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The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma

Maser, Tyler and Zagorski, Joseph and Kelly, Shannon and Ostrander, Anna and Goodyke, Austin and Nagulapally, Abhinav and Bond, Jeffrey and Sholler, Giselle Saulnier (2020) The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma. Cancer Medicine. ISSN 2045-76342045-7634

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, with amplification of the oncogene MYCN being a hallmark of high-risk disease and poor prognosis. Although less frequent, overexpression of MYC is similarly an indicator of poor prognosis. Most NB tumors initially respond to chemotherapy, however, a large number of these cases relapse, resulting in chemoresistant disease. After relapse there is growing evidence of p53 inactivation, which suggests a role for p53 in NB’s chemo-sensitivity. Highly mutated in other cancer types, p53 mutations in NB are rare. With p53 mutations being rare, recent work has suggested that dysregulation of the negative regulator of p53, MDM2, may be a mechanism of p53 suppression in NB. MYC/MYCN and MDM2 have been shown to interact and contribute to NB growth and disease progression. In vitro treatment of NB cells with MDM2 inhibitors has shown promise in increasing the expression of p53, leading to a decrease in proliferation, and increasing apoptosis. BET (Bromodomain and Extra-Terminal domain) inhibitors have also been shown to be effective in treating NB cells in vitro, decreasing MYC/MYCN expression, and resulting in increased apoptosis and differentiation. Our study focuses on the combined treatment of a MDM2 inhibitor (CGM097) with a BET inhibitor (OTX015) resulting in greater p53 activation, lower expression of MYC family proteins and a subsequent synergistic increase in NB cell death.

Item Type: Article
Keywords: HMD2, BET, CGM097, OTX015, MYCN, neuroblasmtoma
Date Deposited: 14 Nov 2020 00:45
Last Modified: 14 Nov 2020 00:45
URI: https://oak.novartis.com/id/eprint/38763

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