Abstract 721: An anaplastic lymphoma kinase antibody targets pancreatic allografts, prevents the progression of pancreatic cancer, and induces changes in microRNA expression

Abstract

Anaplastic lymphoma kinase (ALK) is a transmembrane tyrosine kinase receptor that has an increased expression in various tumors and areas of active angiogenesis. In pancreatic tissues of mice with endogenously expressed mutant KrasG12D under embryonic acinar promoter p48, we detected ALK expression in pre maligant pancreatic intra-epithelial neoplastic ducts (PanIN) as well as malignant adenocarcinoma (PDAC). We have developed an antagonistic mouse monoclonal IgG antibody to the ALK receptor (anti-ALK IgG). To determine the antibody's binding efficacy, we used a quantum dot labeled anti-ALK IgG for the fluorescent visualization of pancreatic allografts in nude mice. Intravenously injected Qdot labeled anti-ALK IgG concentrated in allograft areas more than a Qdot labeled control antibody. In a prospective treatment study, we treated KrasG12D mice to determine the antibody's efficacy at preventing the progression from early to late PanIN and ultimately PDAC. Mice of three different age cohorts were treated with the antibody inta-peritoneal for six weeks. Upon completion of antibody treatment, the pancreata of mice were histologically examined for the appearance of early PanIN, late PanIN, or PDAC. Anti-ALK IgG treatment was most effective at preventing the progression of late PanIN to PDAC, with 8.3% of antibody treated mice harboring PDAC compared to 33.3% of saline treated control mice. Metastasis was also prevented in mice treated with antibody. Anti-ALK IgG treatment did not prevent the progression of early or late PanINs better than control treatment. Preliminary experiments have determined a change in microRNA expression in the pancreatic tissues of mice treated with antibody compared to controls and during different stages of pancreatic cancer progression. Expression of miR-375 decreased approximately 100 fold in PanIN and PDAC tissues compared to control tissues, but this decrease was not seen in PanIN tissues of mice treated with anti-ALK IgG. Reports have shown miR-375's role in pancreas development and the regulation of glucose homeostasis, and that its expression decreased in certain cancers. These data suggest miR-375 is necessary for normal physiological pancreatic activity and has a possible tumor suppressive role, and that anti-ALK IgG can help maintain this function. MiR- 22, 141, 148a, 148b, and 301a also had similar expression patterns in PanIN tissues and controls when pancreata were from mice treated with antibody. Another group of microRNAs, including miR- 10, 16, 21, 100, 155, and 199 showed little change in expression in antibody or control treated mice. These changes in microRNA expression suggest a response to antibody treatment at the genetic level, which may provide further insights into the functional mechanism of anti-ALK IgG's efficacy. 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 721.

A phase I study of the anaplastic lymphoma kinase inhibitor ceritinib in combination with gemcitabine‐based chemotherapy in patients with advanced solid tumors

“…Analysis by our group (unpublished data) showed ALK overexpression in 3 out of 8 pancreatic cancer cell lines, and gene microarray analysis showed relatively high ALK expression compared to IGF‐1R in 7 out of 8 patient‐derived xenografts. ALK expression in pancreatic intraepithelial lesions as well as pancreatic cancer in vivo can be increased, and treatment with anti‐ALK monoclonal inhibited progression to adenocarcinoma, exerting both antiproliferative and anti‐metastatic properties 33 . Ceritinib in combination with gemcitabine has synergistic antitumor effect in pancreatic cancer in vitro and in vivo models 34 .…”

“…28 In our study, with an increase in ceritinib dosing from 450 to 600 mg, the ceritinib AUC 0-24h roliferative and anti-metastatic properties. 33 Ceritinib in combination with gemcitabine has synergistic antitumor effect in pancreatic cancer in vitro and in vivo models. 34 While three out of five evaluable patients with cholangiocarcinoma in our study had prolonged clinical benefit; both patients with pancreatic cancer had PD as best response.…”