Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma

Oncotarget

Volumn 6, Issue 12, 2015, Pages 10207-10221

  Chen, Lindi ^a   Rousseau, Raphaël F ^b   Middleton, Steven A ^c   Nichols, Gwen L ^c   Newell, David R ^a   Lunec, John ^a   Tweddle, Deborah A ^a  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

^b GENENTECH INC   (United States)

^c HOFFMANN LA ROCHE INC   (United States)

Author keywords

Calcusyn; Combination therapy; MDM2 p53 antagonists; Neuroblastoma; RG7388

Indexed keywords

BUSULFAN; CASPASE 3; CASPASE 7; CISPLATIN; CYCLIN DEPENDENT KINASE INHIBITOR 2A; DOXORUBICIN; IDASANUTLIN; PROTEIN P53; TEMOZOLOMIDE; TOPOTECAN; 4 AMINOBENZOIC ACID DERIVATIVE; ANTINEOPLASTIC AGENT; MDM2 PROTEIN, HUMAN; PROTEIN MDM2; PYRROLIDINE DERIVATIVE; TP53 PROTEIN, HUMAN;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CELL CYCLE ARREST; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENTIATION; DRUG SCREENING; ENZYME ACTIVITY; GENE EXPRESSION REGULATION; HUMAN; HUMAN CELL; MDM2 GENE; MONOTHERAPY; MYCN GENE; NEUROBLASTOMA; NEUROBLASTOMA CELL LINE; P14ARF GENE; ANTAGONISTS AND INHIBITORS; BRAIN NEOPLASMS; METABOLISM; TUMOR CELL LINE;

ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BRAIN NEOPLASMS; CELL LINE, TUMOR; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; NEUROBLASTOMA; PARA-AMINOBENZOATES; PROTO-ONCOGENE PROTEINS C-MDM2; PYRROLIDINES; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84929603439     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.3504     Document Type: Article

References (38)

