Abstract 3738: Exploratory patient (pt) stratification markers associated with sensitivity to ABT-263 in small cell lung cancer (SCLC)
Authors: Evelyn McKeegan, Elizabeth M. Litvinovich, Brenda J. Chyla, Philip M. Hemken, Barry Dowell, Sari H. Enschede, Leena Gandhi, Charles M. Rudin, David R. Camidge, Philip D. Bonomi, Divis Khaira, Moacyr Ribeiro de Oliveira, David Gandara, Geoffrey I. Shapiro, Andrew P. Krivoshik, Rod Humerickhouse
Journal: Cancer Research (2010)

Abstract Background ABT-263 is a novel, BH3 mimetic that binds with high affinity (Ki≤1nM) and inhibits antiapoptotic Bcl2 family proteins. ABT-263 displays potent preclinical mechanism-based toxicity against SCLC cell lines. Pro-gastrin-releasing peptide (Pro-GRP) is a plasma protein currently being evaluated as a biomarker to monitor pts with SCLC. SCLC cell lines were previously evaluated for Bcl2 family expression, and Bcl2 and Pro-GRP copy number. A profile correlating expression with sensitivity/resistance to ABT-263 was generated. The aim of this study was to assess whether plasma concentrations of Pro-GRP could be a potential surrogate for Bcl2 gene amplification in ABT-263 treated pts. Methods Bcl2 copy number profiles were tested in samples from pts receiving increasing doses of ABT-263 (10mg-475mg), enrolled in a phase 1/2a open label solid tumor study. Pt whole blood samples were enriched for circulating tumor cells (CTC) using the Cell Search System® and if &amp;gt;7 CTC were obtained, the cells were assessed for Bcl2 copy number using FISH with the LSI Bcl-2® probe Abbott Molecular. When available, tumor biopsy tissue was assessed for Bcl2 copy number by FISH. Plasma Pro-GRP concentrations were measured using kits developed for the Abbott Architect® system. Apoptosis was assessed in 26 ABT-263 treated pts using the M30 antibody which detects the caspase-cleaved cytokeratin-18 products. Results CTC analysis was performed on screening/baseline samples of 44/49 pts of various tumor types including 30 SCLC pts. CTC were detected in 78% of pts with SCLC. 41% of pts had sufficient CTC numbers (&amp;gt;7 CTC) for downstream FISH analysis of Bcl2 copy number. The median Bcl2 copy number for individual pts ranged from 2-15 copies; 73% had ≥3 copies and 18% had ≥5 copies. Plasma Pro-GRP concentrations were determined in 49 pts. Results for both Bcl2 copy number and plasma Pro-GRP concentrations were compared from 22 pts, including 17 SCLC pts. A strong correlation (R2=0.97) between these 2 markers was observed. Correlations were also observed between Pro-GRP and best tumor change (p&amp;lt;0.0001), and ABT-263 dosage (p=0.001) in pts receiving ≥130mg ABT-263. Pts with normal copy number Bcl2 had lower concentrations of Pro-GRP, and the pts with high copy number had high concentrations of Pro-GRP. A dose-dependent increase in M30 product was observed in pts, especially during cycle-2 ABT-263 treatment. Conclusions These observations suggest that circulating Pro-GRP is a potential surrogate marker for Bcl-2 gene copy number. Additional data regarding the correlation and potential predictive value of these markers will be obtained from ongoing and planned studies of ABT-263 alone or in combination with etoposide-cisplatin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3738.