Abstract A115: The CD95 ligand inhibitor APG 101 reduces tumor recurrence and metastasis in an adjuvant orthotopic mouse model of pancreatic cancer as well as primary tumor load in a palliative setting

Abstract

Abstract Since the first description of CD95/Fas this member of the death receptor superfamily has been regarded as paradigmatic for death receptors, capable of induction of caspase-driven apoptosis. More recently, CD95 has also emerged as an inducer of other signaling pathways including pro-inflammatory and migratory mechanisms (for an overview see Roeder C. et al., Eur J Cell Biol. 2011). Previously, we demonstrated a strong induction of NFkB activity after CD95 stimulation of pancreatic cancer cells resulting in increased invasiveness under in vitro conditions. Inhibition of CD95 mediated mechanisms in tumor gains importance since malignant cells may misuse this system for progression as demonstrated by others eg. for ovarian cancer and glioblastoma. From a clinical point of view, several observations also point into the same direction. Studies on colorectal cancer, head and neck, hepatocellular carcinoma for example suggest CD95 ligand expression to correlate negatively with patients prognosis. APG101 is an inhibitor of CD95 ligand consisting of the CD95 receptor extracellular domain fused to the Fc domain of IgG. A randomized controlled phase II ‘proof-of-concept’ study in patients with recurrent glioblastoma was successfully completed recently (NCT01071837). Up to date there exist no in vivo studies concerning the influence of blocking the interaction between CD95 and its ligand using this recombinant inhibitor in pancreatic cancer. Thus we tested this novel tool in a palliative and adjuvant orthotopic xenotransplantation model of human pancreatic cancer. In this study PancTuI Luc cells were used, which establish a highly infiltrating primary tumor with very low/no metastatic capacity in the liver. All mice (n=8/group) survived the operative procedures for the palliative treatment and were randomly assigned into five groups: control group; treatment with different concentrations of APG101: 12.5, 25, 50, and 100 µg/g bw. (i.p. injection, twice per week). Upon tumor resection (2/3rd pancreatectomy 10 days after tumor cell inoculation) local as well as distant recurrent disease (primarily in the liver) is regularly observed. All mice surviving the operative procedures for the adjuvant treatment (n=9/group) were randomly assigned into two groups: control group with 200 µl saline 0.9 % i.p. and the APG 101 group with a dose of 25 µg/g bw i.p (twice a week). Treatment was started three days after subtotal pancreatectomy and lasted for 28 days until sacrifice of the animals. Palliative treatment: mean tumor weight was 353 ± 179 mg for animals in the control group compared to 210.4 ± 86.5 mg to the mice treated with 25 µg APG101/g bw (p = 0.09) and 221.4 ± 94 mg (p = 0.021) in the group treated with 50 µg APG101/g bw Tumor volume was significantly reduced in all treatment groups, again with 25 µg APG101/g bw achieving maximal growth inhibition. Within the 4 weeks no metastases occurred in any group as previously observed within this model. Adjuvant treatment: All mice developed recurrent tumors. The mean weight of locally recurrent tumor was 887.5 ± 467.3 mg in the control group (treated with 0.9% saline). The other group treated with APG101 (25 µg/g bw) showed a local tumor recurrence with a significant lower tumor weight (p=0.027). The average number of metastases per mouse in the therapy group was 2.3 versus 4 metastases / mouse in the control group. Reduced tumor growth in both therapeutic settings was reflected by a reduced Ki67 proliferation index. Our data underline the importance of the CD95 antagonist APG101 as a new option in pancreatic cancer therapy that might be further evaluated also in combination with chemotherapies. Note: These results were published in the International Journal of Cancer as a full-length article before the online publication of this abstract. Citation information: Inhibition of IL-6 signaling significantly reduces primary tumor growth and recurrencies in orthotopic xenograft models of pancreatic cancer. Goumas FA, Holmer R, Egberts JH, Gontarewicz A, Heneweer C, Geisen U, Hauser C, Mende MM, Legler K, Röcken C, Becker T, Waetzig GH, Rose-John S, Kalthoff H. Int J Cancer. 2015 Jan 21. doi: 10.1002/ijc.29445. [Epub ahead of print] PMID: 25604508. Citation Format: Freya Goumas, Khalid Rhashid, Anna Trauzold, Harald Fricke, Michael Kluge, Thomas Becker, Jan Egberts, Holger Kalthoff. The CD95 ligand inhibitor APG 101 reduces tumor recurrence and metastasis in an adjuvant orthotopic mouse model of pancreatic cancer as well as primary tumor load in a palliative setting. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A115.