Combination of electrochemotherapy with poly (adenosin diphosphate-ribose) polymerase inhibitor in treatment of breast cancer

Electrochemotherapy is a local tumor ablation technique. It is based on a physical delivery method, electroporation. In case of electrochemotherapy, cisplatin and bleomycin are two most commonly used cytotoxic drugs. Bleomycin and cisplatin cytotoxicity is based on interactions with DNA, causing DNA breaks or adducts, respectively. Therefore, tumors of different histological types can be effectively treated with electrochemotherapy. Nevertheless, the effectiveness of electrochemotherapy in different histological types of tumors is different. The most effective is in treatment of basal cell carcinoma with approximately 90% of CR (complete response) , followed by melanoma with around 60-70% CR while in breast cancer there are only around 50% of CR. In breast cancer, treatment electrochemotherapy is used for the ablation of cutaneous metastases in advanced patients, who have previously been treated with either systemic therapy, surgery or radiotherapy or combination of those modalities. Any treatment that the patient has received before electrochemotherapy may also contribute to the resistance of breast cancer metastases to electrochemotherapy, therefor the combination with other treatment modalities is crucial for obtaining higher complete response rate. Our research is aimed to combine electrochemotherapy with PARP1 and PARP2 inhibitor. The rationale behind our combination approach is to block DNA repair proteins PARP1 and PARP2 and therefore prevent sufficient repair of DNA breaks caused by bleomycin or repair replication fork stalling caused by cisplatin. We would like to determine the antitumor effectiveness of combined therapy; electrochemotherapy with bleomycin or cisplatin with selected PARP inhibitor for the treatment of different histological types of human breast cancer. The effects will be evaluated in in vitro cell cultures and on 3D human breast cancer spheroids. Based on in vitro results the combined therapy will also be tested in vivo. All the findings are also clinically relevant for further development of electrochemotherapy.