Preclinical investigations with inhibitors of DNA double-strand break repair for improved chemotherapy of malignant brain tumours

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Glioblastoma multiforme (GBM, according to WHO astrocytoma grade III and IV) is a very aggressive type of brain tumour with bad prognosis and weak response to standard therapies, therefore new chemotherapeutic approaches are needed. The main models of the present study will be GBM cell lines and xenografts in immunodeficient nude mice. We will use in our experiments the alkylating drugs temozolomide (TMZ) and the chloronitrosoureas (CNUs) CCNU and ACNU. Due to the DNA alkylating mode of action and cancer cell killing activity, TMZ and the CNUs are used as first choice drugs for adjuvant chemotherapy of primary brain tumors and metastases of various origins. In cancer cells they induce lethal secondary DNA double-strand breaks (DSB) that can be repaired by DSB repair pathways: homologus recombination (HR) and PARP-dependent non-homologous end-joining. For modulation of DSB repair and the sensitivity against TMZ and CNUs, we will use specific HRi (the RAD51i RI-1 and B02) and PARPi. We have already demonstrated that RI-1 increases the sensitivity to CCNU in the subcutaneous xenograft model. The PARPi olaparib has been recently approved for the treatment of ovarian carcinomas in the USA and Europe. It is of interest to investigate if PARPi, depending on their pharmacodynamics, are efficient in killing glioblastoma cells. Olaparib, however, is a substrate of the cellular efflux pump mechanisms, therefore we include in our studies the PARPi veliparib which is not a substrate and may display a better killing efficacy and ‘synthetic lethality’-like effects in combination with RAD51i. The combinations, which do show increased efficacy in vitro, will be tested in animal experiments (subcutaneous xenografts) and, further, in the intracranial model.