LAUSR

Overexpression of survivin, a crucial regulator of the mitotic spindle checkpoint, is associated with poor prognosis in neuroblastoma (NB). Transcriptional inhibitors of survivin have been tested in clinical trials. However, results have been disappointing. We thus investigated the small molecules LQZ-7I and S12 that inhibit dimerization of survivin protein and compared their growth-inhibiting efficacy with that of markedly decreased survivin expression in a novel transgenic NB mouse. Mice hemizygous for BIRC5 were crossed with TH-MYCN mice to generate BIRC5+/−/MYCNtg/+ mice. NB incidence, growth and retransplantation capacity were assessed. In vitro, LQZ-7I and S12 were used to inhibit survivin protein interactions and the effects on proliferation and cell cycle of NB cells were investigated. BIRC5 hemizygous mice developed NB although mRNA and protein expression of survivin was markedly decreased. Surprisingly, incidence and latency of the NB that developed in the BIRC5+/−/MYCNtg/+ mice did not differ from the NB in the TH-MYCN mice, and tumor growth and survival of the mice was not affected. In stark contrast, the survivin interaction inhibitors LQZ-7I and S12 abolished anchorage-independent growth and proliferation of NB cell lines. Reduced growth of NB cells resulted from defects in mitosis induced by LQZ-7I or S12 or. LQZ-7I was the more efficient inhibitor of NB cells while S12 was not able to reduce tumor growth in a xenograft model. Taken together, these results support the notion that inhibiting survivin interaction is more efficacious in NB than inhibiting survivin transcription. Citation Format: Carmen Dorneburg, Celimene Galliger, Voker Rasche, Andre Lechel, Thomas F. Barth, Klaus-Michael Debatin, Christian Beltinger. Inhibition of BIRC5/survivin by LQZ-7I inhibits neuroblastoma growth while hemizygosity of BIRC5 does not: implications for therapy of neuroblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6242.