Top

Published in:

01-02-2014 | Translational Research and Biomarkers

Combination Treatment of Human Pancreatic Cancer Xenograft Models with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib and Oncolytic Herpes Simplex Virus HF10

Authors: Kazuo Yamamura, MD, Hideki Kasuya, MD, PhD, Tevfik Tolga Sahin, MD, PhD, Gewen Tan, MD, Yoshihiro Hotta, MD, Naoko Tsurumaru, MSc, Saori Fukuda, MSc, Mitsuro Kanda, MD, PhD, Daisuke Kobayashi, MD, PhD, Chie Tanaka, MD, PhD, Suguru Yamada, MD, PhD, Goro Nakayama, MD, PhD, Tsutomu Fujii, MD, PhD, Hiroyuki Sugimoto, MD, PhD, Masahiko Koike, MD, PhD, Shuji Nomoto, MD, PhD, Michitaka Fujiwara, MD, PhD, Maki Tanaka, BS, Yasuhiro Kodera, MD, PhD

Published in: Annals of Surgical Oncology | Issue 2/2014

Abstract

Background

There is the potential to use replication-competent oncolytic viruses to treat cancer. We evaluated the efficacy of HF10, a herpes simplex virus type 1 (HSV-1) mutant, in combination with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in human pancreatic cancer xenograft models.

Methods

The viability of human pancreatic cancer cell lines (BxPC-3 and PANC-1) treated with HF10 and erlotinib, on their own or in combination, was determined. Effects of erlotinib on HF10 entry into tumor cells were also investigated. BxPC-3 subcutaneous tumor-bearing mice were treated with HF10 and erlotinib, on their own or in combination, with effects on tumor volume determined. Immunohistochemical examination of HSV-1 and CD31 was conducted to assess virus distribution and angiogenesis within tumors. A peritoneally disseminated BxPC-3 xenograft model was evaluated for survival.

Results

HF10 combined with erlotinib demonstrated the highest cytotoxicity against BxPC-3. A combination effect was not observed in PANC-1 cells, and erlotinib did not affect virus entry into tumor cells. In the peritoneally disseminated model, HF10 combined with erlotinib had no beneficial effect on survival. In the subcutaneous tumor model, combination therapy resulted in the inhibition of tumor growth to a greater extent than using each agent on its own. Immunohistochemistry revealed that virus distribution within the tumor persisted in the combination therapy group.

Conclusions

Combination therapy with HF10 and erlotinib warrants further investigation to establish a new treatment strategy against human pancreatic cancers.

Seino T, Nakadaira H, Endoh K, et al. Changes in pancreatic cancer mortality, period patterns, and birth cohort patterns in Japan: analysis of mortality data in the period 1968–2002. Environ Health Prev Med. 2008;13:234–42.PubMedCentralPubMedCrossRef

Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6.PubMedCrossRef

Teshigahara O, Goshima F, Takao K, et al. Oncolytic viral therapy for breast cancer with herpes simplex virus type 1 mutant HF 10. J Surg Oncol. 2004;85:42–7.PubMedCrossRef

Shimoyama S, Goshima F, Teshigahara O, et al. Enhanced efficacy of herpes simplex virus mutant HF10 combined with paclitaxel in peritoneal cancer dissemination models. Hepatogastroenterology. 2007;54:1038–42.PubMed

Watanabe D, Goshima F, Mori I, Tamada Y, Matsumoto Y, Nishiyama Y. Oncolytic virotherapy for malignant melanoma with herpes simplex virus type 1 mutant HF10. J Dermatol Sci. 2008;50:185–96.PubMedCrossRef

Nawa A, Luo C, Zhang L, et al. Non-engineered, naturally oncolytic herpes simplex virus HSV1 HF-10: applications for cancer gene therapy. Curr Gene Ther. 2008;8:208–21.PubMedCrossRef

Kimata H, Imai T, Kikumori T, et al. Pilot study of oncolytic viral therapy using mutant herpes simplex virus (HF10) against recurrent metastatic breast cancer. Ann Surg Oncol. 2006;13:1078–84.PubMedCrossRef

Nakao A, Kasuya H, Sahin TT, et al. A phase I dose-escalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer. Cancer Gene Ther. 2011;18:167–75.PubMedCrossRef

Choi H. Critical issues in response evaluation on computed tomography: lessons from the gastrointestinal stromal tumor model. Curr Oncol Rep. 2005;7:307–11.PubMedCrossRef

10.

Sahin TT, Kasuya H, Nomura N, et al. Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer. Cancer Gene Ther. 2012;19:229–37.PubMedCrossRef

11.

Bareschino MA, Schettino C, Troiani T, Martinelli E, Morgillo F, Ciardiello F. Erlotinib in cancer treatment. Ann Oncol. 2007;18:vi35–41.

12.

Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res. 2006;66:3197–204.PubMedCrossRef

13.

van Cruijsen H, Giaccone G, Hoekman K. Epidermal growth factor receptor and angiogenesis: opportunities for combined anticancer strategies. Int J Cancer. 2005;117:883–8.PubMedCrossRef

14.

