Optimization of circulating biomarkers of obatoclax-induced cell death in patients with small cell lung cancer.
AuthorsDean, Emma J
Ranson, Malcolm R
Blackhall, Fiona H
AffiliationClinical and Experimental Pharmacology, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
MetadataShow full item record
AbstractSmall cell lung cancer (SCLC) is an aggressive disease in which, after initial sensitivity to platinum/etoposide chemotherapy, patients frequently relapse with drug-resistant disease. Deregulation of the Bcl-2 pathway is implicated in the pathogenesis of SCLC, and early phase studies of Bcl-2 inhibitors have been initiated in SCLC. Obatoclax is a small-molecule drug designed to target the antiapoptotic Bcl-2 family members to a proapoptotic effect. Preclinical studies were conducted to clarify the kinetics of obatoclax-induced apoptosis in a panel of SCLC cell lines to assist with the interpretation of biomarker data generated during early phase clinical trials. In vitro, obatoclax was synergistic with cisplatin and etoposide, and "priming" cells with obatoclax before the cytotoxics maximized tumor cell death. Peak levels of apoptosis, reflected by cleaved cytokeratin 18 (CK18) levels (M30 ELISA) and caspase activity (SR-DEVD-FMK), occurred 24 hours after obatoclax treatment. A phase 1b-2 trial of obatoclax administered using two infusion regimens in combination with carboplatin and etoposide has been completed in previously untreated patients with extensive-stage SCLC. Circulating pharmacodynamic biomarkers of cell death, full-length and/or cleaved CK18, and oligonucleosomal DNA were studied in the phase 1b trial. All SCLC patients classified as "responders" after two cycles of treatment showed significantly increased levels of full-length and cleaved CK18 (M65 ELISA) on day 3 of study. However, the preclinical data and the absence of a peak in circulating caspase-cleaved CK18 in trial patients suggest suboptimal timing of blood sampling, which will need refinement in future trials incorporating obatoclax.
CitationOptimization of circulating biomarkers of obatoclax-induced cell death in patients with small cell lung cancer. 2011, 13 (4):339-47 Neoplasia
- A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer.
- Authors: Chiappori AA, Schreeder MT, Moezi MM, Stephenson JJ, Blakely J, Salgia R, Chu QS, Ross HJ, Subramaniam DS, Schnyder J, Berger MS
- Issue date: 2012 Feb 28
- Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer.
- Authors: Langer CJ, Albert I, Ross HJ, Kovacs P, Blakely LJ, Pajkos G, Somfay A, Zatloukal P, Kazarnowicz A, Moezi MM, Schreeder MT, Schnyder J, Ao-Baslock A, Pathak AK, Berger MS, GEM017 Investigators.
- Issue date: 2014 Sep
- Circulating biomarkers of cell death after treatment with the BH-3 mimetic ABT-737 in a preclinical model of small-cell lung cancer.
- Authors: Micha D, Cummings J, Shoemaker A, Elmore S, Foster K, Greaves M, Ward T, Rosenberg S, Dive C, Simpson K
- Issue date: 2008 Nov 15
- Combination of arsenic trioxide and chemotherapy in small cell lung cancer.
- Authors: Zheng CY, Lam SK, Li YY, Fong BM, Mak JC, Ho JC
- Issue date: 2013 Nov
- Evaluation of circulating tumor cells and serological cell death biomarkers in small cell lung cancer patients undergoing chemotherapy.
- Authors: Hou JM, Greystoke A, Lancashire L, Cummings J, Ward T, Board R, Amir E, Hughes S, Krebs M, Hughes A, Ranson M, Lorigan P, Dive C, Blackhall FH
- Issue date: 2009 Aug