Advertisement

Targeting the Tumor Stroma: the Biology and Clinical Development of Pegylated Recombinant Human Hyaluronidase (PEGPH20)

  • Kit Man Wong
  • Kathryn J. Horton
  • Andrew L. Coveler
  • Sunil R. Hingorani
  • William P. Harris
Evolving Therapies (R Bukowski, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Evolving Therapies

Abstract

The tumor stroma is increasingly recognized as a key player in tumorigenesis through its effects on cell signaling, immune responses, and access of therapeutic agents. A major component of the extracellular matrix is hyaluronic acid (HA), which raises the interstitial gel fluid pressure within tumors and reduces drug delivery to malignant cells, and has been most extensively studied in pancreatic ductal adenocarcinoma (PDA). Pegylated recombinant human hyaluronidase (PEGPH20) is a novel agent that degrades HA and normalizes IFP to enhance the delivery of cytotoxic agents. It has demonstrated promising preclinical results and early clinical evidence of efficacy in the first-line treatment of metastatic PDA with acceptable tolerability. Moreover, intratumoral HA content appears to be a predictive biomarker of response. Phase 2 and 3 trials of PEGPH20 plus chemotherapy are ongoing in metastatic PDA, and it is also being evaluated in other malignancies and in combination with radiation and immunotherapy.

Keywords

Pegylated recombinant human hyaluronidase PEGPH20 Hyaluronic acid Hyaluronan Glycosaminoglycan Pancreatic ductal adenocarcinoma Interstitial fluid pressure Stromal resistance Tumor stroma Tumor microenvironment Extracellular matrix Diffusion Convection Tumor perfusion Gemcitabine Nab-paclitaxel Immunotherapy Thromboembolic events KPC mice CD44 RHAMM 

Notes

Compliance with Ethical Standards

Conflict of Interest

Kit Man Wong declares that she has no conflict of interest.

Kathryn J. Horton declares that she has no conflict of interest.

Andrew L. Coveler has received institutional funding for the conduct of clinical trials from Halozyme, and has received compensation from Halozyme for serving on an advisory board.

Sunil R. Hingorani has received institutional funding for the conduct of clinical trials from Halozyme, and has received compensation from Halozyme for serving on an advisory board and as a consultant.

