Abstract 3738: Exploratory patient (pt) stratification markers associated with sensitivity to ABT-263 in small cell lung cancer (SCLC)
Authors: McKeegan Evelyn , Litvinovich Elizabeth M. , Chyla Brenda J. , Hemken Philip M. , Dowell Barry , Enschede Sari H. , Gandhi Leena , Rudin Charles M. , Camidge David R. , Bonomi Philip D. , Khaira Divis , de Oliveira Moacyr Ribeiro , Gandara David , Shapiro Geoffrey I. , Krivoshik Andrew P. , Humerickhouse Rod 
Published: February 2011

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 &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 (&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&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.