Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (mAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA (HA(high)) in the TME restricts antibody and immune cell access to tumors, suggesting a novel mechanism of in vivo resistance to mAb therapy. We determined that approximately 60% of HER2(3+) primary breast tumors and approximately 40% of EGFR(+) head and neck squamous cell carcinomas are HA(high), and hypothesized that HA(high) tumors may be refractory to mAb therapy. We found that the pericellular matrix produced by HA(high) tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Depletion of HA by PEGPH20, a pegylated recombinant human PH20 hyaluronidase, resulted in increased NK cell access to HA(high) tumor cells, and greatly enhanced trastuzumab- or cetuximab-dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HA(high) tumors, resulting in enhanced trastuzumab- and NK cell-mediated tumor growth inhibition in vivo. These results suggest that HA(high) matrix in vivo may form a barrier inhibiting access of both mAb and NK cells, and that PEGPH20 treatment in combination with anticancer mAbs may be an effective adjunctive therapy for HA(high) tumors.
Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic β -catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and β -catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth.
Abstract The tumor microenvironment is crucial for cancer cell survival and spreading. The glycosaminoglycan hyaluronan (HA) is accumulated in 50% of malignant breast cancer tumors and its accumulation correlates with poor survival of breast cancer patients. HA is synthesized at the cell surface by HA synthase enzymes (HAS1-3) and is extruded to the extracellular space where HA molecules can be attached to the cell surface via interactions with its receptors or HAS proteins. HA can also interact with its binding proteins and be incorporated into surrounding ECM. However, the origin and exact functions of HA in breast cancer are still unclear. The aim of this study was to explore the role of HA in the tumor microenvironment of breast cancer, especially in the interaction of tumor and stromal cells in vitro and in vivo. First, interaction of breast cancer cells and stromal cells were studied in mono- and co-cultures. Human bone marrow-derived mesenchymal stem cells (MSCs) and breast cancer-associated fibroblasts (CAFs) synthesized high amounts of HA, while this was the case for <5% MDA-MB-468 breast cancer cells. In co-culture with MSCs or CAFSs, MDA-MB-468 and MDA-MB-231 cells formed distinct pericellular HA coats. Similar HA coats were observed after addition of exogenous FITC-labeled high molecular weight HA (1,2 MDa) to MDA-MB-468 and MDA-MB-231 cell cultures. Interestingly, binding of FITC-labeled HA was not efficiently blocked by unlabeled HA below 500 kDa. In co-cultures, the high molecular weight HA coats around MDA-MB-468 and MDA-MB-231 cells were prevented by antibody blockade of the HA receptor CD44, indicating that formation of HA coats is CD44-mediated. Knockdown of CD44 by shRNA also inhibited the formation of HA coats when FITC-HA was added to the cultures or when breast cancer cells were co-cultured with MSCs. MSCs also increased proliferation and migration of MDA-MB-468 (parental/Luc) cells, analyzed by luciferin and Transwell migration assays, respectively. MDA-MB-468 cell proliferation was slightly inhibited by removal of HA with pegylated human recombinant hyaluronidase PH20 (PEGPH20), and migration towards exogenous HA could be inhibited by CD44 knockdown. Importance of HA coats around breast cancer cells was also studied in vivo using MDA-MB-468 cells over-expressing HAS3 which forms 4.7-fold larger HA coats than parental MDA-MB-468 cells. MDA-MB-468 HAS3 cells exhibited much enhanced in vivo growth compared to MDA-MB-468 cells, and tumor growth of MDA-MB-468 HAS3 xenografts was inhibited up to 85% by PEGPH20. The