In vivo monitoring of the anti-angiogenic therapeutic effect of the pan-deacetylase inhibitor panobinostat by small animal PET in a mouse model of gastrointestinal cancers

• Published in: Nuclear medicine and biology 2016-01, Vol.43 (1), p.27-34
• Main Authors: Maschauer, Simone, Gahr, Susanne, Gandesiri, Muktheshwar, Tripal, Philipp, Schneider-Stock, Regine, Kuwert, Torsten, Ocker, Matthias, Prante, Olaf
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - blood supply; Adenocarcinoma - diagnosis; Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animals; Caspase 3 - metabolism; Cell Proliferation - drug effects; Colon cancer; Colonic Neoplasms - blood supply; Colonic Neoplasms - diagnosis; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Disease Models, Animal; Enzyme Activation - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Hep G2 Cells; Hepatocellular carcinoma; Histone deacetylase inhibitor; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; HT29 Cells; Humans; Hydroxamic Acids - pharmacology; Hydroxamic Acids - therapeutic use; Indoles - pharmacology; Indoles - therapeutic use; Male; Mice; Mice, Nude; Neovascularization, Pathologic - drug therapy; Panobinostat; Poly(ADP-ribose) Polymerases - metabolism; Positron emission tomography; Prognosis; Proteolysis - drug effects; Radiology; RGD peptide; Treatment Outcome
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2015.10.003

Abstract Introduction Deacetylase inhibitors have recently been established as a novel therapeutic approach to solid and hematologic cancers and have also been demonstrated to possess anti-angiogenic properties. Although these compounds show a good efficacy in vitro and in vivo, no data on monitoring and predicting treatment response are currently available. We therefore investigated the effect of the pan-deacetylase inhibitor panobinostat (LBH589) on gastrointestinal cancer models and the suitability of 2-[18 F]FGlc-RGD as a specific agent for imaging integrin αv β3 expression during tumor angiogenesis using small animal positron emission tomography (PET). Methods The effect of panobinostat on cell viability in vitro was assessed with a label-free impedance based real-time analysis. Nude mice bearing HT29 and HepG2 tumors were treated with daily i.p. injections of 10 mg/kg panobinostat for 4 weeks. During this time, tumor size was determined with a calliper and mice were repeatedly subjected to PET imaging. Tumor tissues were analyzed immunohistochemically with a focus on proliferation and endothelial cell markers (Ki-67, Meca-32) and by Western blot applying specific markers of apoptosis. Results In vitro, panobinostat inhibited the proliferation of HepG2 and HT29 cells. Contrary to the situation in HepG2 tumors in vivo, where panobinostat treatment is known to reduce proliferation and vascularization resulting in a decreased tumor growth, HT29 tumors did not show any effect on these parameters. We demonstrated by Western blotting, that panobinostat induced apoptosis in HT29 tumors in vivo. Longitudinal PET imaging studies in HepG2 tumor-bearing mice using 2-[18 F]FGlc-RGD demonstrated that the standard uptake value (SUVmax ) in HepG2 tumors was significantly decreased by 39% at day 7 after treatment. The comparative PET study using HT29 tumor-bearing animals did not reveal any response of the tumors to panobinostat treatment. Conclusions Small-animal PET imaging using 2-[18 F]FGlc-RGD was successfully applied to the non-invasive monitoring of the HepG2-tumor response to panobinostat in nude mice early after begin of treatment. Thus, PET imaging of angiogenesis using 2-[18 F]FGlc-RGD could be a valuable tool to monitor panobinostat therapy in further preclinical studies. Advances in knowledge and implications for patient care When successfully translated to the clinical surrounding, PET imaging of angiogenesis could therefore facilitate therapy planning