Herbst RS, Sandler A. Bevacizumab and erlotinib: a promising new approach to the treatment of advanced NSCLC. Oncologist. 2008;13:1166–76.PubMedCrossRef

15.

Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the cancer and leukemia group B (GALGB 80303). J Clin Oncol. 2010;28:3617–22.PubMedCrossRef

16.

Nishiyama Y, Kimura H, Daikoku T. Complementary lethal invasion of the central nervous system by nonneuroinvasive herpes simplex virus types 1 and 2. J Virol. 1991;65:4520–4.PubMedCentralPubMed

17.

Takakuwa H, Goshima F, Nozawa N, et al. Oncolytic viral therapy using a spontaneously generated herpes simplex virus type 1 variant for disseminated peritoneal tumor in immunocompetent mice. Arch Virol. 2003;148:813–25.PubMedCrossRef

18.

Carroll NM, Chiocca EA, Takahashi K, Tanabe KK. Enhancement of gene therapy specificity for diffuse colon carcinoma liver metastases with recombinant herpes simplex virus. Ann Surg. 1996;224:323–9.PubMedCrossRef

19.

Kasuya H, Pawlik TM, Mullen JT, et al. Selectivity of an oncolytic herpes simplex virus for cells expressing the DF3/MUC1 antigen. Cancer Res. 2004;64:2561–7.PubMedCrossRef

20.

Yokoyama Y, Dhanabal M, Griffioen AW, Sukhatme VP, Ramakrishnan S. Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth. Cancer Res. 2000;60:2190–6.PubMed

21.

Yu DC, Chen Y, Dilley J, et al. Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel. Cancer Res. 2001;61:517–25.PubMed

22.

Arnoletti JP, Buchsbaum DJ, Huang ZQ, et al. Mechanisms of resistance to Erbitux (anti-epidermal growth factor receptor) combination therapy in pancreatic adenocarcinoma cells. J Gastrointest Surg. 2004;8:960–9.PubMedCrossRef

23.

Patra CR, Bhattacharya R, Wang E, et al. Targeted delivery of gemcitabine to pancreatic adenocarcinoma using cetuximab as a targeting agent. Cancer Res. 2008;68:1970–8.PubMedCrossRef

24.

Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol. 2005;23:1803–10.PubMedCrossRef

25.

Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97:643–55.PubMedCrossRef

26.

Dziadziuszko R, Witta SE, Cappuzzo F, et al. Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in non-small cell lung cancer. Clin Cancer Res. 2006;12:3078–84.PubMedCrossRef

27.

Hirsch FR, Witta S. Biomarkers for prediction of sensitivity to EGFR inhibitors in non-small cell lung cancer. Curr Opin Oncol. 2005;17:118–22.PubMedCrossRef

28.

Buck E, Eyzaguirre A, Barr S, et al. Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition. Mol Cancer Ther. 2007;6:532–41.PubMedCrossRef

29.

Liu TC, Galanis E, Kirn D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat Clin Pract Oncol. 2007;4:101–17.PubMedCrossRef

30.

Parato KA, Senger D, Forsyth PA, Bell JC. Recent progress in the battle between oncolytic viruses and tumours. Nat Rev Cancer. 2005;5:965–76.PubMedCrossRef

31.

Nemunaitis J, Khuri F, Ganly I, et al. Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer. J Clin Oncol. 2001;19:289–98.PubMed

32.

Fan Y, Du W, He B, et al. The reduction of tumor interstitial fluid pressure by liposomal imatinib and its effect on combination therapy with liposomal doxorubicin. Biomaterials. 2013;34:2277–88.PubMedCrossRef

33.

Wojton J, Kaur B. Impact of tumor microenvironment on oncolytic viral therapy. Cytokine Growth Factor Rev. 2010;21:127–34.PubMedCentralPubMedCrossRef

34.

McKee TD, Grandi P, Mok W, et al. Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res. 2006;66:2509–13.PubMedCrossRef

35.

Kim JH, Lee YS, Kim H, Huang JH, Yoon AR, Yun CO. Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy. J Natl Cancer Inst. 2006;98:1482–93.PubMedCrossRef

36.

Cheng J, Sauthoff H, Huang Y, et al. Human matrix metalloproteinase-8 gene delivery increases the oncolytic activity of a replicating adenovirus. Mol Ther. 2007;15:1982–90.PubMedCrossRef

37.

Ganesh S, Gonzalez-Edick M, Gibbons D, Van Roey M, Jooss K. Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses enhances virus potency in metastatic tumor models. Clin Cancer Res. 2008;14:3933–41.PubMedCrossRef

38.

Mok W, Boucher Y, Jain RK. Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus. Cancer Res. 2007;67:10664–8.PubMedCrossRef

39.

Guedan S, Rojas JJ, Gros A, Mercade E, Cascallo M, Alemany R. Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth. Mol Ther. 2010;18:1275–83.PubMedCrossRef

40.

Boucher Y, Jain RK. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res. 1992;52:5110–4.PubMed

41.

Boucher Y, Leunig M, Jain RK. Tumor angiogenesis and interstitial hypertension. Cancer Res. 1996;56:4264–6.PubMed

42.