results suggest that HA in tumor microenvironment, produced by tumor or stromal cells, provides growth benefit for breast cancer cells via promoting their proliferation and migration. Both phenomena seem to be mediated by CD44, which highlights the importance of HA-CD44 interaction in the growth of breast cancer. Citation Format: Anne Kultti, Susan Zimmerman, Lei Huang, Yanling Chen, Jessica Cowell, Rebecca C. Symons, Laurence Jadin, Ping Jiang, Gregory I. Frost, Michael Shepard, John Huang. The role of hyaluronan-CD44 interaction in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 511. doi:10.1158/1538-7445.AM2013-511
Abstract Tumor hypoxia, the pathophysiological result of the structural and functional disruption of the tumor microcirculation and the deterioration of normal diffusion geometry, is strongly associated with tumor proliferation and resistance to therapy, both chemotherapy and radiotherapy. Indeed, hypoxia-associated resistance to photon radiotherapy is a severe clinical problem, as the radiation doses required to achieve the same treatment effect in hypoxic tumors can be three times the doses required in normoxic tumors. The extracellular matrix (ECM) glycosaminoglycan hyaluronan (HA) accumulates to high levels in ∼30% of solid tumors. Since HA is highly hydrophilic, ECM HA accumulation is believed to contribute to the elevated interstitial fluid pressure (IFP) and subsequent tumor vessel constriction observed in solid tumors. This vascular constriction contributes to the pathologic hypoxia present in these tumors. PEGPH20, a pegylated human recombinant hyaluronidase PH20, when delivered intravenously in preclinical models has been shown to enzymatically remove tumor HA and decrease both tumor IFP and water, leading to increased tumor vascular perfusion and enhanced chemotherapeutic delivery (Thompson 2010). Here we aimed to extend these observations and determine whether PEGPH20 would both increase tumor blood flow and reduce tumor hypoxia following PEGPH20-mediated HA removal. Nude mice were inoculated with human BxPC-3 pancreatic cancer cells adjacent to the right tibial periosteum. When tumors reached 15-20 mm in diameter (nα8/group), mice were staged into two treatment groups: (1) vehicle control and (2) PEGPH20 monotherapy. Vehicle or PEGPH20 (4.5 mg/kg) was administered to animals intravenously twice weekly for one week. The hypoxyprobe pimonidazole (60 mg/kg, ip) was administered to animals two hours prior to sacrifice, and fluorescent carbocyanine (75 μL, iv) 5 minutes prior to sacrifice. At sacrifice, whole tumors were removed, bisected, embedded in OCT medium, and processed for immunohistochemistry (hypoxyprobe and CD31) or simply imaged microscopically (carbocyanine). Hypoxia, blood vessel position, and tumor perfusion were assessed using pimonidazole, CD31 and carbocyanine, respectively. Compound images were created and the spatial relationship between hypoxia and vasculature perfusion evaluated. Consistent with prior studies, tumor HA was depleted in the PEGPH20-treated tumors. Further, tumor vascular perfusion (carbocyanine) increased 86% (p=0.0007) and tumor hypoxia decreased by 66% (p=0.03) in PEGPH20-treated animals, relative to the vehicle controls. These findings suggest that PEGPH20-mediated reduction in tumor HA increases tumor perfusion, while concomitantly reducing tumor hypoxia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3796. doi:1538-7445.AM2012-3796
