Project 4: Preclinical Assessment of Bioavailable and Orally Active ATR Kinase Inhibitors for the Treatment of Lung Cancer
Christopher Bakkenist, PhD, Project Co-Leader, Basic Science
Timothy Burns, MD, PhD, Project Co-Leader, Clinical Science
The objective of Project 4 is to complete in vitro and in vivo studies with the first bioavailable and orally active ATR kinase inhibitor to identify appropriate drug combinations and lung cancer patient populations for treatment. In parallel, we will develop biomarkers for response using innovative analytical pharmacokinetic tools such that Hillman will be optimally placed to compete successfully for phase I trials with this novel and promising pharmaceutical.
Specific Aim 1 will determine the efficacy of the AZD6738 ATR kinase inhibitor in combination with cytotoxic agents in molecularly defined lung cancer. This aim will identify AZD6738 ATR kinase inhibitor combinations for lung cancer treatment. We will characterize DNA damage signaling pathways in a panel of eight molecularly defined lung cancer cell lines, two of which have mutated ATM and six of which have mutated KRAS. We will use MTT assays and cell cycle analysis to determine changes in cell proliferation following treatment with AZD6738 ATR inhibitor in combination with DNA damaging agents (cisplatin, gemcitabine, pemetrexed and docetaxel). Our preliminary data indicates significant synergy for cell killing between AZD6738 ATR inhibitor and cisplatin in ATM-deficient lung cancer cell lines. The mechanism of growth inhibition will be investigated.
Specific Aim 2 will determine the efficacy of the combination of AZD6738 ATR inhibitor and cisplatin in vivo. This aim will establish the efficacy and optimal dosing for AZD6738 ATR inhibitor and cisplatin for lung cancer treatment and develop tools for determining the pharmacodynamics (ATM serine 1981 and H2AX phosphorylation, tunnel staining) of the ATR inhibitor. We will use xenograft models of a ATM mutated (H23) lung cancer cell line that shows synergy between AZD 6738 and cisplatin for killing in vitro as well as a KRAS mutant (H460) lung cancer cell line that shows great sensitivity to AZD 6738. Pharmacokinetic analyses will be undertaken using a close chemical analogue to AZD 6738 as a standard.