Lipid Metabolic Enzyme

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Background and Description of Technology: Therapy options for breast cancer patients are generally determined by certain tumor markers. Breast cancers expressing estrogen receptors (ERs) are highly likely to respond to hormonal-based therapies. Conversely, absence of not only ERs, but also progesterone receptors (PRs), often indicates estrogen insensitivity. Similarly, expression of HER2/neu receptor renders tumors responsive to treatments targeting HER2/neu. Consequently, patients negative for ERs, PRs, and HER2, (“Triple Negative”), are categorized with aggressive and harder to treat breast cancer. However, Triple Negative diagnosis is not fully predictive of therapeutic response with findings pointing toward a subset of tumors utilizing androgen receptors (ARs) in place of ERs and a new category designated “Quadruple Negative” (ER-, PR-, HER2-, AR-). As conventional Triple Negative diagnosis is not fully predictive of therapeutic response, new strategies are needed to improve diagnosis and therapy selection. Dr. Monaco has found that the lipid metabolic enzyme acyl-CoA synthetase 4 (ACSL4) negatively correlates with ER, PR, HER2, and AR status in human breast tumor samples and cell lines. 87% of 73 breast cancer cell lines expressing one or more receptor are negative for ACSL4, with increasing negative correlation to ACSL4 when receptors were grouped as Double, Triple or Quadruple Negative cell lines. Meta-analyses of public mRNA expression data comparing ACSL4 expression in Triple Negative tumors to biomarker positive samples yielded similar results. Notably, Dr. Monaco has shown that ACSL4 positivity alone may indicate estrogen and androgen insensitivity even in presence of those respective receptors. Furthermore, data suggests that expression of ACSL4 in human breast cancers has not only prognostic, but therapeutic value. Beyond a target for chemotherapy, depletion of ACSL4 reduced growth, metastases and invasion of ACSL4-expressing tumor cells in a Triple- or Quadruple-Negative manner.   Applications: Measurement of ACSL4 as another prognosis indicator can strengthen the predictive value of traditional ER, PR, and HER2 assays, such as confirmation of triple negative status (i.e. ACSL4+) or non-triple negative status (i.e. ACSL4-). An ACSL4 biomarker can also be used in decision-making preventing effective therapies from being ruled out. Triple negative/ACSL4- status may identify patients responsive to hormonal-based therapies. Conversely, ACSL4+ status may identify patients who may be [ER-, PR-, HER2+] or [ER+, PR+, HER2-] and unresponsive to standard regimens of receptor- or hormonal-based therapies respectively. Elevated ACSL4 expression in colon adenocarcinoma and hepatocellular carcinoma offer biomarker utilities for other cancers.