1. Chen L and Tweddle DA. p53, SKP2, and DKK3 as MYCN Target Genes and Their Potential Therapeutic Significance. Frontiers in oncology. 2012; 2:173.
2. Brown CJ, Lain S, Verma CS, Fersht AR and Lane DP. Awakening guardian angels: drugging the p53 pathway. Nature reviews. 2009; 9(12):862-873.
3. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N and Liu EA. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science (New York, NY. 2004; 303(5659):844-848.
4. Ray-Coquard I, Blay JY, Italiano A, Le Cesne A, Penel N, Zhi J, Heil F, Rueger R, Graves B, Ding M, Geho D, Middleton SA, Vassilev LT, Nichols GL and Bui BN. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-ofmechanism study. Lancet Oncol. 2012; 13(11):1133-1140.
5. Iancu-Rubin C, Mosoyan G, Glenn K, Gordon RE, Nichols GL and Hoffman R. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Experimental hematology. 2014; 42(2):137-145 e135.
6. Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, Chu XJ, Bartkovitz D, Podlaski F, Janson C, Tovar C, Filipovic ZM, Higgins B, Glenn K, Packman K, Vassilev LT, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. Journal of medicinal chemistry. 2013; 56(14):5979-5983.
7. Siu L, Italiano A, Miller W, Blay J, Gietema J, Bang Y, Mileshkin L, Hirte H, Reckner M, Higgins B, Jukofsky L, Blotner S, Zhi J, Middleton S, Nichols G and Chen L. (2014). Phase 1 dose escalation, food effect, and biomarker study of RG7388, a more potent second-generation MDM2 antagonist, in patients (pts) with solid tumors. 2014 ASCO Annual Meeting. (May 30-June 3, 2014, Chicago, IL, USA:J Clin Oncol 32:5s, 2014 (suppl; abstr 2535)).
8. Higgins B, Glenn K, Walz A, Tovar C, Filipovic Z, Hussain S, Lee E, Kolinsky K, Tannu S, Adames V, Garrido R, Linn M, Meille C, Heimbrook D, Vassilev L and Packman K. Preclinical Optimization of MDM2 Antagonist Scheduling for Cancer Treatment by Using a Model-Based Approach. Clin Cancer Res. 2014; 20(14):3742-3752.
9. Park JR, Eggert A and Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematology/oncology clinics of North America. 2010; 24(1):65-86.
10. Cohn SL and Tweddle DA. MYCN amplification remains prognostically strong 20 years after its "clinical debut". Eur J Cancer. 2004; 40(18):2639-2642.
11. Carr-Wilkinson J, O'Toole K, Wood KM, Challen CC, Baker AG, Board JR, Evans L, Cole M, Cheung NK, Boos J, Kohler G, Leuschner I, Pearson AD, Lunec J and Tweddle DA. High Frequency of p53/MDM2/p14ARF Pathway Abnormalities in Relapsed Neuroblastoma. Clin Cancer Res. 2010; 16(4):1108-1118.
12. Michaelis M, Rothweiler F, Barth S, Cinatl J, van Rikxoort M, Loschmann N, Voges Y, Breitling R, von Deimling A, Rodel F, Weber K, Fehse B, Mack E, Stiewe T, Doerr HW, Speidel D, et al. Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell death & disease. 2011; 2:e243.
13. Van Maerken T, Rihani A, Van Goethem A, De Paepe A, Speleman F and Vandesompele J. Pharmacologic activation of wild-type p53 by nutlin therapy in childhood cancer. Cancer letters. 2014; 344(2):157-165.
14. Rew Y, Sun D, Gonzalez-Lopez De Turiso F, Bartberger MD, Beck HP, Canon J, Chen A, Chow D, Deignan J, Fox BM, Gustin D, Huang X, Jiang M, Jiao X, Jin L, Kayser F, et al. Structure-based design of novel inhibitors of the MDM2-p53 interaction. Journal of medicinal chemistry. 2012; 55(11):4936-4954.
15. Zhao Y, Yu S, Sun W, Liu L, Lu J, McEachern D, Shargary S, Bernard D, Li X, Zhao T, Zou P, Sun D and Wang S. A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice. Journal of medicinal chemistry. 2013; 56(13):5553-5561.
16. Hardcastle IR, Liu J, Valeur E, Watson A, Ahmed SU, Blackburn TJ, Bennaceur K, Clegg W, Drummond C, Endicott JA, Golding BT, Griffin RJ, Gruber J, Haggerty K, Harrington RW, Hutton C, et al. Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potency. Journal of medicinal chemistry. 2011; 54(5):1233-1243.
17. Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M, Tardell C, Garrido R, Lee E, Kolinsky K, To KH, Linn M, Podlaski F, Wovkulich P, Vu B and Vassilev LT. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer research. 2013; 73(8):2587-2597.
18. Gamble LD, Kees UR, Tweddle DA and Lunec J. MYCN sensitizes neuroblastoma to the MDM2-p53 antagonists Nutlin-3 and MI-63. Oncogene. 2012; 31(6):752-763.
19. Van Maerken T, Rihani A, Dreidax D, De Clercq S, Yigit N, Marine JC, Westermann F, De Paepe A, Vandesompele J and Speleman F. Functional analysis of the p53 pathway in neuroblastoma cells using the small-molecule MDM2 antagonist nutlin-3. Molecular cancer therapeutics. 2011; 10(6):983-993.