Abstract Hyaluronan (HA) accumulates in the tumor microenvironment (TME) of many solid tumors, including prostate, colon, breast, stomach, ovary, pancreas and lung, and HA accumulation is associated with tumor progression and a negative clinical outcome. Accordingly, the HA degrading enzyme pegylated recombinant human hyaluronidase PH20 (PEGPH20) was developed to allow systemic therapy and enable treatment of HA-high tumors. Preclinical studies have demonstrated that PEGPH20-mediated HA removal from HA-rich xenograft tumors in mice decreases tumor interstitial fluid pressure and water content; resulting in decompression of tumor vasculature, increased tumor perfusion and enhanced chemotherapeutic (CTX) activity. As non-small cell lung cancer (NSCLC) is the most common cancer worldwide and is characterized by high levels of HA (∼30%), we aimed to evaluate PEGPH20 enhancement of anti-tumor activity of NSCLC CTXs. Specifically, using both cell derived xenograft (CDX) models, peritibial H2170/HAS3 human NSCLC xenografts, and patient derived xenograft (PDX) models, we investigated CTX tumor growth inhibition (TGI)+/- PEGPH20. Nude mice were inoculated with either H2170/HAS3 cells adjacent to the tibial periosteum or patient derived tumor fragments of human NSCLCs implanted subcutaneously, and tumor growth was monitored via ultrasonography or caliper, respectively. When tumors reached ∼400 mm3, mice were staged into four groups: (1) vehicle; (2) PEGPH20, (3) CTX(s), or (4) PEGPH20 + CTX(s). PEGPH20 alone depleted tumor HA in both CDX and PDX models. In CDX studies, PEGPH20 increased tumor perfusion, reduced hypoxia and decreased HIF-1α expression (p<0.05). A summary table of the TGI data is shown below. The average TGI for PEGPH20 plus CTX(s) was superior to all CTX(s) alone, suggesting that enzymatic depletion of TME HA increases tumor sensitivity to NSCLC CTXs, likely due to increased CTX access into the TME. PEGPH20 clinical trials in NSCLC are currently in development. Summary of TGIsGroup (n≥5/group)CDX%TGI w/ docetaxelCDX%TGI w/ nab-paclitaxel + carboplatinPDX%TGI w/ docetaxelPDX%TGI w/ gemcitabine + cisplatin(p-value vs. V)Vehicle (V)----PEGPH20 (P)28.5 (p<0.05)11.5 (p>0.05)44.4 (p<0.01)29.3 (p>0.05)CTX(s)19.8 (p>0.05)68.6 (p<0.0001)52.5 (p<0.001)38.4 (p>0.05)P + CTX56.1 (p<0.001)93.5 (p<0.0001)>100 (p<0.0001)76.6 (p<0.01) Citation Format: Jessica A. Cowell, Xiaoming Li, Ping Jiang, Susan Zimmerman, Rebecca Symons, H. Michael Shepard, Daniel C. Maneval, Curtis B. Thompson. PEGPH20 enhances chemotherapy in patient-derived and traditional cell-derived xenograft NSCLC models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2547. doi:10.1158/1538-7445.AM2015-2547
Abstract Hyaluronan (HA), a nonsulfated glycosaminoglycan, is a significant component of the extracellular matrix of many solid tumors. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. We have previously demonstrated that sustained HA removal, accomplished with a novel pegylated human recombinant hyaluronidase PH20 (PEGPH20), inhibited tumor growth and enhanced chemotherapeutic activity in HA-rich xenografts (Thompson et al, 2010). As endogenous lysosomal hyaluronidase expression has been implicated as a tumor promoter (Kovar et al, 2006), and exogenous hyaluronidase has been shown to act as a tumor suppressor (Shuster et al, 2002), we aimed to determine whether exogenous PEGPH20 administration alters the metastatic behavior of malignant cells in solid tumors. In a first set of experimental metastasis studies, HA-rich prostate PC3 (2e5) or breast MDA-MB-231 (1e5) cells were intracardially injected (IC) into nude mice (NCR nu/nu). Mice were subsequently treated (>20 min) with a single dose of PEGPH20 (4.5 mg/kg, IV) or vehicle and tumor seeding into organs tracked via bioluminescent imaging over time (n=8/group). In a second set of spontaneous metastasis experiments, prostate PC3 (2e6) or breast MDA-MB-231-Has2 (2e6) cells were injected into either the tibia periosteum or mammary fad pad of nude mice, respectively. MDA-MB-231-Has2 cells are a MDA-MB-231 Has 2 synthase overexpressing clone, shown to overexpress HA both in vitro and in vivo. When PC3 tumors reached ∼375 mm3 (n=11/group), and MDA-MB-231-Has2 reached ∼400 mm3 (n=6/group), mice received PEGPH20 (4.5 mg/kg, IV) or vehicle, q3d × 8 or q3d × 5, respectively. Mice were subsequently sacrificed and