B185
Preclinical development of obatoclax therapy for small cell lung cancer
Emma Dean1, Malcolm Ranson1, Dean Fennell2, Anne Roulston3, Jean Viallet3, Mark Berger3, Caroline Dive1
1Paterson Institute for Cancer Research, Manchester, UK, 2Queen's University Belfast, Belfast, UK, 3Gemin X Pharmaceuticals, Inc., Montreal, Quebec, Canada
Lung cancer is the leading cause of cancer death worldwide, representing 22% of UK cancer deaths. Two-thirds of small cell lung cancer (SCLC) cases present with extensive stage disease. Palliative chemotherapy with platinum/etoposide extends survival, but mortality rates remain dismal. The Bcl-2 family of proteins are key regulators of apoptosis, with most apoptotic stimuli converging at the mitochondrial surface where interactions between Bcl-2 family members determine cell fate. The observation that Bcl-2 is present in 75% of SCLC clinical specimens and that over-expression of anti-apoptotic Bcl-2 family members confers resistance to chemo-radiation in vitro has promoted clinical development of Bcl-2 targeted therapies in SCLC.
Obatoclax, a novel BH3 mimetic, is believed to bind inclusively to the BH3-binding groove of anti-apoptotic Bcl-2 family proteins inducing apoptosis. The IC50 values for obatoclax were in the range 0.07-1.04 µM against a panel of eight SCLC cell lines determined using the short-term viability assay (MTS). Induction of apoptosis (PARP cleavage) in response to obatoclax was both time- and concentration-dependent. Chou-Talalay combination index studies demonstrated schedule-dependent synergy of obatoclax with cisplatin and etoposide over 96 h. Exposure of cells to 48 h obatoclax prior to cisplatin and etoposide resulted in greater synergy than either the reverse sequence or 96 h concomitant treatment, in all eight cell lines. Experiments determining the timing of apoptosis in relation to obatoclax sensitivity as a single agent and in combination with cytotoxics will be reported.
