Program Official

Principal Investigator

Vinata B
Lokeshwar
Awardee Organization

Augusta University
United States

Fiscal Year
2019
Activity Code
R01
Project End Date

Dietary Combination For Prevention of Metastatic Renal Cell Carcinoma

More than 1/3rd of renal cell carcinoma (RCC) patients either have or develop metastatic-RCC (mRCC) despite nephrectomy and adjuvant treatments. Survival of mRCC patients at 5-years is < 10%. The major goal of this project is to develop a dietary supplement-based prevention and treatment strategy against mRCC. Nexavar? (SF) is an FDA approved oral angiogenesis inhibitor which improves overall survival by 12- 18%, causes disease stabilization for about 8-weeks and has a high failure rate. Although the cause of SF failure is unknown, its glucuronidation by UDP-Glucuronyltransferase-1A9 (A9) is a plausible one, because glucuronidation inactivates SF. Preliminary results presented in this application show for the first time that when compared to the SF-responders, A9 levels and SF-glucuronidation are significantly higher in tumors from those patients who fail SF treatment. Furthermore, a non-toxic dietary supplement Hymecromone (HC), consumed extensively in Asia and Europe, inhibits SF glucuronidation by downregulating A9 expression. In RCC and endothelial cells, the combination of HC and SF inhibited viability, motility, invasion and capillary formation. By inhibiting novel molecular targets in RCC and stromal cells, including A9, the combination abrogated signaling pathways that drive RCC cell survival, metastasis and angiogenesis. At concentrations less than ten-fold of those used for consumption, HC when combined with SF completely eliminated tumor growth in a SF-resistant RCC model, without toxicity. Tissue and plasma levels of SF and HC were well above the doses needed for the activity of HC+SF. The central hypothesis is that by inhibiting novel targets, HC+SF combination abrogates RCC and endothelial cell functions leading to the prevention and elimination of RCC growth, angiogenesis and metastasis. To test this hypothesis, the molecular basis of HC+SF activity will be examined in RCC and stromal cell co-cultures. Next the bioavailability and toxicity of HC+SF will be evaluated, along with the analysis of the molecular targets of HC and SF, as biomarkers, to predict RCC metastasis and response to SF. Finally, the efficacy of the HC+SF combination, to prevent tumor growth and metastasis, will be examined in spontaneously metastatic-orthotopic RCC models. Impact: This study should lead to an effective strategy for the prevention and control of mRCC that combines HC, a non-toxic dietary supplement, with SF. Evaluation of activity, bioavailability and toxicity in pre-clinical models and prediction of response may advance this dietary combination for clinical application.

