ID: 2177

• Title:
  Combining small molecule inhibitors with electrochemotherapy, preclinical research
  
  Authors:
  

  Bosnjak, Masa 1
  Jesenko, Tanja 1,2 
  Markelc, Bostjan 1
  Cemazar, Maja 1,3 
  Sersa, Gregor 1,4
  1 Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia
  2 Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000, Ljubljana, Slovenia
  3 Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310 Izola, Slovenia
  4 Faculty of Health Sciences, University of Ljubljana, Zdravstven

  
  
  Abstract:
  Small molecules are, in addition to monoclonal antibodies, the main molecules for targeted cancer therapy. In the last two decades numerous small-molecule targeted drugs have been developed for the treatment of malignancies. Despite good response in a subpopulation of patients, small molecules still face challenges, such as a low response rate or development of drug resistance. Therefore, combined therapies with other targeted or local therapies are necessary to ensure good therapeutic effect. One of such local treatment can be electrochemotherapy, which is used for the treatment of several tumor histologies, for cutaneous and also deep-seated tumors. Here we will present the results of our previous preclinical research of combined electrochemotherapy and small molecule inhibitors and reviewed future perspectives. So far, we have tested three different small molecules in combination with electrochemotherapy; vemurafenib, sunitinib and olaparib, each for the pertinent cancer type. First, electrochemotherapy with bleomycin was tested in two human melanoma cell lines, with (SK-MEL-28) or without (CHL-1) BRAF V600E mutation, and later combined treatment with BRAF inhibitor vemurafenib was determined in BRAF mutated cells. Electrochemotherapy was effective, regardless of the mutational status of melanoma cells and synergistic interaction between vemurafenib and electrochemotehrapy with bleomycin was demonstrated in the BRAF V600E mutated melanoma cells. Second, PARP inhibitor olaparib was combined with electrochemotherapy with the aim to inhibit the repair of bleomycin or cisplatin induced DNA damage and thus potentiate the effectiveness of electrochemotherapy. Study was performed in vitro in BRCA1 mutated (HCC1937) and non-mutated (HCC1143) triple negative breast cancer cells and in vivo on subcutaneous HCC1937 tumors in mice. The mechanism of combined therapy was determined with the γH2AX foci evaluation. Combined therapy of electrochemotherapy with bleomycin and olaparib potentiated the effectiveness of electrochemotherapy in BRCA1 mutated, but not in non-mutated cells. Synergistic effect of combined therapy was due to the increased number of DNA double strand breaks. However, single olaparib treatment combined to electrochemotherapy with bleomycin in vivo had only minimal antitumor effect, indicating repetitive olaparib treatment would be needed. In the last research, sunitinib was combined with electrochemotherapy in BxPC-3 human pancreatic carcinoma cell line and interactions between two treatments were evaluated. The combined treatment of sunitinib and electrochemotherapy was synergistic for bleomycin only at the higher concentrations (> 0.14 μM bleomycin), whereas with lower doses of bleomycin, this effect was not observed. Future perspectives of combined therapy are focused on new targeted drugs such as CDK inhibitors or newly developed first MYC-targeted therapy.
  
  Keywords:
  electrochemotherapy, targeted therapy, cancer
  
  Refs:
  
  
  Topic 1:
  6. Cancer treatment and tumor ablation
  
  Topic 2:
  12. Biomedical applications