Enzymatic Depletion of Tumor Hyaluronan Induces Antitumor Responses in Preclinical Animal Models

Abstract

Hyaluronan (HA) is a glycosaminoglycan polymer that often accumulates in malignancy. Megadalton complexes of HA with proteoglycans create a hydrated connective tissue matrix, which may play an important role in tumor stroma formation. Through its colloid osmotic effects, HA complexes contribute to tumor interstitial fluid pressure, limiting the effect of therapeutic molecules on malignant cells. The therapeutic potential of enzymatic remodeling of the tumor microenvironment through HA depletion was initially investigated using a recombinant human HA-degrading enzyme, rHuPH20, which removed HA-dependent tumor cell extracellular matrices in vitro. However, rHuPH20 showed a short serum half-life (t 1/2 < 3 minutes), making depletion of tumor HA in vivo impractical. A pegylated variant of rHuPH20, PEGPH20, was therefore evaluated. Pegylation improved serum half-life (t 1/2 = 10.3 hours), making it feasible to probe the effects of sustained HA depletion on tumor physiology. In high-HA prostate PC3 tumors, i.v. administration of PEGPH20 depleted tumor HA, decreased tumor interstitial fluid pressure by 84%, decreased water content by 7%, decompressed tumor vessels, and increased tumor vascular area >3-fold. Following repeat PEGPH20 administration, tumor growth was significantly inhibited (tumor growth inhibition, 70%). Furthermore, PEGPH20 enhanced both docetaxel and liposomal doxorubicin activity in PC3 tumors (P < 0.05) but did not significantly improve the activity of docetaxel in low-HA prostate DU145 tumors. The ability of PEGPH20 to enhance chemotherapy efficacy is likely due to increased drug perfusion combined with other tumor structural changes. These results support enzymatic remodeling of the tumor stroma with PEGPH20 to treat tumors characterized by the accumulation of HA. Mol Cancer Ther; 9(11); 3052-64. ©2010 AACR.

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

“…S6) despite the fact that both muscle and heart have substantial HA content (36). Taken together, these data show that HA depletion by PEGPH20 increased trastuzumab and NK cell accessibility to HA high xenograft tumors in the SKOV3/HAS2 tumor model, probably as a result of tumor vasculature decompression (3,(8)(9)(10)(11).…”

“…Accumulation of HA in tumors is associated with malignancy and predictive of more aggressive disease (1)(2)(3)(4)(5). Elevation of HA levels in tumors, sometimes in combination with collagen, results in blood vessel compression, increased interstitial fluid pressure (IFP), and decreased perfusion (7,8). HA depletion from solid tumors with a tumor microenvironment (TME) containing high levels of HA (HA high ) reverses these physiologic effects, resulting in reperfusion of the tumor vasculature, increased chemotherapeutic drug accumulation, and tumor growth inhibition (TGI) in preclinical animal models (8)(9)(10)(11).…”

Hyaluronan Synthase 1 (HAS1) Requires Higher Cellular UDP-GlcNAc Concentration than HAS2 and HAS3*

“…The increased glucose metabolism may, through increased UDP-GlcNAc content, contribute to the hyaluronan deposits found in most cancers (50). Excessive hyaluronan promotes cancer growth and is one of the novel targets of therapy (51). In summary, it is highly likely that many pathological reactions are eventually initiated or supported by an enhanced UDP-GlcNAc supply derived from glucose.…”

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

“…The combination of Sonic Hedgehog (SHH) inhibition by the semisynthetic cyclopamine derivative IPI-926 and gemcitabine resulted in stromal depletion, significantly increased microvessel density and patency, and improved drug delivery in a GEMM of pancreas cancer (12). In addition, megadalton glycosaminoglycan hyaluronan (HA) is profusely found in the ECM of murine and human PDA and maintains a high interstitial fluid pressure, thus compressing blood vessels (13)(14)(15). We and others have recently provided evidence that enzymatic degradation of HA by PEGPH20 significantly increased vessel patency and perfusion without increasing the density of tumor vessels, resulting in increased active gemcitabine levels in the tumor (15,16).…”