interesting study on EPA and breast cancer in 2018, published in oncogene...never followed up with clinical studies
Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux
Angie M. Torres-Adorno,1,2 Heidi Vitrac,3 Yuan Qi,4 Lin Tan,5 Kandice R. Levental,6 Yang-Yi Fan,7 Peiying Yang,5 Robert S. Chapkin,7 Bedrich L. Eckhardt,2,* and Naoto T. Ueno2,*
The publisher's final edited version of this article is available at Oncogene
Abstract
Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, currently lacks effective targeted therapy options. Eicosapentaenoic acid (EPA), an omega-3 fatty acid and constituent of fish oil, is a common supplement with anti-inflammatory properties. Although it is not a mainstream treatment, several preclinical studies have demonstrated that EPA exerts anti-tumor activity in breast cancer. However, against solid tumors, EPA as a monotherapy is clinically ineffective; thus, we sought to develop a novel targeted drug combination to bolster its therapeutic action against TNBC. Using a high-throughput functional siRNA screen, we identified Ephrin type-A receptor 2 (EPHA2), an oncogenic cell-surface receptor tyrosine kinase, as a therapeutic target that sensitizes TNBC cells to EPA. EPHA2 expression was uniquely elevated in TNBC cell lines and patient tumors. In independent functional expression studies in TNBC models, EPHA2 gene-silencing combined with EPA significantly reduced cell growth and enhanced apoptosis compared with monotherapies, both in vitro and in vivo. EPHA2 specific inhibitors similarly enhanced the therapeutic action of EPA. Finally, we identified that therapy-mediated apoptosis was attributed to a lethal increase in cancer cell membrane polarity due to ABCA1 inhibition and subsequent dysregulation of cholesterol homeostasis. This study provides new molecular and pre-clinical evidence to support a clinical evaluation of EPA combined with EPHA2 inhibition in patients with TNBC.
Triple-negative breast cancer (TNBC) is an aggressive disease that comprises 10–20% of all breast cancers. It is a heterogeneous disease that is often characterized by its strong metastatic potential and poor prognosis compared to estrogen receptor (ER)/progesterone receptor (PgR)-positive and HER2-positive breast cancers 1. While conventional chemotherapy is effective in the short term, TNBC often becomes refractory, and the lack of targeted therapy hampers a clinical solution for this disease 2.
Inflammation, a biological process designed to fight infections and heal wounds, can inadvertently support tumor formation and growth by supplying bioactive molecules that facilitate tumor progression and metastasis 3. Pathological assessment of TNBC has identified increased expression of molecular mediators of inflammation, such as prostaglandin G/H synthase 2 (COX2), and prostaglandin E2 (PGE2), representing potential therapeutic targets 4. Recent finding by our laboratory have observed that inhibition of inflammatory pathways through administration of celecoxib (a COX2 inhibitor) 5, or as observed by other using Lovaza (a highly purified, prescription-strength form of the omega-3 acid ethyl esters [O3AEE]: docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA) 6, can impair the growth of TNBC cells in vitro. Supporting our results, omega-3 fatty acid supplementation has been shown to reduce the growth of rat sarcoma tumors and DMBA-induced mammary tumors in vivo 7–9. Collectively, these studies suggest that the anti-inflammatory action of O3AEE have therapeutic potential. However, the translation of these compounds has been hindered by: 1) inconsistencies in sources, routes of administration and O3AEE composition 9, 2) absence of an established biomarker for therapeutic action, and 3) no definitive subpopulation of breast cancer patients that would benefit from therapy. As a result, there is a critical and unmet need to develop a rational, targeted-approach for the clinical testing of O3AEE in TNBC.
Towards greater clarity regarding the use of O3AEE as a therapeutic, we sought to investigate the anti-tumor effect of highly purified EPA (Vascepa, icosapent ethyl; Amarin Pharma Inc), which was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of hypertriglyceridemia 10. We demonstrate that EPA has potent tumor suppressive activity in preclinical models of TNBC. However, with no established therapeutic role for EPA in the TNBC patient population, translation of an EPA-based therapy through combination with conventional cancer therapy requires justification.
The main goal of this study was to identify a molecular target that could be targeted in combination with EPA for the effective clinical treatment of TNBC. To this end, we detail a functional genomics-based screen that identified the receptor tyrosine kinase EPHA2 as a therapeutically druggable target that enhances EPA-based therapy in TNBC, and present relevant preclinical studies that ESTABLISH THE RATIONAL FOR A PHASE 1 CLINICAL TRIAL the rationale for patients with TNBC....(however, phase 1 testing has never been done, to my knowledge)
Results
EPA inhibits the growth of TNBC tumor xenografts
While O3AEE demonstrate anti-tumor effects 8, EPA as a monotherapy in TNBC has not yet been tested. Thus, we initially assessed the anti-tumorigenic potential of EPA in a preclinical xenograft tumor model of TNBC (SUM149PT). EPA therapy was well tolerated at both 0.4 g/kg and 0.8 g/kg doses (equivalent to the human FDA-approved EPA dose; Supplementary Figure S1), with no change in body weight noted (data not shown). EPA levels were readily detectable in the sera obtained from mice undergoing therapy (Figure 1A) and, importantly, were significantly elevated in the cell membrane (phospholipid) fraction of TNBC tumor xenografts (Figure 1B). EPA therapy dose-dependently inhibited the growth of SUM149PT xenografts (Figure 1C), which led to a significant extension in survival (designated as the time required to obtain a 1 500 mm3 tumor) (Figure 1D). These data suggest that EPA is THERAPEUTICALLY ACTIVE active in VIVO and can reduce the growth of aggressive TNBC xenografts.