Publications

  • Yates TJ, Lopez LE, Lokeshwar SD, Ortiz N, Kallifatidis G, Jordan A, Hoye K, Altman N, Lokeshwar VB. Dietary supplement 4-methylumbelliferone: an effective chemopreventive and therapeutic agent for prostate cancer. Journal of the National Cancer Institute. 2015 Apr 13;107. (7). Print 2015 Jul. PMID: 25868577
  • Benitez A, Yates TJ, Shamaldevi N, Bowen T, Lokeshwar VB. Dietary supplement hymecromone and sorafenib: a novel combination for the control of renal cell carcinoma. The Journal of urology. 2013 Jul;190(1):285-90. Epub 2012 Dec 7. PMID: 23228386
  • Jordan AR, Racine RR, Hennig MJ, Lokeshwar VB. The Role of CD44 in Disease Pathophysiology and Targeted Treatment. Frontiers in immunology. 2015 Apr 21;6:182. doi: 10.3389/fimmu.2015.00182. eCollection 2015. PMID: 25954275
  • Lokeshwar SD, Talukder A, Yates TJ, Hennig MJP, Garcia-Roig M, Lahorewala SS, Mullani NN, Klaassen Z, Kava BR, Manoharan M, Soloway MS, Lokeshwar VB. Molecular Characterization of Renal Cell Carcinoma: A Potential Three-MicroRNA Prognostic Signature. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2018 Apr;27(4):464-472. Epub 2018 Feb 12. PMID: 29440068
  • Morera DS, Hennig MS, Talukder A, Lokeshwar SD, Wang J, Garcia-Roig M, Ortiz N, Yates TJ, Lopez LE, Kallifatidis G, Kramer MW, Jordan AR, Merseburger AS, Manoharan M, Soloway MS, Terris MK, Lokeshwar VB. Hyaluronic acid family in bladder cancer: potential prognostic biomarkers and therapeutic targets. British journal of cancer. 2017 Nov 7;117(10):1507-1517. Epub 2017 Oct 3. PMID: 28972965
  • Wang J, Jordan AR, Zhu H, Hasanali SL, Thomas E, Lokeshwar SD, Morera DS, Alexander S, McDaniels J, Sharma A, Aguilar K, Sarcan S, Zhu T, Soloway MS, Terris MK, Thangaraju M, Lopez LE, Lokeshwar VB. Targeting hyaluronic acid synthase-3 (HAS3) for the treatment of advanced renal cell carcinoma. Cancer cell international. 2022 Dec 29;22(1):421. PMID: 36581895
  • Kallifatidis G, Smith DK, Morera DS, Gao J, Hennig MJ, Hoy JJ, Pearce RF, Dabke IR, Li J, Merseburger AS, Kuczyk MA, Lokeshwar VB, Lokeshwar BL. β-Arrestins Regulate Stem Cell-Like Phenotype and Response to Chemotherapy in Bladder Cancer. Molecular cancer therapeutics. 2019 Apr;18(4):801-811. Epub 2019 Feb 20. PMID: 30787175
  • Garcia-Roig M, Ortiz N, Lokeshwar V. Molecular marker for predicting treatment response in advanced renal cell carcinoma: does the promise fulfill clinical need? Current urology reports. 2014 Jan;15(1):375. PMID: 24337833
  • Morera DS, Hasanali SL, Belew D, Ghosh S, Klaassen Z, Jordan AR, Wang J, Terris MK, Bollag RJ, Merseburger AS, Stenzl A, Soloway MS, Lokeshwar VB. Clinical Parameters Outperform Molecular Subtypes for Predicting Outcome in Bladder Cancer: Results from Multiple Cohorts, Including TCGA. The Journal of urology. 2020 Jan;203(1):62-72. Epub 2019 May 21. PMID: 31112107
  • Jordan AR, Lokeshwar SD, Lopez LE, Hennig M, Chipollini J, Yates T, Hupe MC, Merseburger AS, Shiedlin A, Cerwinka WH, Liu K, Lokeshwar VB. Antitumor activity of sulfated hyaluronic acid fragments in pre-clinical models of bladder cancer. Oncotarget. 2017 Apr 11;8(15):24262-24274. PMID: 27419371
  • Lokeshwar VB, Mirza S, Jordan A. Targeting hyaluronic acid family for cancer chemoprevention and therapy. Advances in cancer research. 2014;123:35-65. PMID: 25081525
  • Gosalbez M, Hupe MC, Lokeshwar SD, Yates TJ, Shields J, Veerapen MK, Merseburger AS, Rosser CJ, Soloway MS, Lokeshwar VB. Differential expression of SDF-1 isoforms in bladder cancer. The Journal of urology. 2014 Jun;191(6):1899-1905. Epub 2013 Nov 26. PMID: 24291546
  • Jordan AR, Wang J, Yates TJ, Hasanali SL, Lokeshwar SD, Morera DS, Shamaladevi N, Li CS, Klaassen Z, Terris MK, Thangaraju M, Singh AB, Soloway MS, Lokeshwar VB. Molecular targeting of renal cell carcinoma by an oral combination. Oncogenesis. 2020 May 19;9(5):52. PMID: 32427869