Abstract 4136: Marked decrease of BIRC5/Survivin by haploinsufficiency does not inhibit neuroblastoma in transgenic mice: Implications for survivin as a therapeutic target in neuroblastoma

Abstract

Abstract Overexpression of survivin, a crucial regulator of the mitotic spindle checkpoint with additional antiapoptotic effects, is associated with poor prognosis in neuroblastoma (NB) and other cancers. Thus, survivin is a promising therapeutic target in NB. Transcriptional inhibitors of survivin show preclinical efficacy and have been tested in clinical trials. The results of these trials, however, have been disappointing, due to modest efficacy and unexpected off-target effects. We thus investigated the consequences of marked, yet incomplete decrease of survivin on NB in a novel transgenic mouse model. To this end, we crossed mice haploinsufficient for survivin with TH-MYCN mice to generate BIRC5+/- MYCN tg/+ mice. These mice developed NB with markedly decreased mRNA and protein expression of survivin. Surprisingly, incidence and latency of the NB that developed in the BIRC5+/- MYCN tg/+ mice were not different from those in the TH-MYCN mice. Growth of tumors was not decreased in BIRC5+/- MYCN tg/+ mice, as assessed by serial MRI imaging, and survival of the mice was not increased. Immunohistochemistry of the NB did not show decreased proliferation (Ki67), increased apoptosis (activated caspase 3) or a change in vascularity (CD31). No difference in copy number variations between the two NB mouse models was discernible using CGH arrays. To determine whether dysfunctional T cells described in mice haploinsufficient for survivin could have masked any loss of aggressiveness of NB cells haploinsufficient for survivin, NB of BIRC5+/- MYCN tg/+ mice were retransplanted into survivin sufficient mice. No difference in tumor incidence, latency and growth was detected. Taken together, despite a marked decrease in the expression of BIRC5/survivin by haploinsufficiency development and growth of NB were not inhibited. While a further decrease of survivin beyond that seen in haploinsufficiency will inhibit NB, it most likely will also elicit marked side effects, given that survivin is essential for normal cells. Our results cast doubt on the efficacy of inhibitors of survivin expression in NB and call for targeting survivin by alternative approaches, such as inhibiting protein-protein interactions of survivin. Citation Format: Carmen Dorneburg, Volker Rasche, Andre Lechel, Sarah-Fee Katz, Klaus-Michael Debatin, Christian Beltinger. Marked decrease of BIRC5/Survivin by haploinsufficiency does not inhibit neuroblastoma in transgenic mice: Implications for survivin as a therapeutic target in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4136.