William P. Harris has received institutional funding for the conduct of clinical trials from Halozyme, and has received travel support from Halozyme for a scientific presentation at the ESMO annual conference.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Pitt JM, Marabelle A, Eggermont A, Soria JC, Kroemer G, Zitvogel L. Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. Ann Oncol. 2016;27:1482–92.CrossRefPubMedGoogle Scholar
  3. 3.
    Provenzano PP, Hingorani SR. Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br J Cancer. 2013;108:1–8.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    • Thompson CB, Shepard HM, O’Connor PM, et al. Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models. Mol Cancer Ther. 2010;9:3052–64. This was the first preclincal evaluation of PEGPH20. It demonstrated that PEGPH20 effectively decreased tumor HA, reduced IFP, increased tumor vasculature, and inhibited tumor growth in a xenograft prostate-cancer model. Google Scholar
  5. 5.
    • Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:418–29. This study demonstrated the role of HA in the resistance of PDAs and provided convincing preclinical evidence for PEGPH20 in an autochthonous murine PDA model. Importantly, a randomized placebo-controlled trial of gemcitabine in combination with PEGPH20 vs. placebo in the PDA murine model showed superior overall survival with the addition of PEGPH20. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Jiang P, Li X, Thompson CB, et al. Effective targeting of the tumor microenvironment for cancer therapy. Anticancer Res. 2012;32:1203–12.PubMedGoogle Scholar
  7. 7.
    Whatcott CJ, Diep CH, Jiang P, et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res. 2015;21:3561–8.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    •• Hingorani SR, Harris WP, Beck JT, et al. Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin Cancer Res. 2016;22:2848–54. This Phase 1b study established the safety, tolerability and maximal tolerated dose of PEGPH20 with gemcitabine in PDA patients. This study demonstrated a sigificant objective response rate with PEGPH20. CrossRefPubMedGoogle Scholar
  9. 9.
    Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004;4:528–39.CrossRefPubMedGoogle Scholar
  10. 10.
    Jacobetz MA, Chan DS, Neesse A, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62:112–20.CrossRefPubMedGoogle Scholar
  11. 11.
    Sironen RK, Tammi M, Tammi R, Auvinen PK, Anttila M, Kosma VM. Hyaluronan in human malignancies. Exp Cell Res. 2011;317:383–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Kultti A, Li X, Jiang P, Thompson CB, Frost GI, Shepard HM. Therapeutic targeting of hyaluronan in the tumor stroma. Cancers (Basel). 2012;4:873–903.CrossRefGoogle Scholar
  13. 13.
    Setala LP, Tammi MI, Tammi RH, et al. Hyaluronan expression in gastric cancer cells is associated with local and nodal spread and reduced survival rate. Br J Cancer. 1999;79:1133–8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Whatcott CJ, Jiang P, Watanabe A. Hyaluronan deposition correlates with poor survival in pancreatic cancer. Cancer Res. 2011;71:abstr LB-307.CrossRefGoogle Scholar
  15. 15.
    Mahadevan D, Von Hoff DD. Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2007;6:1186–97.CrossRefPubMedGoogle Scholar
  16. 16.
    Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007;67:9518–27.CrossRefPubMedGoogle Scholar
  17. 17.
    Aukland K, Reed RK. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev. 1993;73:1–78.PubMedGoogle Scholar
  18. 18.
    Sherwood L. Human physiology from cells to systems. Third ed. Florence: Wadsworth Publishing Company; 1997.Google Scholar
  19. 19.
    De Smedt SC, Lauwers A, Demeester J, Engelborghs Y, De Mey G, Du M. Structural information on hyaluronic acid solutions as studied by probe diffusion experiments. Macromolecules. 1994;27:141–6.CrossRefGoogle Scholar
  20. 20.
    Bian L, Guvendiren M, Mauck RL, Burdick JA. Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis. Proc Natl Acad Sci U S A. 2013;110:10117–22.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Blundell CD, Seyfried NT, Day AJ. Chapter 8: structural and functional diversity of hyaluronan-binding proteins. In: Garg HG, Hales CA, editors. Chemistry and biology of hyaluronan. Elsevier: Oxford; 2004.Google Scholar
  22. 22.
    Garg HG, Hales CA. Chapter 6: the role of hyaluronan receptor RHAMM in wound repair and tumorigenesis. Garg HG, Hales CA, eds. Elsevier: In; 2004.Google Scholar
  23. 23.
    Ingber DE. Mechanical control of tissue morphogenesis during embryological development. Int J Dev Biol. 2006;50:255–66.CrossRefPubMedGoogle Scholar
  24. 24.
    Orian-Rousseau V. CD44, a therapeutic target for metastasising tumours. Eur J Cancer. 2010;46:1271–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Hofmann M, Rudy W, Gunthert U, et al. A link between ras and metastatic behavior of tumor cells: ras induces CD44 promoter activity and leads to low-level expression of metastasis-specific variants of CD44 in CREF cells. Cancer Res. 1993;53:1516–21.PubMedGoogle Scholar
  26. 26.