lymph node metastasis assessed histologically. Following the initial set of IC experiments, no significant difference in the number or frequency of metastatic nodules, as assessed by bioluminescence, was observed following PEGPH20 treatment versus control in either cell line (PC3, p=0.49; MDA-MB-231, p=0.89). In the second set of experiments, no difference in lymph node metastasis in either cell line was detected (PC3, p=0.68; MDA-MB-231, p=0.55). Finally, no histological evidence of increased metastases was observed in any organs examined (liver, kidney, heart, spleen or lung) following PEGPH20 administration in either study. Taken together, these results suggest exogenous PEGPH20 administration does not impact metastatic behavior in the PC3 prostate, MDA-MB-231 breast or MDA-MB-231-Has2 breast preclinical models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 442. doi:10.1158/1538-7445.AM2011-442
Collectively, primary and secondary brain tumors represent a major public health challenge. Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with a dismal 5-year survival of only 10%. Breast cancer causes secondary tumors; it occurs in 200,000 patients yearly and 30% of these individuals develop brain metastases which also lead to a very poor prognosis. GBM and primary breast tumors are known to express hyaluronan (HA) which may serve as a therapeutic target.For the present study we had two aims: (I) to identify suitable preclinical models for HA in GBM by examining HA expression in human GBM cell lines implanted orthotopically in mice; and (II) to determine whether breast cancer brain metastases in human patients express HA similar to the primary tumor. Forty human surgical samples of primary breast tumors and breast cancer brain metastases were processed and stained for HA. Athymic nu/nu mice were orthotopically implanted with one of 15 GBM lines and after tumors were established, quantitative immunohistochemistry determined whether.HA was expressed. All GBM cell lines and patient-derived orthotopic tumors did express HA, with 3 primary human lines expressing the highest staining intensity, above that of normal brain. All 40 human primary breast tumors and brain metastases examined also contained HA, though staining intensity was highly variable.Our data support the use of specific patient-derived GBM cell lines in nu/nu mice for preclinical studies on HA-targeting therapies. Additionally, our research provides a basis for the assessment of HA expression and HA-targeting therapeutic agents for the treatment of breast cancer brain metastases.
Abstract The accumulation of the glycosaminoglycan hyaluronan (HA) in the extracellular matrix (ECM) of solid tumors contributes to increased tumor interstitial fluid pressure IFP), localized edema and reduced intratumoral blood flow. We recently reported that sustained enzymatic depletion of tumor HA with a pegylated recombinant human hyaluronidase PH20 (PEGPH20) decreases tumor IFP and water content, while significantly increasing vascular perfusion within HA-rich prostate PC3 tumors (Thompson et al, 2010). As localized tissue hypoxia reduces the effectiveness of radiation therapy (Baumgartner et al, 1998), we hypothesized that PEGPH20 treatment would reduce tumor hypoxia, thereby radio-sensitizing tumor cells. To evaluate whether PEGPH20 sensitizes HA-rich tumors, radiotherapy resistant human prostate PC3 cells (2×106) were inoculated into the right tibia periosteum of nude mice (NCR nu/nu) and tumor growth monitored with a high resolution 3D ultrasound. When the tumors reached ∼800 mm3 (n ≥ 8/group), mice were staged into 4 treatment groups: (1) vehicle control; (2) mono-radiotherapy at 2.5 Gy, q3d; (3) PEGPH20 monotherapy, 4.5 mg/kg, i.v. q3d; or (4) PEGPH20 plus radiotherapy. To increase intra-tumoral blood flow, PEGPH20 was administrated 3 hours prior to radiation therapy. Histological evaluation of a subset of