imaging study was performed on a separate cohort of mice. Longitudinal dynamic contrast enhanced (DCE)-MRI was performed before, after 4 days, and after 1 week of treatment. The mice were then perfused with a radiopaque vascular casting agent, and the tumors excised for micro-CT angiography. Subsequently, tumors were sectioned and stained with lectin and for Ki67 or α-smooth muscle actin to quantify endothelial cell proliferation and vessel maturity, respectively. Partial least squares discriminant analysis was performed on the multivariate HR MAS MRS data, and non-parametric univariate analyses using Mann-Whitney U tests (α = 0.05) were performed on all other data.
Glycerophosphocholine and PGE2 levels, measured by HR MAS MRS and EIA, respectively, were lower in treated tumors after 2 days of treatment. These molecular changes are expected downstream effects of cPLA2α inhibition and were followed by significant tumor growth inhibition after 8 days of treatment. DCE-MRI revealed that AVX235 treatment caused a decrease in tumor perfusion. Concordantly, micro-CT angiography showed that vessel volume fraction, density, and caliber were reduced in treated tumors. Moreover, histology showed decreased endothelial cell proliferation and fewer immature vessels in treated tumors.
These results demonstrate that cPLA2α inhibition with AVX235 resulted in decreased vascularization and perfusion and subsequent inhibition of tumor growth. Thus, cPLA2α inhibition may be a potential new therapeutic option for triple-negative basal-like breast cancer.