Abstract 2835: MDM2 antagonist-based therapeutic response is discriminated by a 4-gene signature in acute myeloid leukemia patients
Authors: Zhong Hua , Chen Gong , Jukofsky Lori , Geho David , Han Sung Won , Birzele Fabian , Bader Sabine , Himmelein Lucia , Cai James , Albertyn Zayed , Rothe Mark , Essioux Laurent , Burtscher Helmut , Middleton Steven A. , Chen Lin-Chi , Dangl Markus , Pierceall William E. , Nichols Gwen 
Published: August 2015

The activity of p53, a key tumor suppressor is tightly controlled by MDM2-mediated ubiquination and degradation. Nutlins, a class of small-molecule MDM2 antagonists, have been characterized as drivers of p53 re-activation. Acute myeloid leukemia (AML) is uniquely sensitive to p53 re-activation as ∼90% of cases have wild-type TP53 and frequent MDM2 overexpression to overcome mechanisms of oncogene addiction. Personalized theranostic strategies may distinguish patients likely to clinically benefit from MDM2-antagonist therapy.

Association between MDM2 antagonist (RG7112) growth inhibition (IC50s) in 287 human cancer cell lines (Cell Lines for Oncology/Chugai Accumulative Tumor Encyclopedia), and pretreatment RNAseq profiling established a classifier comprising MDM2, XPC, BBC3, and CDKN2A. This signature significantly associated with cell-line efficacy to MDM2 antagonist (odds ratio = 2.53; P&lt;0.001) and discriminated MDM2 antagonist-sensitive (IC50 10 uM) better than MDM2 mRNA or TP53 mutation status alone (AUC = 0.92). Multivariate logistic regression indicated signature scores were significant (odds ratio = 1.84; P&lt;0.001) when adjusted for TP53 mutation status.

RG7112 treatment was assessed in a phase 1 dose escalation trial in relapsed/refractory AML patients (NO21279). Signature scores of AML patient blood specimens at baseline significantly associated with clinical response (PD&lt;HI&lt;MLFS&lt;CR; Spearman correlation coefficient 0.58; P&lt;0.001); and with pharmacodynamic biomarker response, defined as change in MDM2 mRNA expression in blood (Spearman correlation coefficient 0.41; P = 0.02). Patient response was discriminated by the signature with 100% sensitivity/71% specificity (Wilcoxon p = .0007, AUC = 0.72). Monitoring of signature with clinical response in a second AML Phase 1/1b clinical trial NP28679 with a next generation nutlin-class MDM2 Antagonist RG7388 validated this panel as significantly discriminating MDM2 antagonist therapeutic responders and non-responders in AML patients (Wilcoxon Rank Sum Test P = 0.008; AUC = .75).

In summary, we demonstrate that a biological classifier discriminates response broadly to MDM2-antagonist therapy. The level of evidence attained by cell line efficacy modeling and response assessments in trial NO21279 (with MDM2 antagonist RG7112) and now in trial NP28679 (with MDM2 antagonist RG7388) adds substantial weight to the validity of this panel.

Citation Format: Hua Zhong, Gong Chen, Lori Jukofsky, David Geho, Sung Won Han, Fabian Birzele, Sabine Bader, Lucia Himmelein, James Cai, Zayed Albertyn, Mark Rothe, Laurent Essioux, Helmut Burtscher, Steven A. Middleton, Lin-Chi Chen, Markus Dangl, William E. Pierceall, Gwen Nichols. MDM2 antagonist-based therapeutic response is discriminated by a 4-gene signature in acute myeloid leukemia patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2835. doi:10.1158/1538-7445.AM2015-2835