title: Inhibition of Rho-Associated Kinase 1/2 Attenuates Tumor Growth in Murine Gastric Cancer.
abstract: Gastric cancer (GC) remains a malignant disease with high mortality. Patients are frequently diagnosed in advanced stages where survival prognosis is poor. Thus, there is high medical need to find novel drug targets and treatment strategies. Recently, the comprehensive molecular characterization of GC subtypes revealed mutations in the small GTPase RHOA as a hallmark of diffuse-type GC. RHOA activates RHO-associated protein kinases (ROCK1/2) which regulate cell contractility, migration and growth and thus may play a role in cancer. However, therapeutic benefit of RHO-pathway inhibition in GC has not been shown so far. The ROCK1/2 inhibitor 1-(5-isoquinoline sulfonyl)-homopiperazine (HA-1077, fasudil) is approved for cerebrovascular bleeding in patients. We therefore investigated whether fasudil (i.p., 10 mg/kg per day, 4 times per week, 4 weeks) inhibits tumor growth in a preclinical model of GC. Fasudil evoked cell death in human GC cells and reduced the tumor size in the stomach of CEA424-SV40 TAg transgenic mice. Small animal PET/CT confirmed preclinical efficacy. Mass spectrometry imaging identified a translatable biomarker for mouse GC and suggested rapid but incomplete in situ distribution of the drug to gastric tumor tissue. RHOA expression was increased in the neoplastic murine stomach compared with normal non-malignant gastric tissue, and fasudil reduced (auto) phosphorylation of ROCK2 at THR249 in vivo and in human GC cells in vitro. In sum, our data suggest that RHO-pathway inhibition may constitute a novel strategy for treatment of GC and that enhanced distribution of future ROCK inhibitors into tumor tissue may further improve efficacy.
authors: Dept. of Internal Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany.
authors: Isabel
authors: I
authors: Hinsenkamp
authors: Center for Applied Research in Biomedical Mass Spectrometry (ABIMAS) and Institute of Medical Technology of Heidelberg University and Mannheim University of Applied Sciences, Mannheim, Germany.
authors: Sandra
authors: S
authors: Schulz
authors: Dept. of Clinical Radiology and Nuclear Medicine (Molecular Imaging and Radiochemistry), Universitätsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany.
authors: Mareike
authors: M
authors: Roscher
authors: Dept. of Clinical Radiology and Nuclear Medicine (Molecular Imaging and Radiochemistry), Universitätsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany.
authors: Anne-Maria
authors: AM
authors: Suhr
authors: Center for Applied Research in Biomedical Mass Spectrometry (ABIMAS) and Institute of Medical Technology of Heidelberg University and Mannheim University of Applied Sciences, Mannheim, Germany.
authors: Björn
authors: B
authors: Meyer
authors: Center for Applied Research in Biomedical Mass Spectrometry (ABIMAS) and Institute of Medical Technology of Heidelberg University and Mannheim University of Applied Sciences, Mannheim, Germany.
authors: Bogdan
authors: B
authors: Munteanu
authors: Bruker Daltonik GmbH, Bremen, Germany.
authors: Jens
authors: J
authors: Fuchser
authors: Dept. of Clinical Radiology and Nuclear Medicine (Molecular Imaging and Radiochemistry), Universitätsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany.
authors: Stefan O
authors: SO
authors: Schoenberg
authors: Dept. of Internal Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany.
authors: Matthias P A
authors: MP
authors: Ebert
authors: Dept. of Clinical Radiology and Nuclear Medicine (Molecular Imaging and Radiochemistry), Universitätsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany.
authors: Björn
authors: B
authors: Wängler
authors: Center for Applied Research in Biomedical Mass Spectrometry (ABIMAS) and Institute of Medical Technology of Heidelberg University and Mannheim University of Applied Sciences, Mannheim, Germany.
authors: Carsten
authors: C
authors: Hopf
authors: Dept. of Internal Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany. Electronic address: elke.burgermeister@medma.uni-heidelberg.de.
authors: Elke
authors: E
authors: Burgermeister
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000072078:Positron Emission Tomography Computed Tomography; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013274:Stomach Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein