title: A serum metabolomic fingerprint of bevacizumab and temsirolimus combination as first-line treatment of metastatic renal cell carcinoma.
abstract: BACKGROUND
  Renal cell carcinoma is one of the most chemoresistant cancers, and its metastatic form requires administration of targeted therapies based on angiogenesis or mTOR inhibitors. Understanding how these treatments impact the human metabolism is essential to predict the host response and adjust personalised therapies. We present a metabolomic investigation of serum samples from patients with metastatic RCC (mRCC) to identify metabolic signatures associated with targeted therapies.
  
  
  METHODS
  Pre-treatment and serial on-treatment sera were available for 121 patients participating in the French clinical trial TORAVA, in which 171 randomised patients with mRCC received a bevacizumab and temsirolimus combination (experimental arm A) or a standard treatment: either sunitinib (B) or interferon-α+bevacizumab (C). Metabolic profiles were obtained using nuclear magnetic resonance spectroscopy and compared on-treatment or between treatments.
  
  
  RESULTS
  Multivariate statistical modelling discriminates serum profiles before and after several weeks of treatment for arms A and C. The combination A causes faster changes in patient metabolism than treatment C, detectable after only 2 weeks of treatment. Metabolites related to the discrimination include lipids and carbohydrates, consistently with the known RCC metabolism and side effects of the drugs involved. Comparison of the metabolic profiles for the three arms shows that temsirolimus, an mTOR inhibitor, is responsible for the faster host metabolism modification observed in the experimental arm.
  
  
  CONCLUSIONS
  In mRCC, metabolomics shows a faster host metabolism modification induced by a mTOR inhibitor as compared with standard treatments. These results should be confirmed in larger cohorts and other cancer types.
authors.affiliation: Centre de RMN à Très Hauts Champs, Institut des Sciences Analytiques (CNRS/ENS Lyon/UCB Lyon 1), Université de Lyon, 69100 Villeurbanne, France.|Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Jobard
authors.affiliation: Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Ellen
authors.initials: E
authors.lastname: Blanc
authors.affiliation: Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Négrier
authors.affiliation: Institut Gustave Roussy, 94805 Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.affiliation: Institut Paoli Calmette, 13009 Marseille, France.
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Gravis
authors.affiliation: Institut Claudius Regaud, 31059 Toulouse, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Chevreau
authors.affiliation: Centre de RMN à Très Hauts Champs, Institut des Sciences Analytiques (CNRS/ENS Lyon/UCB Lyon 1), Université de Lyon, 69100 Villeurbanne, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Elena-Herrmann
authors.affiliation: Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Trédan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D016898:Interferon-alpha / Q000378:metabolism; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D055442:Metabolome / Q000502:physiology; D008875:Middle Aged; D011758:Pyrroles / Q000627:therapeutic use; D044967:Serum / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D016898:Interferon-alpha; D011758:Pyrroles; D000068258:Bevacizumab; C401859:temsirolimus; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib; D020123:Sirolimus