title: Biomarkers of evasive resistance predict disease progression in cancer patients treated with antiangiogenic therapies.
abstract: Numerous antiangiogenic agents are approved for the treatment of oncological diseases. However, almost all patients develop evasive resistance mechanisms against antiangiogenic therapies. Currently no predictive biomarker for therapy resistance or response has been established. Therefore, the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Thereby we measured levels of angiogenic growth factors, tumor perfusion, circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and tumor endothelial markers (TEM) in patients during the course of therapy with antiangiogenic agents, and correlated them with the time to antiangiogenic progression (aTTP). Importantly, at disease progression, we observed an increase of proangiogenic factors, upregulation of CEC/CEP levels and downregulation of TEMs, such as Robo4 and endothelial cell-specific chemotaxis regulator (ECSCR), reflecting the formation of torturous tumor vessels. Increased TEM expression levels tended to correlate with prolonged aTTP (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). This indicates that loss of vascular stabilization factors aggravates the development of antiangiogenic resistance. Thus, our observations confirm that CEP/CEC populations, proangiogenic cytokines and TEMs contribute to evasive resistance in antiangiogenic treated patients. Higher TEM expression during disease progression may have clinical and pathophysiological implications, however, validation of our results is warranted for further biomarker development.
authors.affiliation: Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pircher
authors.affiliation: Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Jöhrer
authors.affiliation: Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria.|Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Kocher
authors.affiliation: Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Normann
authors.initials: N
authors.lastname: Steiner
authors.affiliation: Department of Internal Medicine II, Gastroenterology and Hepatology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Ivo
authors.initials: I
authors.lastname: Graziadei
authors.affiliation: Department of Urology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Isabel
authors.initials: I
authors.lastname: Heidegger
authors.affiliation: Department of Urology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Pichler
authors.affiliation: Department of Urology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Leonhartsberger
authors.affiliation: Department of Radiology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Kremser
authors.affiliation: Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Johann
authors.initials: J
authors.lastname: Kern
authors.affiliation: Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Gerold
authors.initials: G
authors.lastname: Untergasser
authors.affiliation: Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Gunsilius
authors.affiliation: Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria.|Department of Oncology, Hematology and Palliative Care Wilhelminenspital, Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hilbe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010865:Pilot Projects; D011379:Prognosis; D015996:Survival Rate
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor
keywords: Robo4; angiogenesis; antiangiogenic therapies; placental growth factor (PlGF); vascular endothelial growth factor (VEGF)