Abstract 2265: Expression of hyaluronan in human cancer tissue: A predictive biomarker for PEGPH20-mediated therapy

Abstract

Abstract Background: Hyaluronan (HA), a ubiquitous, high-molecular-mass polysaccharide in the precellular and extracellular matrix, is frequently elevated in malignancy, and associated with aggressive disease. Interaction of HA and tumor cells may activate receptor tyrosine kinases, enhance drug resistance, and facilitate tumor progression. A pegylated recombinant human PH20 hyaluronidase (PEGPH20) has been developed to systemically target tumors that accumulated with HA. Systemic PEGPH20 administration in mice bearing PC3 tumors induced a decrease in tumor interstitial fluid pressure (IFP), a decrease in tumor water content, and an increase in tumor vascular volume by enzymatically depleting the HA from the extracellular tumor microenvironment and resulted in significant tumor growth inhibition. PEGPH20 therefore represents an innovative potential treatment approach that may provide improved therapeutic outcomes for cancer patients. Methods: The present study investigated the expression of HA in paraffin embedded human tissue from 9 tumor types as well as corresponding normal tissue by immunohistochemical staining of BioMax tissue arrays with biotinylated HA binding protein (HABP) as a probe. Staining intensity was quantified using Aperio Spectrum plus software. The correlation between HA expression and PEGPH20 response has also been explored using established preclinical models. Results: Strong HA expression was found in 87% of pancreatic, 64% of breast, 50% of multiple myeloma, 46% of NSCLC, 39% of gastric, and 22% of prostate cancer tissues, when compared with corresponding normal tissue (p<0.05). BxPc3 (HA high), MIA PaCa-2 (HA low) and AsPC-1 (HAlow) pancreatic tumor xenografts were evaluated for tumor growth inhibition (TGI) after systemic PEGPH20 treatment and TGI's of 25%, 9% and 15% were observed respectively. In addition, 3 prostate cancers, PC3 (HA high), MatLylu (HA high) and Du145 (HA low) were also evaluated in xenografts with significant growth inhibition shown for PC3 (72%) and MatLylu (34%). Systemic PEGPH20 treatment also induced tumor growth inhibition (60%) for 4T1 (HA high) breast cancer. Conclusion: Accumulation of HA compared to normal tissue was commonly observed and most frequent in pancreatic adenocarcinomas (87%). Furthermore, accumulation of HA was shown to predict response to PEGPH20 therapy in xenograft models (R2=0.805, p<0.01). This work provides strong rationale for exploring efficacy of PEGPH20 in clinical trials. 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 2265.