Heldin CH, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer. 2004;4:806–13.PubMedCrossRef

43.

Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004;64:3731–36.PubMedCrossRef

44.

Libertini S, Iacuzzo I, Perruolo G, et al. Bevacizumab increases viral distribution in human anaplastic thyroid carcinoma xenografts and enhances the effects of E1A-defective adenovirus dl922–947. Clin Cancer Res. 2008;14:6505–14.PubMedCrossRef

45.

Kurozumi K, Hardcastle J, Thakur R, et al. Effect of tumor microenvironment modulation on the efficacy of oncolytic virus therapy. J Natl Cancer Inst. 2007;99:1768–81.PubMedCrossRef

46.

Deguchi T, Shikano T, Kasuya H, et al. Combination of the tumor angiogenesis inhibitor bevacizumab and intratumoral oncolytic herpes virus injections as a treatment strategy for human gastric cancers. Hepatogastroenterology. 2012;59:1844–50.PubMed

47.

Aghi M, Rabkin SD, Martuza RL. Angiogenic response caused by oncolytic herpes simplex virus-induced reduced thrombospondin expression can be prevented by specific viral mutations or by administering a thrombospondin-derived peptide. Cancer Res. 2007;67:440–4.PubMedCrossRef

48.

Kurozumi K, Hardcastle J, Thakur R, et al. Oncolytic HSV-1 infection of tumors induces angiogenesis and upregulates CYR61. Mol Ther. 2008;16:1382–91.PubMedCentralPubMedCrossRef

49.

Hardcastle J, Kurozumi K, Dmitrieva N, et al. Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1. Mol Ther. 2010;18:285–94.PubMedCrossRef

50.

Boshoff C. Kaposi’s sarcoma. Coupling herpesvirus to angiogenesis. Nature. 1998;391:24–25.

51.

Zheng M, Schwarz MA, Lee S, Kumaraguru U, Rouse BT. Control of stromal keratitis by inhibition of neovascularization. Am J Pathol. 2001;159:1021–9.PubMedCrossRef

52.

Zheng M, Klinman DM, Gierynska M, Rouse BT. DNA containing CpG motifs induces angiogenesis. Proc Natl Acad Sci USA. 2002;99:8944–9.PubMedCentralPubMedCrossRef

53.

Choudhary A, Hiscott P, Hart CA, Kaye SB, Batterbury M, Grierson I. Suppression of thrombospondin 1 and 2 production by herpes simplex virus 1 infection in cultured keratocytes. Mol Vis. 2005;11:163–8.PubMed

54.

Hayashi K, Hooper LC, Detrick B, Hooks JJ. HSV immune complex (HSV-IgG: IC) and HSV-DNA elicit the production of angiogenic factor VEGF and MMP-9. Arch Virol. 2009;154:219–26.PubMedCrossRef

55.

Wuest TR, Carr DJ. VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis. J Exp Med. 2010;207:101–15.PubMedCentralPubMedCrossRef

Title: Combination Treatment of Human Pancreatic Cancer Xenograft Models with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib and Oncolytic Herpes Simplex Virus HF10
Authors: Kazuo Yamamura, MD
Hideki Kasuya, MD, PhD
Tevfik Tolga Sahin, MD, PhD
Gewen Tan, MD
Yoshihiro Hotta, MD
Naoko Tsurumaru, MSc
Saori Fukuda, MSc
Mitsuro Kanda, MD, PhD
Daisuke Kobayashi, MD, PhD
Chie Tanaka, MD, PhD
Suguru Yamada, MD, PhD
Goro Nakayama, MD, PhD
Tsutomu Fujii, MD, PhD
Hiroyuki Sugimoto, MD, PhD
Masahiko Koike, MD, PhD
Shuji Nomoto, MD, PhD
Michitaka Fujiwara, MD, PhD
Maki Tanaka, BS
Yasuhiro Kodera, MD, PhD
Publication date: 01-02-2014
Publisher: Springer US
Published in: Annals of Surgical Oncology / Issue 2/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-013-3329-3

2024 ASCO Annual Meeting

Springer Medicine

Combination Treatment of Human Pancreatic Cancer Xenograft Models with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib and Oncolytic Herpes Simplex Virus HF10

Abstract

Background

Methods

Results

Conclusions

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2014

Differences Between Hepatocellular Carcinoma and Hepatitis B Virus Infection in Patients With and Without Cirrhosis

Prognostic Biomarkers in Patients with Resected Cholangiocarcinoma: A Systematic Review and Meta-analysis

Immunological Impact of Neoadjuvant Chemoradiotherapy in Patients with Borderline Resectable Pancreatic Ductal Adenocarcinoma

Impact of Charlson Comorbidity Index Varies by Age in Patients with Prostate Cancer Treated by Radical Prostatectomy: A Competing Risk Regression Analysis

Salvage Surgery for Residual Primary and Locally Recurrent Anal Squamous Cell Carcinoma After Chemoradiotherapy in HIV-positive Individuals

Isolated Hepatic Perfusion for Ocular Melanoma Metastasis: Registry Data Suggests a Survival Benefit