Targeting the DNA Damage Response for Cancer Therapy (Cancer Treatment and Research, 186)

This book discusses the latest developments in Poly (ADP-ribose) polymerase (PARP) inhibitor drug development. It focuses on the translational and clinical development of the latest drugs, as well as the evidence for regulatory approval of PARP inhibitors in multiple different molecular subtypes and tumor indications. The most-up-to-date information on basic scientific research on DNA repair pathways and the DNA Damage Response (DDR) is also covered. Every chapter contains insight into the preclinical, translational along with clinical aspects of a specific DDR inhibitor with key and expert opinion points reinforcing the most important concepts detailed to enable the reader to develop a deep understanding of the topic. Targeting the DNA Damage Response for Cancer Therapy comprehensively reviews the application of PARP and other DDR inhibitors across oncology disciplines. Therefore, it is a valuable resource for all medical professionals and researchers who use or who are researching the use of these inhibitors on a day-to-day basis. Preface Contents About the Editors 1 Evolution of the Development of PARP Inhibitors 1.1 Introduction 1.2 FIH/FIC Trials and PARP Inhibition Biomarker Development—Chemo Potentiation 1.3 Emergence of Concept of Synthetic Lethality and Change in Development Path 1.4 Interaction with the Immune System—Widening the Field 1.5 Conclusion References 2 Exploiting Cancer Synthetic Lethality in Cancer—Lessons Learnt from PARP Inhibitors 2.1 Introduction 2.2 Lesson 1: Synthetic Lethal Penetrance Is Important 2.3 Lesson 2: Synthetic Lethal Phenocopy Effects Provide Additional Indications for DDR Inhibitors 2.4 Lesson 3: Resistance Can Emerge via Modulation of Either Synthetic Lethal Partner 2.5 Lesson 4: Synthetic Lethal Interactions that Appear to Be Digenic Are Probably Polygenic and Complex 2.6 Lesson 5: Drug Resistance Could Be Targeted via Evolutionary Double Binds 2.7 Horizon Scanning—What’s Next ? References 3 Mechanisms of PARP Inhibitor Resistance 3.1 Introduction 3.2 Overview of PARP Inhibitor Mechanisms of Resistance 3.3 BRCA/HRR-Independent Mechanisms of PARPi Resistance 3.3.1 Increased P-glycoprotein Expression and Drug Efflux 3.3.2 Epithelial-Mesenchymal Transition 3.3.3 Loss of SLFN11 Expression 3.3.4 Low Levels of Trapped PARP1 on DNA 3.3.5 PARG Deficiency 3.4 BRCA/HRR-Dependent Mechanisms of PARPi Resistance 3.4.1 The Importance of Dynamic Markers of HRR Status 3.4.2 Secondary Reversion Mutations in HRR Genes 3.4.3 Restoration of HRR Gene Expression 3.4.4 Expression of BRCA1 Hypomorphs 3.4.5 DDR Re-wiring to Promote End-Resection and HRR 3.4.6 Restoration of Replication Fork Protection 3.5 Strategies to Overcome PARP Inhibitor Resistance 3.6 Conclusions References 4 Development of Homologous Recombination Functional Assays for Targeting the DDR 4.1 Introduction 4.2 Methods for Testing for Homologous Recombination Deficiency 4.2.1 Clinical Selection 4.2.2 Sequencing 4.2.3 Genomic Scars/Signatures 4.2.4 The Rationale for Functional HRD Assays 4.3 Functional RAD51 Foci Assays: How Do They Work? 4.4 RAD51 Foci Assays: Pre-Clinical Data and Method Considerations 4.4.1 Co-staining 4.4.2 