Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study

EBioMedicine. 2016 Apr:6:87-95. doi: 10.1016/j.ebiom.2016.02.026. Epub 2016 Feb 17.

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.

Findings: 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.

Interpretation: 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.

Funding: This study was funded by institutional and philanthropic grants.

Keywords: Adrenergic receptor; Angiosarcoma; Metronomic chemotherapy; Propranolol; Vascular tumor.

MeSH terms

  • Administration, Metronomic
  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cell Line
  • Cell Transformation, Neoplastic / drug effects
  • Drug Repositioning
  • Drug Synergism
  • Epithelial Cells / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic
  • HeLa Cells
  • Hemangiosarcoma / drug therapy*
  • Hemangiosarcoma / genetics
  • Humans
  • Male
  • Middle Aged
  • Pilot Projects
  • Propranolol / administration & dosage*
  • Propranolol / pharmacology
  • Receptors, Adrenergic, beta-1 / genetics*
  • Receptors, Adrenergic, beta-2 / genetics*
  • Survival Analysis
  • Treatment Outcome
  • Vinblastine / administration & dosage*
  • Vinblastine / pharmacology
  • Young Adult

Substances

  • ADRB1 protein, human
  • ADRB2 protein, human
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • Vinblastine
  • Propranolol