Renal cell carcinoma (RCC) is the sixth most common cancer in the U.S. afflicting 11,000 patients per year, and is one of the few cancers whose incidence is increasing. In light of the paucity of effective treatments and the frequency of late stage diagnosis, the 5-year survival of patients with metastatic RCC remains dismal. For the one-third of patients who present at the metastatic stage, there are several FDA-approved drugs available, among them the multi-kinase inhibitors and the mTOR inhibitors. Since progression-free survival even with these new drugs is only one to two years due to drug resistance, it is imperative that novel therapeutic approaches for patients with metastatic RCC be identified and validated. Sorafenib was the first FDA- approved targeted therapy for advanced RCC and works principally through its effect on VEGF and thus causes angiogenesis inhibition. Given that the vast majority of RCCs are associated with VHL mutations and are thus highly angiogenic, any means to augment the anti-angiogenic effects of existing drugs would be a major advance in the therapy of RCC. We have previously demonstrated a pronounced inhibitory effect of sorafenib's on the enzyme, soluble epoxide hydrolase (sEH), and our preliminary data show that the combination of sEH inhibitors with docosahexaenoic acid (DHA;a major component of fish oil) has synergistic anti-angiogenic effects in various cancers. For these reasons we hypothesize that sEH inhibition by sorafenib in the presence of fish-oil supplementation stabilizes epoxy docosapentaenoic acid (EDP;a metabolite of DHA) and thereby prevents RCC metastasis through modulation of tumor angiogenesis. In addition, we have evidence that fish-oil supplementation decreases the most prevalent and disabling adverse effect of sorafenib, systemic hypertension. Work in this project will demonstrate for the first time that the simple addition of fish oil to the FDA-approved drug sorafenib has great potential in the prevention and treatment of advanced kidney cancer.
Kidney cancer is the 6th most common cancer which afflicts 11,000 people in the US. Sadly, its incidence is increasing, in stark contrast to many other cancers, for reasons that we don't understand. There are currently very few effective treatments available when kidney cancer has spread throughout the body (occurs in one-third of patients), and all of the available treatments fail within 1-2 years. In this project, we will introduce fish il as a sensitizer of kidney cancer to one of the currently available drugs. Success in this work will lead to a novel combination treatment of sorafenib and fish oil, which is commonly used for a supplement, and will result in the saving of many lives by preventing cancer spread by the simple addition of a natural product to an available drug.
|Abu Aboud, Omran; Habib, Samy L; Trott, Josephine et al. (2017) Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging. Cancer Res 77:6746-6758|
|Hwang, Vicki J; Zhou, Xia; Chen, Xiaonan et al. (2017) Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease. Kidney Int 92:922-933|
|Trott, Josephine F; Kim, Jeffrey; Abu Aboud, Omran et al. (2016) Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer. Oncotarget 7:66540-66557|
|Kim, Jeffrey; Ulu, Arzu; Wan, Debin et al. (2016) Addition of DHA Synergistically Enhances the Efficacy of Regorafenib for Kidney Cancer Therapy. Mol Cancer Ther 15:890-8|
|Abu Aboud, Omran; Chen, Ching-Hsien; Senapedis, William et al. (2016) Dual and Specific Inhibition of NAMPT and PAK4 By KPT-9274 Decreases Kidney Cancer Growth. Mol Cancer Ther 15:2119-29|
|Hu, Susie L; Chang, Anthony; Perazella, Mark A et al. (2016) The Nephrologist's Tumor: Basic Biology and Management of Renal Cell Carcinoma. J Am Soc Nephrol 27:2227-37|
|Wettersten, Hiromi I; Hakimi, A Ari; Morin, Dexter et al. (2015) Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis. Cancer Res 75:2541-52|
|Hwang, Vicki J; Kim, Jeffrey; Rand, Amy et al. (2015) The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate. Am J Physiol Renal Physiol 309:F492-8|