Abstract 5392: Synergistic anti-tumor effects of pegylated recombinant human hyaluronidase (PEGPH20) with Gemcitabine in subcutaneous pancreatic cancer xenograft models

Abstract

Abstract Hyaluronan (HA) is a large glycosaminoglycan, and a significant component of stromal extracellular matrix (ECM) in many tissues and malignancies. It's accumulation on cancer cells and the surrounding stroma predicts unfavorable disease outcome, suggesting that HA enhances tumor growth and progression. PEGPH20 is a pegylated recombinant human hyaluronidase that depletes HA substrate from extracellular tumor microenvironment, decreases tumor interstitial fluid pressure (IFP) and water content and increases tumor vascular area. We have previously demonstrated significant anti-tumor effects of PEGPH20 when used as a single agent and in combination with Docetaxel and liposomal Doxorubicin in peritibial PC3 xenograft prostate carcinoma model. Herein, we evaluated PEGPH20 therapeutic potential in combination with Gemcitabine in the HA-high (BxPC-3) and HA-low (AsPC-1, MIAPaCa-2) subcutaneous pancreatic cancer xenograft models. Assessment of HA levels in the culture supernatants of BxPC-3, AsPC-1 and MIAPaCa-2 cell lines produced 9.4, 1.2 and 0.2 µg of HA per 1E6 tumor cells, respectively following 3 days of cell culture incubation. These HA levels correlated with the respective in vivo HA tumor expression and in vitro area of fixed red blood cell exclusion (‘halo’) for each of the three tumor lines. In the BxPC-3 model IV administration of PEGPH20 at 4.5 mg/kg concurrently with Gemcitabine given IP at 30 mg/kg on Days 1, 4, 7, 10 followed by second treatment cycle on Days 22, 25, 28 and 31 resulted in a synergistic antitumor effect with a significantly superior tumor growth inhibition (TGI) compared to Gemcitabine alone. Following completion of the 1st treatment cycle, PEGPH20 + Gemcitabine (4.5 mg/kg + 30 mg/kg) induced 51% TGI, compared to 29% TGI for PEGPH20 (4.5 mg/kg) and 13% TGI for Gemcitabine (30 mg/kg) by Day 21 post-treatment. Initiation of the 2nd treatment cycle with PEGPH20 + Gemcitabine (4.5 mg/kg + 30 mg/kg) at Day 22 resulted in potent and sustained TGI of large size (>1,000 mm3) tumors with tumor volumes remaining relatively unchanged until study termination (Day 36). PEGPH20 activity in the sera of BxPC-3 tumor bearing mice was found to be elevated following treatment with either PEGPH20 alone or PEGPH20 + Gemcitabine; whereas measurements of soluble HA in the same serum samples were below quantification levels. In contrast to the observed PEGPH20 + Gemcitabine induction of synergistic anti-tumor activity in the HA-high BxPC-3 tumor, no significant anti-tumor effects were evident following treatment of HA-low AsPC-1 and MIAPaCa-2 tumors with identical regimens and dosages. We conclude that PEGPH20 could represent an innovative potential treatment approach that may provide improved therapeutic benefit and survival when used with current standard of care treatments for highly HA positive pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5392.