PARP inhibitor olaparib increases the oncolytic activity of dl922‐947 in in vitro and in vivo model of anaplastic thyroid carcinoma

Abstract

PARP inhibitors are mostly effective as anticancer drugs in association with DNA damaging agents. We have previously shown that the oncolytic adenovirus dl922-947 induces extensive DNA damage, therefore we hypothesized a synergistic antitumoral effect of the PARP inhibitor olaparib in association with dl922-947. Anaplastic thyroid carcinoma was chosen as model since it is a particularly aggressive tumor and, because of its localized growth, it is suitable for intratumoral treatment with oncolytic viruses. Here, we show that dl922-947 infection induces PARP activation, and we confirm in vitro and in vivo that PARP inhibition increases dl922-947 replication and oncolytic activity. In vitro, the combination with olaparib exacerbates the appearance of cell death markers, such as Annexin V positivity, caspase 3 cleavage, cytochrome C release and propidium iodide permeability. In vivo, we also observed a better viral distribution upon PARP inhibition. Changes in CD31 levels suggest a direct effect of olaparib on tumor vascularization and on the viral distribution within the tumor mass. The observation that PARP inhibition enhances the effects of dl922-947 is highly promising not only for the treatment of anaplastic thyroid carcinoma but, in general, for the treatment of other tumors that could benefit from the use of oncolytic viruses.

The oncolytic virusdl922-947 reduces IL-8/CXCL8 and MCP-1/CCL2 expression and impairs angiogenesis and macrophage infiltration in anaplastic thyroid carcinoma

“…Indeed, dl 922-947 treatment of tumor xenografts established in athymic mice reduces IL8 mRNA level after 1 week and Cd31 mRNA level and TMD after 3 weeks of treatment. These observations are in line with the anti-angiogenic effect of dl 922-947 observed in ATC xenografts established with FRO cells [ 29 ]. Although our results strongly suggest that the anti-angiogenic activity of dl 922-947 relies on the decreased production of IL-8 by ATC cells, we cannot exclude that the in vivo effects of dl 922-947 treatment on TMD are triggered by additional mechanisms.…”

“…These animals remained tumor-free until the end of the experiment. In previous studies performed with a different ATC cell line we did not observe a significant effect of the virus within 8 days of treatment [ 26 , 28 , 29 ], and a complete tumor regression rarely occurred (Portella G., personal observations). These discrepancies can be explained by taking into account the higher viral dose used in the present study.…”

“…In several experimental neoplastic models, including ATC, dl 922-947 treatment, alone or in combination with molecularly-targeted drugs or ionizing radiations, can induce cancer cell death and tumor regression [ 23 - 30 ]. Although these studies were aimed to demonstrate synergistic effects of the combined treatments, we also observed an anti-angiogenic effect of the virus [ 29 ]. It is still unclear whether and how dl 922-947 virotherapy modulates ATC microenvironment.…”

Induction of cell fusion/apoptosis in anaplastic thyroid carcinoma in orthotopic mouse model by urokinase‐specific oncolytic Sendai virus

“…49 Other types of anticancer treatment combined with oncolytic adenovirus dl922-947 demonstrated potential to increase the antitumor activity. 42,50,51 Furthermore, ionizing radiation induces synergistic cell killing in combinatorial treatment with dl922-947 against subcutaneous xenografts of ATC. 52 Combined therapy based on the cytotoxic mechanism of a virus can be expected to further increase the therapeutic effect, including for BioKnife.…”

Olaparib modulates DNA repair efficiency, sensitizes cervical cancer cells to cisplatin and exhibits anti-metastatic property

“…Olaparib has been demonstrated to exert anticancer property in BRCA1 or BRCA2 deficient breast cancer 8 , 10 , loss of ERCC1 and synergistic interaction with cisplatin in non-small cell lung carcinoma 11 – 13 , ATM depletion in breast cancer 14 , MRE11 loss in endometrial cancer 15 and defect in homologous recombination 16 , 17 . Olaparib also tends to increase oncolytic activity of dl922-947 in a model of anaplastic thyroid carcinoma 18 . Contribution of PARP1 in regulation of metastatic events has also been thoroughly investigated in DNA repair independent manner in lung cancer via S100A4 and in melanoma via regulation of vimentin expression 19 – 21 .…”