The overall objective of this proposal is to target the tumor-associated hyaluronic acid-hyaluronidase (HA-HAase) system to develop novel therapeutics for prostate cancer (CaP). HA is a glycosaminoglycan that promotes tumor growth and metastasis and HAase is an endoglycosidase that degrades HA into angiogenic fragments. HYAL1 is a tumor-derived HAase, secreted by CaP cells. Combined HA-HYAL1 expression in CaP tissues is an independent prognostic indicator for predicting CaP progression. Blocking HYAL1 expression in CaP cells, by antisense cDNA transfection, decreases tumor growth, invasion and vascularization in xenografts. Sulfated HA (sHA) polymer and small sHA oligosaccharides are potent inhibitors of HYAL1 activity which inhibit CaP cell growth by causing cell-cycle arrest and inhibit the growth of CaP xenografts. These agents decrease activation of focal adhesion kinase and down regulate androgen receptor levels and activity. 4-methyl-umbelliferone (4-MU), used as a dietary supplement for the treatment of liver aliments, inhibits HA synthesis. By blocking pericellular HA formation, 4-MU induces apoptosis in CaP cells by caspase-8 activation and inhibits the growth of CaP xenografts. Both sHA and 4-MU are orally bioavailable, active against both androgen dependent and independent CaP cells and show no histologic or systemic toxicity upon long-term treatment. The main hypothesis to be tested in the proposed project is that, sHA and 4-MU, either alone or in combination, will abrogate CaP growth and its progression. The efficacy of sHA compounds to inhibit cell growth and invasion will be evaluated in vitro. Inhibition of tumor growth, metastasis and angiogenesis will be examined in 3 CaP xenograft models (i.e., orthotopic tumor implant, induced metastasis and intra-osseous growth models). Effect of sHA on HA-HYAL1 mediated intracellular signaling will also be investigated (Aim 1). Effect of 4-MU in controlling CaP cell growth, invasion and motility will be investigated in vitro. Inhibition of tumor growth and metastasis by 4-MU, either alone or in combination with sHA, will be examined in the three CaP xenograft models, as described above. Mechanism of 4-MU induced apoptosis and abrogation of HA- mediated intracellular signaling will also be investigated (Aim 2). Efficacy of sHA and 4-MU, either alone or in combination, as stage-specific treatments for CaP growth and metastasis will be investigated in two transgenic models of CaP (Aim 3). Relevance: This is the first study that proposes to evaluate inhibitors of the HA-HYAL1 system as therapeutic agents for the treatment of CaP. If proven efficacious, sHA compounds and 4-MU will be a novel class of glycosaminoglycan-based target-specific anti-tumor drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA123063-04
Application #
7767001
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
2007-04-01
Project End
2014-02-28
Budget Start
2010-08-04
Budget End
2014-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$260,623
Indirect Cost
Name
University of Miami School of Medicine
Department
Urology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Yates, Travis J; Lopez, Luis E; Lokeshwar, Soum D et al. (2015) Dietary supplement 4-methylumbelliferone: an effective chemopreventive and therapeutic agent for prostate cancer. J Natl Cancer Inst 107:
Lokeshwar, Vinata B; Mirza, Summan; Jordan, Andre (2014) Targeting hyaluronic acid family for cancer chemoprevention and therapy. Adv Cancer Res 123:35-65
Benitez, Anaid; Yates, Travis J; Lopez, Luis E et al. (2011) Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells. Cancer Res 71:4085-95
Kramer, Mario W; Escudero, Diogo O; Lokeshwar, Soum D et al. (2011) Association of hyaluronic acid family members (HAS1, HAS2, and HYAL-1) with bladder cancer diagnosis and prognosis. Cancer 117:1197-209
Lokeshwar, Vinata B; Lopez, Luis E; Munoz, Daniel et al. (2010) Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells. Cancer Res 70:2613-23
Gomez, Christopher S; Gomez, Pablo; Knapp, Judith et al. (2009) Hyaluronic acid and HYAL-1 in prostate biopsy specimens: predictors of biochemical recurrence. J Urol 182:1350-6
Simpson, Melanie A; Lokeshwar, Vinata B (2008) Hyaluronan and hyaluronidase in genitourinary tumors. Front Biosci 13:5664-80
Golshani, Roozbeh; Lopez, Luis; Estrella, Veronica et al. (2008) Hyaluronic acid synthase-1 expression regulates bladder cancer growth, invasion, and angiogenesis through CD44. Cancer Res 68:483-91
Lokeshwar, Vinata B; Gomez, Pablo; Kramer, Mario et al. (2008) Epigenetic regulation of HYAL-1 hyaluronidase expression. identification of HYAL-1 promoter. J Biol Chem 283:29215-27
Caruso, Daniel J; Carmack, Adrienne J K; Lokeshwar, Vinata B et al. (2008) Osteopontin and interleukin-8 expression is independently associated with prostate cancer recurrence. Clin Cancer Res 14:4111-8

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