    Bourguignon LY, Singleton PA, Zhu H, Diedrich F. Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. J Biol Chem. 2003;278:29420–34.CrossRefPubMedGoogle Scholar
  27. 27.
    Cheng XB, Sato N, Kohi S, Koga A, Hirata K. Receptor for hyaluronic acid-mediated motility is associated with poor survival in pancreatic ductal adenocarcinoma. J Cancer. 2015;6:1093–8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hingorani SR, Wang L, Multani AS, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7:469–83.CrossRefPubMedGoogle Scholar
  29. 29.
    Borad MJ, Ramanathan RK, Bessudo A. Targeting hyaluronan (HA) in tumor stroma: a phase I study to evaluate the safety, pharmacokinetics (PK), andpharmacodynamics (PD) of pegylated hyaluronidase (PEGPH20) in patients with solid tumors. J Clin Oncol. 2012;30(suppl):abstr 2579.Google Scholar
  30. 30.
    Pelzer U, Opitz B, Deutschinoff G, et al. Efficacy of prophylactic low-molecular weight heparin for ambulatory patients with advanced pancreatic cancer: outcomes from the CONKO-004 trial. J Clin Oncol. 2015;33:2028–34.CrossRefPubMedGoogle Scholar
  31. 31.
    Habib M, Saif MW. Thromboembolism and anticoagulation in pancreatic cancer. Jop. 2013;14:135–7.PubMedGoogle Scholar
  32. 32.
    • Hingorani S, Harris W, Seery T, et al. Interim results of a randomized phase II study of PEGPH20 added to nab-paclitaxel/gemcitabine in patients with stage IV previously untreated pancreatic cancer. 2016 Gastrointestinal cancers symposium. This abstract presented the interim analysis of the Phase 2 trial of PEGPH20 with gemcitabine and nab-paclitaxel in the first-line treatment of metastatic PDA. The preliminary results showed improved signfiicantly increased progression-free survival and objective response rate in the experimental arm in patients with HA-high tumors. Google Scholar
  33. 33.
    Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Bullock AJ, Hingorani SR, Wu XW. Final analysis of stage 1 data from a randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients (pts), utilizing Ventana companion diagnostic assay. J Clin Oncol. 2016;34(suppl):abstr 4104.Google Scholar
  35. 35.
    Hingorani SR, Harris WP, Beck JT. Exploratory biomarker results from early investigation of PEGPH20 in combination with gemcitabine (Gem) in patients with pancreatic cancer (PDA). J Clin Oncol. 2015;33(suppl 3):abstr 300.CrossRefGoogle Scholar
  36. 36.
    Maneval DC, Ramanathan RK, Infante JR. Abstract 2672: phase 1 pharmacokinetics (PK) & pharmacodynamics (PD) of PEGylated hyaluronidase PH20 (PEGPH20) in patients with solid tumors. Cancer Res. 2012;72(8 suppl):abstr 2672.CrossRefGoogle Scholar
  37. 37.
    Singha NC, Nekoroski T, Zhao C, et al. Tumor-associated hyaluronan limits efficacy of monoclonal antibody therapy. Mol Cancer Ther. 2015;14:523–32.CrossRefPubMedGoogle Scholar
  38. 38.
    Bollyky PL, Wu RP, Falk BA, et al. ECM components guide IL-10 producing regulatory T-cell (TR1) induction from effector memory T-cell precursors. Proc Natl Acad Sci U S A. 2011;108:7938–43.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Padrnos LJ, Marella M, Kosiorek H. Assessment of hyaluronic acid in tumor microenvironment (TME) of intrahepatic cholangiocarcinoma (CCA). J Clin Oncol. 2016;34(suppl 4S):abstr 248.CrossRefGoogle Scholar
  40. 40.
    Tredan O, Galmarini CM, Patel K, Tannock IF. Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst. 2007;99:1441–54.CrossRefPubMedGoogle Scholar
  41. 41.
    DuFort CC, DelGiorno KE, Hingorani SR. Mounting pressure in the microenvironment: fluids, solids, and cells in pancreatic ductal adenocarcinoma. Gastroenterology. 2016;150:1545–57. e2 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Matrosova VY, Orlovskaya IA, Serobyan N, Khaldoyanidi SK. Hyaluronic acid facilitates the recovery of hematopoiesis following 5-fluorouracil administration. Stem Cells. 2004;22:544–55.CrossRefPubMedGoogle Scholar
  43. 43.
    Khaldoyanidi S, Moll J, Karakhanova S, Herrlich P, Ponta H. Hyaluronate-enhanced hematopoiesis: two different receptors trigger the release of interleukin-1beta and interleukin-6 from bone marrow macrophages. Blood. 1999;94:940–9.PubMedGoogle Scholar
  44. 44.
    Lyman GH, Eckert L, Wang Y, Wang H, Cohen A. Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis. Oncologist. 2013;18:1321–9.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Verheye S, Markou CP, Salame MY, et al. Reduced thrombus formation by hyaluronic acid coating of endovascular devices. Arterioscler Thromb Vasc Biol. 2000;20:1168–72.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Kit Man Wong
    • 1
    • 2
  • Kathryn J. Horton
    • 3
  • Andrew L. Coveler
    • 1
    • 2
  • Sunil R. Hingorani
    • 1
    • 2
    • 4
  • William P. Harris
    • 1
    • 2
  1. 1.Division of Medical Oncology, Department of MedicineUniversity of Washington School of MedicineSeattleUSA
  2. 2.Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  3. 3.Department of MedicineUniversity of Washington Medical CenterSeattleUSA
  4. 4.Public Health Sciences DivisionFred Hutchinson Cancer Research CenterSeattleUSA

Personalised recommendations