Dysfunction in cell cycle checkpoint promotes genomic instability and represents a pathological hallmark of cancer. Our primary objective is to improve both the efficacy and selectivity of chemotherapeutic agents by combining them with inhibitors of cell cycle checkpoints. Our hypothesis is that pharmacological disruption of collateral checkpoint pathways may create """"""""synthetic lethality"""""""" in tumors with intrinsic checkpoint defects, e.g. mutated p53, following genotoxic stress. Our initial focus was on 7-hydroxystaurosporine (UCN-01), an inhibitor of the critical checkpoint kinase, Chk1. UCN-01 potentiates cytotoxicity of the topoisomerase I poison, SN-38, by abrogating the S and G2/M checkpoints. Preliminary data have shown that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) also abrogates the G2/M checkpoint, by destabilizing Chk1 as well as another key checkpoint kinase, Wee1. This application incorporates both laboratory studies using checkpoint inhibitors as pharmacological probes for the fundamentals of checkpoint control, and a clinical trial that capitalizes on the concept of combining checkpoint inhibitor with cytotoxic agents. We propose: 1) To determine the molecular mechanisms by which the Hsp90 inhibitor 17AAG abrogates the G2/M checkpoint induced by SN-38 selectively in p53-defective cells, focusing on Chk1 and Wee1 as two putative targets. 2) To study a novel mechanism by which the expression of cdc25A is regulated by p53, focusing on transcriptional repression of the cdc25A promoter by p53. 3) To conduct a phase I clinical study of 17AAG in combination with irinotecan and to perform correlative studies on pre- and post-treatment tumor biopsies for expression of the biomarkers identified in our pre-clinical studies. The proposed studies are expected to provide insights of how checkpoint defects in tumors can be exploited to render them more susceptible to combined treatment with chemotherapy and checkpoint inhibitors such as 17AAG.
| McNeely, Samuel; Conti, Chiara; Sheikh, Tahir et al. (2010) Chk1 inhibition after replicative stress activates a double strand break response mediated by ATM and DNA-dependent protein kinase. Cell Cycle 9:995-1004 |
| Tse, Archie N; Klimstra, David S; Gonen, Mithat et al. (2008) A phase 1 dose-escalation study of irinotecan in combination with 17-allylamino-17-demethoxygeldanamycin in patients with solid tumors. Clin Cancer Res 14:6704-11 |
