Glycosaminoglycan-based inhibitors for treatment of prostate cancer

Summary

Principal Investigator: Vinata Lokeshwar
Abstract: 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.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. doi Hyaluronic acid synthase-1 expression regulates bladder cancer growth, invasion, and angiogenesis through CD44
    Roozbeh Golshani
    Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA
    Cancer Res 68:483-91. 2008
  2. pmc Hyalurondiase: both a tumor promoter and suppressor
    Vinata B Lokeshwar
    Department of Urology, University of Miami, Miller School of Medicine, Miami, FL 33101, USA
    Semin Cancer Biol 18:281-7. 2008
  3. pmc Hyaluronan and hyaluronidase in genitourinary tumors
    Melanie A Simpson
    Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA
    Front Biosci 13:5664-80. 2008
  4. pmc Osteopontin and interleukin-8 expression is independently associated with prostate cancer recurrence
    Daniel J Caruso
    Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
    Clin Cancer Res 14:4111-8. 2008
  5. pmc Epigenetic regulation of HYAL-1 hyaluronidase expression. identification of HYAL-1 promoter
    Vinata B Lokeshwar
    Department of Urology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA
    J Biol Chem 283:29215-27. 2008
  6. pmc Hyaluronic acid and HYAL-1 in prostate biopsy specimens: predictors of biochemical recurrence
    Christopher S Gomez
    Department of Urology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA
    J Urol 182:1350-6. 2009
  7. pmc Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells
    Vinata B Lokeshwar
    Division of Urology Research, Department of Urology M 800, University of Miami Miller School of Medicine, P O Box 016960, Miami, FL 33101, USA
    Cancer Res 70:2613-23. 2010
  8. pmc Association of hyaluronic acid family members (HAS1, HAS2, and HYAL-1) with bladder cancer diagnosis and prognosis
    Mario W Kramer
    Department of Urology, Hannover Medical School MHH, Hannover, Germany
    Cancer 117:1197-209. 2011
  9. pmc Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells
    Anaid Benitez
    Department of Urology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA
    Cancer Res 71:4085-95. 2011

Scientific Experts

  • Vinata Lokeshwar
  • Roozbeh Golshani
  • Mario W Kramer
  • Anaid Benitez
  • Christopher S Gomez
  • Mark S Soloway
  • Daniel J Caruso
  • Melanie A Simpson
  • Obi O Ekwenna
  • Travis J Yates
  • Kristell Acosta
  • Soum D Lokeshwar
  • Mark Soloway
  • Ashraf Bakkar
  • Luis E Lopez
  • Diogo O Escudero
  • Wolfgang H Cerwinka
  • Axel S Merseburger
  • Pablo Gomez
  • Merce Jorda
  • Judith Knapp
  • Adrienne J K Carmack
  • Mario Kramer
  • Luis Lopez
  • Bal L Lokeshwar
  • Naoko Iida
  • Veronica Estrella
  • Robert C Duncan

Detail Information

Publications9

  1. doi Hyaluronic acid synthase-1 expression regulates bladder cancer growth, invasion, and angiogenesis through CD44
    Roozbeh Golshani
    Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA
    Cancer Res 68:483-91. 2008
    ..These results show that HAS1 regulates bladder cancer growth and progression by modulating HA synthesis and HA receptor levels...
  2. pmc Hyalurondiase: both a tumor promoter and suppressor
    Vinata B Lokeshwar
    Department of Urology, University of Miami, Miller School of Medicine, Miami, FL 33101, USA
    Semin Cancer Biol 18:281-7. 2008
    ..In this part of the review, we will focus on the recent advances in our understanding of the role of HAases in cancer...
  3. pmc Hyaluronan and hyaluronidase in genitourinary tumors
    Melanie A Simpson
    Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA
    Front Biosci 13:5664-80. 2008
    ..Importantly, the major tumor-derived HAase enzyme, HYAL-1, either alone or together with HA, is an accurate diagnostic and prognostic marker for genitourinary tumors...
  4. pmc Osteopontin and interleukin-8 expression is independently associated with prostate cancer recurrence
    Daniel J Caruso
    Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
    Clin Cancer Res 14:4111-8. 2008
    ..The two inflammatory chemokines, osteopontin and interleukin-8 (IL-8), are associated with tumor angiogenesis and metastasis. We investigated whether osteopontin and IL-8 expression in prostate cancer correlates with disease progression...
  5. pmc Epigenetic regulation of HYAL-1 hyaluronidase expression. identification of HYAL-1 promoter
    Vinata B Lokeshwar
    Department of Urology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA
    J Biol Chem 283:29215-27. 2008
    ..Thus, HYAL-1 expression is epigenetically regulated by the binding of different transcription factors to the methylated and unmethylated HYAL-1 promoter...
  6. pmc Hyaluronic acid and HYAL-1 in prostate biopsy specimens: predictors of biochemical recurrence
    Christopher S Gomez
    Department of Urology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA
    J Urol 182:1350-6. 2009
    ..We examined whether hyaluronic acid and HYAL-1 staining in biopsy specimens predicts biochemical recurrence and correlates with staining in matched prostatectomy specimens...
  7. pmc Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells
    Vinata B Lokeshwar
    Division of Urology Research, Department of Urology M 800, University of Miami Miller School of Medicine, P O Box 016960, Miami, FL 33101, USA
    Cancer Res 70:2613-23. 2010
    ..Therefore, the anticancer effects of 4-MU, an orally bioavailable and relatively nontoxic agent, are primarily mediated by inhibition of HA signaling...
  8. pmc Association of hyaluronic acid family members (HAS1, HAS2, and HYAL-1) with bladder cancer diagnosis and prognosis
    Mario W Kramer
    Department of Urology, Hannover Medical School MHH, Hannover, Germany
    Cancer 117:1197-209. 2011
    ..However, the diagnostic and prognostic potential of these 7 HA family members has not been compared simultaneously in any cancer. We evaluated the diagnostic and prognostic potential of HA family members in BCa...
  9. pmc Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells
    Anaid Benitez
    Department of Urology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA
    Cancer Res 71:4085-95. 2011
    ..Taken together, our findings offer mechanistic insights into the tumor-associated HA-HAase system and a preclinical proof-of-concept of the safety and efficacy of sHA to control prostate cancer growth and progression...