Background: We have reported that the anti-malarial drug, quinacrine (QC), has significant in vivo anti-tumor activity (Neznanov et al, Cell Cycle, 2009, 8: 1-11). We have since identified curaxins, a more potent class of compounds with similar mechanism of action, whose anti-cancer activity results from chromatin-trapping of the Facilitates Chromatin Transcription (FACT) complex (Gasparian et al, Science Transl. Med, 2011, 3, 95ra74). These novel nongenotoxic agents, like QC, cause simultaneous p53 activation and NF-kB inhibition and tumor cell death. We have now studied the effects of QC and one of the most active curaxins, CBL0137, in the TH-MYCN mouse model of neuroblastoma as well as a nude mouse xenograft model of the disease.
Methods: Cohorts of homozygous TH-MYCN mice with small palpable tumors or of human MYCN-amplified BE(2)-C neuroblastoma tumor-bearing nude mice (n=10) were treated with QC (TH-MYCN mice only) or CBL0137, alone or combined with chemotherapeutic drugs.
Results: QC alone had no significant effect on tumor progression and did not enhance cisplatin or VP16 activity. However, strong anti-tumor activity was observed when QC was combined with cyclophosphamide (CPM) (4/10 QC/CPM-treated vs 0/10 CPM-treated long-term survivors, P<0.001). The effect of CBL0137 alone, administered either orally or iv, on tumor progression was more dramatic. Oral CBL0137 significantly extended survival (median survival time from start of treatment = 31.0±9.9 days versus controls = 3.0±0.2 days; P<0.0001), and was as effective as cisplatin or CPM single-agent treatment. Remarkably, CBL0137 administered iv resulted in a significant number of long-term tumor free survivors (7/9 alive at Day 120). When oral CBL0137 treatment was combined with CPM, survival was substantially increased (7/10 long-term tumor-free TH-MYCN mice) compared to either CBL0137 (0/10 alive) or CPM (1/10 alive) alone (P<0.005 in each case). Most dramatic results were observed when CBL0137 was combined with the standard neuroblastoma relapse protocol of CPM plus topotecan (TOPO). CPM/TOPO treatment resulted in 0/10 long-term survivors, however when combined with either oral or iv CBL0137, this combination cured 5/8 or 11/12 TH-MYCN mice, respectively. Moreover, the combination of iv CBL0137/CPM/TOPO resulted in more than a doubling of lifespan in BE(2)-C tumor-bearing mice compared to those treated with CPM/TOPO or CBL0137 alone (P<0.0001).
Conclusions: These are the most impressive results that we have ever observed for any therapeutic protocol in either the TH-MYCN homozygous or BE(2)-C xenograft mouse models. The combination of CPM/TOPO with iv CBL0137 appears to be a highly promising new treatment approach for refractory neuroblastoma. Safety and efficacy of CBL0137 is currently being investigated in a Phase I clinical trial in advanced cancer patients.
Citation Format: Michelle Haber, Jayne Murray, Ashleigh Carnegie-Clark, Hannah Webber, Glenn M. Marshall, Katerina V. Gurova, Catherine A. Burkhart, Andrei Purmal, Andrei V. Gudkov, Murray D. Norris. Anticancer compound curaxin CBL0137, that simultaneously suppresses NF-κB and activates p53, is highly effective in two independent mouse models of neuroblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2759. doi:10.1158/1538-7445.AM2013-2759