P3 - Mechanism-Based Use of Chk1 Inhibitors in Pancreas Cancer

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A strategy that shows great promise for treating pancreatic cancer is to combine cytotoxic treatments with agents that abrogate the already-tenuous checkpoint functionality exhibited by most tumor cells. Drugs that target the checkpoint protein Chk1 (such as AZD7762, currently in Phase-I clinical trials) are of particular interest in the context of pancreatic cancer because Chkl has also been shown to have a critical role in mediating the activity of Rad51, a key protein in homologous recombination repair (HRR) that is associated with resistance to DNA damaging treatments, and is upregulated in human pancreatic tumors. The long term goal of our work Is to improve the outcome of patients with pancreatic cancer by rationally adding Chk1 inhibitors to the combination of Gem and radiation. Our preliminary data demonstrate that both chemo- and radiosensitization by AZD7762 vary substantially among human pancreatic tumor cell lines, and that under conditions of sensitization, AZD7762 affects several endpoints related to HRR. We also found that endpoints related to G2/M checkpoint abrogation reflected sensitization in some cases but not in others. Specific Aim 1 is to determine the mechanisms by which AZD7762 treatment affects HRR activity and sensitivity to Gem and IR in pancreatic cancer cell lines, in vitro. This work will allow us to identify mechanism-based molecular endpoints to be interrogated in future clinical studies, and to identify new targets for therapeutic intervention, related to HRR activity. Although the mechanistic basis for therapeutic effects of Chkl inhibitors is not yet completely understood, our data in vitro and in vivo already provide strong motivation for conducting an initial clinical trial. Specific Aim 2 is to use xenograft models to establish the basis for conducting a clinical trial combining AZD7762 with Gem and radiation. The results of Aim 2 will help to define the design of our subsequent clinical trial. Specific Aim 3 is to carry out a clinical trial using AZD7762 in combination with Gem and radiation in patients with resected pancreatic cancer. We will use a combination of Gem and radiation followed by Gem alone, combined with dose-escalating AZD7762, based on the schedule suggested in Aim 2. We hypothesize that the MTD for AZD7762 will be similar to that detennined in the current phase I trials using Gem alone (i.e. that adding conformal radiation will have a minimal impact on the MTD of AZD7762 in combination with Gem). Also, we hypothesize that AZD7762 will inhibit Chkl activity in surrogate normal tissues when administered at the MTD, and, possibly, at lower doses.