mice confirmed that HA was completely degraded 3 hours post- PEGPH20 treatment. At study Day 15, tumor growth inhibition (TGI) with radiation alone or PEGPH20 alone was 99.2% (p=0.009) and 71.4% (p=0.08), respectively, relative to vehicle treated animals. PEGPH20 plus radiotherapy inhibited tumor growth by 140.6% (p=0.0002), relative to vehicle treated animals. The mean tumor size of the PEGPH20 plus radiotherapy group was reduced to ∼550 mm3, with 3-out-of-8 partial regressors (i.e. tumor size decrease to 50% or less of tumor staging size). These findings suggest that PEGPH20-mediated HA removal, and subsequent increase in tumoral blood flow, may increase the efficacy of radiation therapy in hyaluronan-rich tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2501. doi:10.1158/1538-7445.AM2011-2501
Abstract Pancreatic cancer is one of most deadly cancers with a 5-year survival rate of 6%. Accumulation of hyaluronan (HA) is found in about 87% of human pancreatic adenocarcinomas, and removal of HA suppresses tumor growth in HA-rich preclinical models. In a transgenic pancreatic cancer mouse model (LSL-KrasG12D/+;LSLTrp53R172H/+;Pdx-1-Cre, KPC), removal of HA by pegylated human recombinant PH20 hyaluronidase (PEGPH20) inhibits tumor growth and increases survival in combination with gemcitabine compared to gemcitabine monotherapy. In this study, we explored the role of HA synthesizing (HAS) enzymes HAS2 and HAS3 and HA accumulation in pancreatic cancer tumor growth and remodeling of tumor microenvironment. HAS2 and HAS3 were overexpressed in BxPC3 human pancreatic cancer cells using lentiviral vectors. Stable HAS2 and HAS3 overexpressing pancreatic cancer cell lines secreted more HA to culture medium and produced larger pericellular HA matrices than parental BxPC3 cells. In vivo, overexpression of HAS2 or HAS3 led to an increase in BxPC3 xenograft tumor growth (peritibial i.m. tumor model) compared to parental cells. Interestingly, overexpression of HAS3 was more effective to enhance tumor growth than overexpression of HAS2. In addition, massive accumulation of extracellular HA was found in HAS3 overexpressing tumors while HAS2 overexpressing tumors contained both extracellular and intracellular HA. Treatment with PEGPH20 removed the majority of extracellular HA and induced a 87% reduction of tumor volume in BxPC3 HAS3 model (p<0.001) but had weaker effect on BxPC3 HAS2 (33%, p<0.001) and BxPC3 tumors (36%, p<0.01). Accumulation of extracellular HA was associated with enriched tumor stroma, loss of membranous E-cadherin and accumulation of cytoplasmic β-catenin in pancreatic cancer cells, suggesting HA-induced epithelial-mesenchymal transition (EMT). Removal of HA by PEGPH20 reversed the remodeling of the tumor stroma and induced translocation of E-cadherin and β-catenin to the plasma membrane.Translocation of E-cadherin was also observed in the KPC pancreatic tumors after PEGPH20 treatment. In conclusion, accumulation of extracellular HA by HAS3 overexpression favors tumor growth and leads to a strong response to PEGPH20 in a pancreatic cancer xenograft model. Deposition of extracellular HA is associated with optimization of the tumor microenvironment and EMT. Depletion of HA by PEGPH20 reverses changes in the tumor stroma and induces translocation of epithelial markers to the plasma membrane. Citation Format: Anne Kultti, Chunmei Zhao, Susan Zimmerman, Ryan J. Osgood, Yanling Chen, Rebecca Symons, Ping Jiang, Curtis B. Thompson, David A. Tuveson, Gregory I. Frost, H Michael Shepard, Zhongdong Huang. Extracellular hyaluronan accumulation by hyaluronan synthase 3 promotes pancreatic cancer growth and modulates tumor microenvironment via epithelial-mesenchymal transition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4844. doi:10.1158/1538-7445.AM2014-4844
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.
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