In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 12_Supplement ( 2023-12-01), p. B132-B132
Abstract:
Background: We used the TH-MYCN mouse model of neuroblastoma (NB) to determine the importance of simultaneously inhibiting both polyamine uptake and synthesis when added to standard-of-care chemotherapy/immunotherapy. Polyamines are essential cations frequently upregulated in tumors. We have shown the benefit of adding DFMO, an irreversible polyamine synthesis inhibitor, to standard-of-care chemotherapy in several NB mouse models (Evageliou, Clin Cancer Res 2016). Based on our work, a randomized Phase 2 COG trial of DFMO, added to chemotherapy/anti-GD2 immunotherapy, is ongoing for relapsed NB (NCT03794349). We recently showed in NB mouse models that DFMO efficacy is enhanced by adding the polyamine uptake inhibitor AMXT1501 (Gamble, Sci Transl Med, 2019). DFMO/AMXT1501 is now in adult clinical trial (NCT05500508). Preclinical modelling of polyamine-targeted therapeutics in TH-MYCN mice has been invaluable for supporting clinical trial design but has yet to include anti-GD2 immunotherapy. Methods: TH-MYCN mice were used to optimize DFMO/AMXT1501 therapy combined with temozolomide/irinotecan (TEM/IRI) or cyclophosphamide/topotecan (CYCLO/TOPO), and anti-GD2 (14G2a) antibody. We studied escalating doses of DFMO and AMXT1501 (n=10/group), with or without TEM/IRI or CYCLO/TOPO. 14G2a regimen was titrated toward human-relevant pharmacokinetic exposures to establish suitable conditions for combination therapies. Results: In the absence of chemo-immunotherapy, highest-dose DFMO (1.5%) and AMXT1501 (2.5 mg/kg/d) had greatest efficacy without increased toxicity. Median mouse survival was 2-fold greater compared with lower dose DFMO/AMXT1501 combinations, suggesting that maximising DFMO dose is critical. Similar improved efficacy was observed in combination with TEM/IRI or CYCLO/TOPO. Combining 14G2a (100ug 2x/wk, 18 wks; McNerney, Oncoimmunology, 2022) with either CYCLO/TOPO (single 5-day chemo cycle) or DFMO/AMXT1501 (1.5%/2.5 mg/kg/d) increased survival compared with either treatment alone. Combining all 5 drugs resulted in 100% survival at 1 year, with minimal toxicity. However substantial dose reductions of 14G2a ( & lt;25µg, 2 doses) and TEM/IRI or CYCLO/TOPO (single 2-day chemo cycle) were needed to identify clinically relevant backbones which achieved human-relevant 14G2a pharmacokinetics. Addition of DFMO alone to the clinically relevant CYCLO/TOPO/14G2a backbone did not result in benefit compared to backbone alone. In contrast, addition of AMXT1501 plus DFMO to the backbone significantly extended survival (P & lt; 0.001). Conclusions: We have increased the utility of the TH-MYCN mouse model for preclinical modelling of polyamine inhibition, and other investigational treatments, by pharmacokinetics-driven optimization of anti-GD2 therapy with standard-of-care chemotherapy backbones. This approach will improve optimisation for future NB clinical trials. Our data highlight the importance of adding AMXT1501 to DFMO for polyamine inhibition and support a planned international DFMO/AMXT1501/chemotherapy/anti-GD2 trial for refractory NB. Citation Format: Jayne Murray, Ruby Pandher, Lin Xiao, Klaartje Somers, Jennifer Brand, Erin Mosmann, Stephanie Alfred, Frances Kusuma, Adam Kearns, Julie R Park, Lynley V Marshall, Chiara Gorrini, Louis Chesler, Michael D Hogarty, Andrew D J Pearson, Mark Burns, Jamie I Fletcher, David Ziegler, Murray D Norris, Michelle Haber. Addition of AMXT1501 (polyamine uptake inhibitor) plus DFMO (polyamine synthesis inhibitor) to standard-of-care chemotherapy/anti-GD2 antibody in the TH-MYCN mouse neuroblastoma model, enhances efficacy compared to addition of DFMO alone [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B132.
Type of Medium:
Online Resource
ISSN:
1538-8514
DOI:
10.1158/1535-7163.TARG-23-B132
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
2062135-8
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