The AACR Judah Folkman Fellowship for Angiogenesis Research represents a joint effort to encourage and support a postdoctoral or clinical research fellow to conduct research in the field of tumor angiogenesis and to establish a successful career path in this field. Eligibility is limited to postdoctoral and clinical research fellows who have completed their most recent doctoral degree within the past five years. Proposed research projects can be basic, translational, clinical, or epidemiological in nature, and must substantially advance the field of tumor angiogenesis.
Amelia A. Rand, PhD
University of California, Davis
Regulation of cancer
angiogenesis from the metabolism of epoxy omega-6 fats
Arachidonic acid is an essential omega-6 fatty acid metabolized by three classes of enzymes, cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450s (CYP). The CYP epoxygenase pathway transforms arachidonic acid into epoxyeicosatrienoic acids (EETs), which are anti-inflammatory, analgesic, and anti-hypertensive. However, EETs have also been shown to enhance angiogenesis, tumor growth, and metastasis. EETs undergo further metabolism by soluble epoxide hydrolase (sEH). Inhibition of sEH prolongs the biological effects of EETs by blocking their major route of metabolism, potentiating their angiogenic, procancer activity. Surprisingly, this procancer activity was suppressed in animals co-treated with an sEH and COX inhibitor, suggesting that the angiogenic activity attributed to EETs may be due to downstream metabolites whose production is catalyzed by COX. This research explores a new pathway of arachidonic acid metabolism, where EETs are metabolized by COX to produce hydroxy-EET signaling molecules that are regulators of angiogenesis, tumor growth, and metastasis.
The hydroxy-EETs have been shown to form from purified COX enzymes. In this research, the metabolic contribution of the two COX enzymes to the formation of hydroxy-EETs will be further characterized using in vitro models. Evidence from an in vivo angiogenesis assay that monitors formation of blood vessels in artificial tumors in mice suggests that the hydroxy-EETs are angiogenic, yet it is currently unclear which stage or stages of angiogenisis are affected by the hydroxy-EETs. This research will determine the influence the hydroxy-EETs have on these stages and the mechanisms involved will be elucidated using a human endothelial cell model. Additionally, the role of hydroxy-EETs on lung tumor growth and metastasis will be determined. It is possible that tumor growth can be altered by blocking this COX pathway with therapeutic treatments developed in the laboratory of Prof. Hammock. Through this research, the role that these arachidonic acid metabolites have on cancer angiogenesis will be determined, contributing to the development of innovative therapeutics for the treatment of cancer. This research will enhance understanding regarding omega-6 fatty acids, including the diversity of metabolites that form from them and how these influence human health.
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