Intro; Contents; Contributors; Chapter 1: Targeting DNA Repair in Anti-Cancer Treatments; 1.1 PARP Inhibitors to Targeted DNA Repair; 1.2 Limits to the Synthetic Lethal Approach of Targeting Cancer; 1.3 Combining Chemotherapy Treatment with DNA Repair Inhibitors; 1.4 Exploiting the Inherent High Level of DNA Damage in Cancers; Replication Stress; 1.5 Future Challenges in Targeting DNA Repair for Cancer Treatments; References; Chapter 2: The DNA Damage Response: Roles in Cancer Etiology and Treatment; 2.1 Problems Associated with Current Chemo- and Radiotherapies

2.2 The Promise of Targeted Cancer Treatment2.3 The DNA Damage Response (DDR); 2.4 Oncogenes Cause Genomic Instability and DDR Activation; 2.5 Tumor Suppression Through Checkpoint Activation and DNA Repair; 2.6 Targeting HR and ATM Deficiencies with PARP and DNA-PK Inhibition; 2.7 Targeting Oncogenic Stress, ATM-p53 Loss, and HR Deficiency with ATR, CHK1 and WEE1 Inhibitors; 2.8 Future Areas of Research; References; Chapter 3: Control of DNA Replication by ATR; 3.1 Introduction; 3.2 ATR Is a PI3K-Related Kinase (PIKK); 3.3 ATR Activation

3.3.1 First Step: ssDNA Recruits the ATR-ATRIP Complex3.3.2 Second Step: TOPBP1 Is Necessary for Full Activation of ATR-ATRIP; 3.3.3 Third Step: CLASPIN Is an Adaptor for CHK1 Phosphorylation; 3.3.4 Fine Tuning: Post-Translational Modifications Regulate the Activation of ATR-ATRIP; 3.4 Local, Regional and Global Checkpoint Functions of ATR-ATRIP; 3.4.1 Local Action of ATR-ATRIP on Replication Forks; 3.4.2 Regional Modulation of Replication Factories; 3.4.3 Global Regulation of DNA Replication and the Cell Cycle; 3.5 Functions of ATR and CHK1 in Cancer; 3.5.1 ATR and CHK1 Are Essential

3.5.2 Malignant Transformation Generates Replication Stress3.5.3 The Replication Stress Response Favours Malignant Transformation; 3.5.4 Targeting the Replication Stress Response in Cancer; 3.6 Concluding Remarks; References; Chapter 4: Targeting ATR for Cancer Therapy: Profile and Expectations for ATR Inhibitors; 4.1 Role of ATR in the DNA Damage Response; 4.1.1 ATR Signaling to Regulate DNA Replication and Cell Cycle Progression; 4.1.2 ATR Signaling to DNA Repair; 4.2 Validation of ATR as a Therapeutic Target; 4.3 Development of ATR Inhibitors

4.4 ATR Inhibition as Combination Therapy with DNA Damaging Chemotherapy4.5 ATR Inhibition as Combination Therapy with Ionising Radiation (IR); 4.6 ATR Inhibition as Monotherapy; 4.7 ATR Inhibition in Combination with Targeted Drugs; 4.8 Conclusion; References; Chapter 5: Targeting ATR for Cancer Therapy: ATR-Targeted Drug Candidates; 5.1 Background; 5.2 Current Clinical Candidates; 5.2.1 VX-970 (M6620); 5.2.1.1 NCT02157792: First-in-Human Study of VX-970 (M6620) in Combination with Cytotoxic Chemotherapy; 5.2.2 AZD6738