DNA Damage Induction 4.4.3 Tissue Source 4.4.4 Other Method Considerations 4.5 Summary of Pre-clinical Development 4.6 Clinical Applicability 4.6.1 Observational Data 4.6.2 RAD51 Assays: Biomarker Development Utilising Phase II Trial Datasets 4.7 Final Considerations and Limitations 4.7.1 RAD51 Foci Testing in Other Tumour Types 4.7.2 Accuracy of the RAD51 Foci Test 4.7.3 Where and When to Sample 4.7.4 Alternative Functional HRD Tests 4.8 Conclusion References 5 Clinical Application of Poly(ADP-Ribose) Polymerase (PARP) Inhibitors in Ovarian Cancer 5.1 Epithelial Ovarian Cancer 5.2 Frontline Maintenance 5.2.1 SOLO1 5.2.2 PRIMA/ENGOT-OV26 5.2.3 PAOLA-1/ENGOT-OV25 5.2.4 VELIA/GOG-3005 5.3 Recurrent, Platinum Sensitive Maintenance 5.4 Treatment in the Recurrent Setting 5.5 Treatment Considerations and Management of Common Toxicities 5.5.1 Managing Hematologic Toxicities 5.5.2 Managing GI and Renal Toxicities 5.5.3 Managing Fatigue 5.5.4 Managing Secondary Malignancies 5.6 Future Directions References 6 Clinical Use of PARP Inhibitors in BRCA Mutant and Non-BRCA Mutant Breast Cancer 6.1 Introduction 6.2 Clinical Use of PARP Inhibitors for Advanced BRCA-Mutant Breast Cancer 6.2.1 Monotherapy 6.2.2 In Combination with Chemotherapy 6.2.3 In Combination with Immunotherapy 6.3 Clinical Use of PARP Inhibitors for Early BRCA-Mutant Breast Cancer 6.3.1 Neoadjuvant Setting 6.3.2 Adjuvant Setting 6.4 Clinical Use of PARP Inhibitors in Non-BRCA Mutant Breast Cancer 6.5 Conclusion References 7 Development of PARP Inhibitors in Targeting Castration-Resistant Prostate Cancer 7.1 Prostate Cancer and the DNA Damage Response 7.2 The Evolving Role of PARP Inhibitors in Prostate Cancer 7.3 PARP Inhibitor Biomarkers in Prostate Cancer 7.4 PARP Inhibitor Combinations 7.4.1 Second Generation AR-Targeted Agents (ARTAs) 7.4.2 Immune Checkpoint Inhibitors (ICIs) 7.4.3 Radiopharmaceuticals 7.4.4 PI3K/AKT/mTOR Inhibitors 7.4.5 Epigenetic Modifiers 7.5 Targeting the DNA Damage Response in Prostate Cancer: Beyond PARP Inhibitors 7.6 Summary and Conclusions References 8 Strategies for the Management of Patients with Pancreatic Cancer with PARP Inhibitors 8.1 Pancreatic Cancer is a Rising Threat 8.1.1 Targeting the DNA Repair Pathway in PDAC 8.1.2 Ongoing Clinical Trials 8.1.3 Expanded Targeting of DNA Damage Response Mechanisms 8.1.4 Novel Therapies and Therapeutic Resistance References 9 Combining Poly (ADP-Ribose) Polymerase (PARP) Inhibitors with Chemotherapeutic Agents: Promise and Challenges 9.1 Introduction 9.2 Clinical Development of Poly (ADP-Ribose) Polymerase (PARP) Inhibitors 9.3 Combination of PARP with Cytotoxic Chemotherapeutic Agents 9.4 Early Phase Combination Trials in Advanced Solid Tumors 9.5 Breast Cancer 9.6 Gynecological Malignancies 9.7 Lung Cancers 9.8 Gastrointestinal Malignancies 9.9 Other Cancers Including Cancers Affecting the Pediatric and Adolescent Population 9.10 Challenges, Remaining Questions, and Future Directions References 10 Rational Combinations of PARP Inhibitors with HRD-Inducing Molecularly Targeted Agents 10.1 Introduction 10.2 Anti-angiogenic Inhibition 10.3 PI3K Pathway Inhibition 10.4 MAPK Pathway Inhibition 10.5 BET Inhibition 10.6 EZH2 Inhibitors 10.7 HDAC Inhibition 10.8 Hsp90 Inhibition 