An Evaluation of the Efficacy of Nutlin-3 and Topotecan in Combination with Lu-DOTATATE for the Treatment of Neuroblastoma

Overview

Journal Oncotarget

Specialty Oncology

Date 2018 Jul 19

PMID 30018737

Citations 4

Authors

Mathias Tesson

Richa Vasan

Andreas Hock

Colin Nixon

Colin Rae

Mark Gaze

Robert Mairs

Affiliations

Soon will be listed here.

Abstract

Targeted radiotherapy of metastatic neuroblastoma using the somatostatin receptor (SSTR)-targeted octreotide analogue DOTATATE radiolabelled with lutetium-177 (Lu-DOTATATE) is a promising strategy. This study evaluates whether its effectiveness may be enhanced by combination with radiosensitising drugs. The growth rate of multicellular tumour spheroids, derived from the neuroblastoma cell lines SK-N-BE(2c), CHLA-15 and CHLA-20, was evaluated following treatment with Lu-DOTATATE, nutlin-3 and topotecan alone or in combination. Immunoblotting, immunostaining and flow cytometric analyses were used to determine activation of p53 signalling and cell death. Exposure to Lu-DOTATATE resulted in a significant growth delay in CHLA-15 and CHLA-20 spheroids, but not in SK-N-BE(2c) spheroids. Nutlin-3 enhanced the spheroid growth delay induced by topotecan in CHLA-15 and CHLA-20 spheroids, but not in SK-N-BE(2c) spheroids. Importantly, the combination of nutlin-3 with topotecan enhanced the spheroid growth delay induced by X-irradiation or by exposure to Lu-DOTATATE. The efficacy of the combination treatments was p53-dependent. These results indicate that targeted radiotherapy of high risk neuroblastoma with Lu-DOTATATE may be improved by combination with the radiosensitising drugs nutlin-3 and topotecan.

Citing Articles

p53-Mediated Radiosensitization of Lu-DOTATATE in Neuroblastoma Tumor Spheroids.

Lundsten S, Berglund H, Jha P, Krona C, Hariri M, Nelander S Biomolecules. 2021; 11(11).

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MI-773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1.

Chen Y, Zhang Z, Li X, Tao Y, Wu S, Fang F Oncol Lett. 2021; 22(6):838.

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Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells.

Nile D, Rae C, Walker D, Waddington J, Vincent I, Burgess K Cancer Metab. 2021; 9(1):24.

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Molecular targeting therapies for neuroblastoma: Progress and challenges.

Zafar A, Wang W, Liu G, Wang X, Xian W, McKeon F Med Res Rev. 2020; 41(2):961-1021.

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References

Tomicic M, Christmann M, Kaina B . Topotecan-triggered degradation of topoisomerase I is p53-dependent and impacts cell survival. Cancer Res. 2005; 65(19):8920-6. DOI: 10.1158/0008-5472.CAN-05-0266. View

ODorisio M, Chen F, ODorisio T, Wray D, Qualman S . Characterization of somatostatin receptors on human neuroblastoma tumors. Cell Growth Differ. 1994; 5(1):1-8. View

Giono L, Manfredi J . The p53 tumor suppressor participates in multiple cell cycle checkpoints. J Cell Physiol. 2006; 209(1):13-20. DOI: 10.1002/jcp.20689. View

Matthay K, Yanik G, Messina J, Quach A, Huberty J, Cheng S . Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol. 2007; 25(9):1054-60. DOI: 10.1200/JCO.2006.09.3484. View

Tweddle D, Malcolm A, Bown N, Pearson A, Lunec J . Evidence for the development of p53 mutations after cytotoxic therapy in a neuroblastoma cell line. Cancer Res. 2001; 61(1):8-13. View

Csaba Z, Peineau S, Dournaud P . Molecular mechanisms of somatostatin receptor trafficking. J Mol Endocrinol. 2011; 48(1):R1-12. DOI: 10.1530/JME-11-0121. View

Ballangrud A, Yang W, Dnistrian A, Lampen N, Sgouros G . Growth and characterization of LNCaP prostate cancer cell spheroids. Clin Cancer Res. 1999; 5(10 Suppl):3171s-3176s. View

Kwok T, Twentyman P . The relationship between tumour geometry and the response of tumour cells to cytotoxic drugs--an in vitro study using EMT6 multicellular spheroids. Int J Cancer. 1985; 35(5):675-82. DOI: 10.1002/ijc.2910350517. View

Chen L, Rousseau R, Middleton S, Nichols G, Newell D, Lunec J . Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma. Oncotarget. 2015; 6(12):10207-21. PMC: 4496350. DOI: 10.18632/oncotarget.3504. View

10.

Ribeiro C, Rodrigues C, Moreira R, Santos M . Chemical Variations on the p53 Reactivation Theme. Pharmaceuticals (Basel). 2016; 9(2). PMC: 4932543. DOI: 10.3390/ph9020025. View

11.

Mairs R, Boyd M . Preclinical assessment of strategies for enhancement of metaiodobenzylguanidine therapy of neuroendocrine tumors. Semin Nucl Med. 2011; 41(5):334-44. DOI: 10.1053/j.semnuclmed.2011.03.004. View

12.

Gaze M, Chang Y, Flux G, Mairs R, Saran F, Meller S . Feasibility of dosimetry-based high-dose 131I-meta-iodobenzylguanidine with topotecan as a radiosensitizer in children with metastatic neuroblastoma. Cancer Biother Radiopharm. 2005; 20(2):195-9. DOI: 10.1089/cbr.2005.20.195. View

13.

Ventura A, Kirsch D, McLaughlin M, Tuveson D, Grimm J, Lintault L . Restoration of p53 function leads to tumour regression in vivo. Nature. 2007; 445(7128):661-5. DOI: 10.1038/nature05541. View

14.

Chen Z, Wang L, Yao D, Yang T, Cao W, Dou J . Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis. Sci Rep. 2016; 6:38011. PMC: 5171816. DOI: 10.1038/srep38011. View

15.

Tomicic M, Christmann M, Kaina B . Topotecan triggers apoptosis in p53-deficient cells by forcing degradation of XIAP and survivin thereby activating caspase-3-mediated Bid cleavage. J Pharmacol Exp Ther. 2009; 332(1):316-25. DOI: 10.1124/jpet.109.159962. View

16.

Kraal K, Tytgat G, van Eck-Smit B, Kam B, Caron H, Van Noesel M . Upfront treatment of high-risk neuroblastoma with a combination of 131I-MIBG and topotecan. Pediatr Blood Cancer. 2015; 62(11):1886-91. DOI: 10.1002/pbc.25580. View

17.

Maggi M, Baldi E, Finetti G, Franceschelli F, Brocchi A, Lanzillotti R . Identification, characterization, and biological activity of somatostatin receptors in human neuroblastoma cell lines. Cancer Res. 1994; 54(1):124-33. View

18.

Daoud S, Munson P, Reinhold W, Young L, Prabhu V, Yu Q . Impact of p53 knockout and topotecan treatment on gene expression profiles in human colon carcinoma cells: a pharmacogenomic study. Cancer Res. 2003; 63(11):2782-93. View

19.

Wilson J, Gains J, Moroz V, Wheatley K, Gaze M . A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma. Eur J Cancer. 2013; 50(4):801-15. DOI: 10.1016/j.ejca.2013.11.016. View

20.

Selivanova G . Wild type p53 reactivation: from lab bench to clinic. FEBS Lett. 2014; 588(16):2628-38. DOI: 10.1016/j.febslet.2014.03.049. View