20. Chen L, Iraci N, Gherardi S, Gamble LD, Wood KM, Perini G, Lunec J and Tweddle DA. p53 Is a Direct Transcriptional Target of MYCN in Neuroblastoma. Cancer research. 2010; 70(4):1377-1388.
21. Carr-Wilkinson J, Griffiths R, Elston R, Gamble LD, Goranov B, Redfern CP, Lunec J and Tweddle DA. Outcome of the p53-mediated DNA damage response in neuroblastoma is determined by morphological subtype and MYCN expression. Cell cycle (Georgetown, Tex. 2011; 10(21):3778-3787.
22. Carr J, Bell E, Pearson AD, Kees UR, Beris H, Lunec J and Tweddle DA. Increased frequency of aberrations in the p53/MDM2/p14(ARF) pathway in neuroblastoma cell lines established at relapse. Cancer research. 2006; 66(4):2138-2145.
23. Rodriguez-Lopez AM, Xenaki D, Eden TO, Hickman JA and Chresta CM. MDM2 mediated nuclear exclusion of p53 attenuates etoposide-induced apoptosis in neuroblastoma cells. Molecular pharmacology. 2001; 59(1):135-143.
24. Mergui X, Leteurtre F, Lipinski M, Benard J and Amor-Gueret M. Two distinctly altered cellular responses to DNA double-strand breaks in human neuroblastoma. Biochimie. 2008; 90(11-12):1656-1666.
25. Barbieri E, Mehta P, Chen Z, Zhang L, Slack A, Berg S and Shohet JM. MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death. Molecular cancer therapeutics. 2006; 5(9):2358-2365.
26. Fulda S, Lutz W, Schwab M and Debatin KM. MycN sensitizes neuroblastoma cells for drug-induced apoptosis. Oncogene. 1999; 18(7):1479-1486.
27. Slack A, Chen Z, Tonelli R, Pule M, Hunt L, Pession A and Shohet JM. The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. Proc Natl Acad Sci U S A. 2005; 102(3):731-736.
28. Kracikova M, Akiri G, George A, Sachidanandam R and Aaronson SA. A threshold mechanism mediates p53 cell fate decision between growth arrest and apoptosis. Cell death and differentiation. 2013; 20(4):576-588.
29. Bell E, Premkumar R, Carr J, Lu X, Lovat PE, Kees UR, Lunec J and Tweddle DA. The role of MYCN in the failure of MYCN amplified neuroblastoma cell lines to G1 arrest after DNA damage. Cell cycle (Georgetown, Tex. 2006; 5(22):2639-2647.
30. Ladenstein RL, Poetschger U, Luksch R, Brock P, Castel V, Yaniv I, Papadakis V, Laureys G, Malis J, Balwierz W, Ruud E, Kogner P, Schroeder H, Forjaz De Lacerda A, Beck Popovic M, Bician P, et al. (2011). Busulphanmelphalan as a myeloablative therapy (MAT) for high-risk neuroblastoma: Results from the HR-NBL1/SIOPEN trial. 2011 ASCO Annual Meeting. (June 3-7, 2011, Chicago, IL, USA: Journal of Clinical Oncology).
31. Ohnstad HO, Paulsen EB, Noordhuis P, Berg M, Lothe RA, Vassilev LT and Myklebost O. MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines. BMC cancer. 2011; 11:211:211-211.
32. de Lange J, Ly LV, Lodder K, Verlaan-de Vries M, Teunisse AF, Jager MJ and Jochemsen AG. Synergistic growth inhibition based on small-molecule p53 activation as treatment for intraocular melanoma. Oncogene. 2012; 31(9):1105-1116.
33. Vassilev LT. Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell cycle (Georgetown, Tex. 2004; 3(4):419-421.
34. Delaisi C, Meaux I, Dos-Santos O, Barrière C, Duffieux F, Hoffmann D, Rak A, Wolfrom M, Flèche F, Zhou-Liu Q, Lalleman V, Bégassat F, Lowinski M, Besnard S, De Chalain D, Bastien H, et al. (2012). In vitro characterization of spiro-oxindole-based modulators of the MDM2-p53 interaction and their interspecies selectivity. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research 2012-Mar 31-Apr 4, 2012. (Chicago, IL, Philadelphia (PA): Cancer Res 2012;72(8 Suppl):Abstract nr 4648).
35. Khoo KH, Verma CS and Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nature reviews Drug discovery. 2014; 13(3):217-236.
36. Ding K, Lu Y, Nikolovska-Coleska Z, Wang G, Qiu S, Shangary S, Gao W, Qin D, Stuckey J, Krajewski K, Roller PP and Wang S. Structure-based design of spirooxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. Journal of medicinal chemistry. 2006; 49(12):3432-3435.
37. Watson AF, Liu J, Bennaceur K, Drummond CJ, Endicott JA, Golding BT, Griffin RJ, Haggerty K, Lu X, McDonnell JM, Newell DR, Noble ME, Revill CH, Riedinger C, Xu Q, Zhao Y, et al. MDM2-p53 protein-protein interaction inhibitors: a-ring substituted isoindolinones. Bioorganic & medicinal chemistry letters. 2011; 21(19):5916-5919.
38. Chen L, Zhao Y, Halliday GC, Berry P, Rousseau RF, Middleton SA, Nichols GL, Del Bello F, Piergentili A, Newell DR, Lunec J and Tweddle DA. Structurally diverse MDM2-p53 antagonists act as modulators of MDR-1 function in neuroblastoma. British journal of cancer. 2014; 111(4):716-725.