title: Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study.
abstract: BACKGROUND
  Angiosarcomas are rare malignant tumors of vascular origin that represent a genuine therapeutic challenge. Recently, the combination of metronomic chemotherapy and drug repositioning has been proposed as an attractive alternative for cancer patients living in developing countries.
  
  
  METHODS
  In vitro experiments with transformed endothelial cells were used to identify synergistic interactions between anti-hypertensive drug propranolol and chemotherapeutics. This led to the design of a pilot treatment protocol combining oral propranolol and metronomic chemotherapy. Seven consecutive patients with advanced/metastatic/recurrent angiosarcoma were treated with this combination for up to 12months, followed by propranolol-containing maintenance therapy.
  
  
  RESULTS
  Gene expression analysis showed expression of ADRB1 and ADRB2 adrenergic receptor genes in transformed endothelial cells and in angiosarcoma tumors. Propranolol strongly synergized with the microtubule-targeting agent vinblastine in vitro, but only displayed additivity or slight antagonism with paclitaxel and doxorubicin. A combination treatment using bi-daily propranolol (40mg) and weekly metronomic vinblastine (6mg/m(2)) and methotrexate (35mg/m(2)) was designed and used in 7 patients with advanced angiosarcoma. Treatment was well tolerated and resulted in 100% response rate, including 1 complete response and 3 very good partial responses, based on RECIST criteria. Median progression-free and overall survival was 11months (range 5-24) and 16months (range 10-30), respectively.
  
  
  CONCLUSIONS
  Our results provide a strong rationale for the combination of β-blockers and vinblastine-based metronomic chemotherapy for the treatment of advanced angiosarcoma. Furthermore, our study highlights the potential of drug repositioning in combination with metronomic chemotherapy in low- and middle-income country setting.
  
  
  BACKGROUND
  This study was funded by institutional and philanthropic grants.
authors.affiliation: INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille, France; Metronomics Global Health Initiative, Marseille, France; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia. Electronic address: epasquier@ccia.unsw.edu.au.
authors.forename: Eddy
authors.initials: E
authors.lastname: Pasquier
authors.affiliation: INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille, France; Metronomics Global Health Initiative, Marseille, France; Service d'Hématologie & Oncologie Pédiatrique, AP-HM, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: André
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia.
authors.forename: Janine
authors.initials: J
authors.lastname: Street
authors.affiliation: Department of Medical Oncology, Tata Memorial Centre, Mumbai, India.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Chougule
authors.affiliation: Department of Pathology, Tata Memorial Centre, Mumbai, India.
authors.forename: Bharat
authors.initials: B
authors.lastname: Rekhi
authors.affiliation: Department of Medical Oncology, Tata Memorial Centre, Mumbai, India.
authors.forename: Jaya
authors.initials: J
authors.lastname: Ghosh
authors.affiliation: Department of Medical Oncology, Tata Memorial Centre, Mumbai, India.
authors.forename: Deepa S J
authors.initials: DSJ
authors.lastname: Philip
authors.affiliation: INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille, France; Service d'Oncologie Médicale, AP-HM, Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Meurer
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: MacKenzie
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW Australia, Sydney, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Kavallaris
authors.affiliation: Metronomics Global Health Initiative, Marseille, France; Department of Medical Oncology, Tata Memorial Centre, Mumbai, India. Electronic address: banavali_2000@yahoo.com.
authors.forename: Shripad D
authors.initials: SD
authors.lastname: Banavali
mesh_terms: D059250:Administration, Metronomic; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D058492:Drug Repositioning; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006394:Hemangiosarcoma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011433:Propranolol / Q000008:administration & dosage* / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage* / Q000494:pharmacology; D055815:Young Adult
chemical_list: C547787:ADRB1 protein, human; C553443:ADRB2 protein, human; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D014747:Vinblastine; D011433:Propranolol
keywords: Adrenergic receptor; Angiosarcoma; Metronomic chemotherapy; Propranolol; Vascular tumor