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

Abstract

BackgroundGroup 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.MethodsMice 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.ResultsGlycerophosphocholine 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.ConclusionsThese 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.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…This inhibitor exhibited in vivo anti-inflammatory effects comparable to the reference drugs methotrexate and Enbrel in a prophylactic and in a therapeutic collagen-induced arthritis model, respectively. More recently, the anti-angiogenic effects of this inhibitor, in a patient-derived triple-negative basal-like breast cancer model was evaluated and significant tumor growth inhibition was observed after 8 days of treatment [22]. Decreased endothelial cell proliferation and fewer immature vessels in treated tumors were shown by histology.…”

A New Generation of Arachidonic Acid Analogues as Potential Neurological Agent Targeting Cytosolic Phospholipase A2

“…Thus as part of our efforts to develop cPLA 2 inhibitors as potential drug candidates for the treatment of neurological disorders, we have synthesized a new series of AA analogues 1 – 2 and evaluated them for their PLA 2 inhibitory activities and ability to cross the BBB. In our inhibitor design, we have focused on the arachidonyl scaffold as earlier studies have shown that this pharmacophore is strongly recognized by cPLA 2 19 – 23 . We herein present the synthesis of AA analogues 1 – 2 and the investigation of these compounds for their (i) inhibition of cPLA 2 , (ii) cytotoxicity, (iii) selectivity and anti-neuroinflammatory properties and (iv) ability to cross the blood-brain barrier; finally computational studies were performed to understand how the compounds bind to cPLA 2 .…”

Review of quantitative multiscale imaging of breast cancer

“…The resolutions listed in this table are for demonstrated breast imaging applications and do not necessarily reflect the capability of the modality in other applications. All modalities have been combined and validated with qualitative histopathology, and many with 2-D quantitative histopathology, so these combinations were not included in the 84 FMT, 85 OCT, 70 μ PET, 86 μ SPECT, 87 MRI, 17 US, radiography, PAT 88 SPC-μCT 100 89,c Advanced μCT has been demonstrated on mastectomy samples, but not non-invasively with patients.…”

“…Preclinical μCT has already been paired with many other imaging modalities for QMIB over a wide range of biomedical applications ( Table 3). Some examples include characterizing the biodynamics of molecular imaging agents, 83,86,87,117,118 the biological effects of therapeutic interventions, 84,[119][120][121][122] rapid ex vivo IMA on resected tumors or tumor morphology analysis, [57][58][59]123,124 and the study of vasculature and angiogenesis. 17,84,120,122,125 There is still much room to expand the preclinical applications of this technology.…”

“…Other small-animal research groups demonstrated multicontrast characterization of cancer, 82 monitoring of therapy response, 94 and visualization of vasculature and angiogenesis. 84,120 A few groups studied MRM of human tissue samples. They found MRM useful for diagnosis and for ex vivo tumor margin assessment.…”