10.9 GAS6/AXL Inhibition 10.10 Conclusion References 11 Combination DNA Damage Response (DDR) Inhibitors to Overcome Drug Resistance in Ovarian Cancer 11.1 Introduction 11.2 Mechanisms of Resistance to PARPi 11.2.1 Strategies to Overcome PARP-Resistance with DDR-DDR Combinations 11.2.2 DDR Inhibitor Combinations in the Setting of Platinum-Resistance 11.3 Other DDR-DDR Combinations References 12 Combining PARP Inhibition and Immunotherapy in BRCA-Associated Cancers 12.1 Cytotoxic T-Cell Recruitment and Activation in Response to PARP Inhibition in BRCA-Deficient Cancers 12.2 Mechanisms of PARP Inhibitor-Induced T-Cell Infiltration and Activation 12.3 PARP Inhibition and PD-L1 Expression 12.4 Clinical Trials of Combination PARP Inhibitors and Immuno-Oncology Agents 12.5 Effects of PARP Inhibition on the Macrophage Component of the Immune Microenvironment 12.6 Combined PARP Inhibition and STING Agonism 12.7 Confirmation of Preclinical Findings on Immune Stimulation in Clinical Samples 12.8 Summary References 13 Mitotic MTH1 Inhibitors in Treatment of Cancer 13.1 Introduction 13.2 Biological Roles of MTH1 13.2.1 MTH1 in Inflammation and Cancer 13.3 MTH1 as an Anti-cancer Target 13.3.1 Genetic Validation of MTH1 in Cancer 13.3.2 Edgetic Perturbation Limits Genetic Validation of Anti-cancer Targets 13.3.3 Generation of MTH1 Inhibitors 13.3.4 Enzymatic Inhibition of MTH1 Is Insufficient to Kill Cancer Cells 13.3.5 Mechanism of Action of MTH1 Inhibitor TH588 and TH1579 13.3.6 Interference of MTH1, TH588 and TH1579 on Tubulin Polymerisation 13.3.7 Structurally Distinct MTH1 Inhibitor AZ19 (Non-tubulin Inhibitor) Generates Mitotic Arrest 13.4 Conclusions and a Selection of Outstanding Questions 13.5 Perspective 13.6 Conflicts of Interest References 14 Targeting ATR in Cancer Medicine 14.1 Introduction 14.2 ATR Acts as a Gatekeeper of DNA Damage Repair 14.3 ATR Signaling Fosters Cancer Cell Survival 14.4 Early Development of ATR Inhibitors 14.5 ATR Inhibitors in the Clinic 14.5.1 Berzosertib (M6620/VX-970/VE-822) 14.5.2 Ceralasertib (AZD6738) 14.5.3 Elimusertib (BAY1895344) 14.5.4 Gartisertib (M4344/VX-803) 14.5.5 Camonsertib (RP-3500) 14.5.6 M1774 14.5.7 ART0380 14.6 ATR and PARP Inhibitor Combination Strategies 14.7 ATR and Immune-Checkpoint Inhibitor Combination Strategies 14.8 Candidate Biomarkers of ATR Sensitization 14.9 Concluding Remarks References 15 Targeting Polymerase Theta (POLθ) for Cancer Therapy 15.1 Double Strand Break Repair by POLθ-Mediated Microhomology-Mediated End-Joining 15.2 Synthetic Lethality of POLθ in Cancers 15.3 Development of POLθ Inhibitors 15.4 Clinical Use of POLθ Inhibitors 15.5 Predictive Biomarkers for POLθ Inhibitor Responsiveness 15.6 Summary References 16 Targeting DNA-PK 16.1 Introduction 16.1.1 Insights from SCID Mice and Other DNA-PK Loss-of-Function Phenotypes 16.1.2 DNA-PK Roles in DNA Damage Repair 16.1.3 DNA-PK Roles in Immunity and Autoimmune Disorders 16.1.4 DNA-PK Inhibition as Therapeutic Strategy References 17 WRN Is a Promising Synthetic Lethal Target for Cancers with Microsatellite Instability (MSI) 17.1 Introduction 17.2 Microsatellite Instability and DNA Mismatch Repair 17.3 Clinical Characteristics of Microsatellite Instability 17.4 Synthetic Lethality of WRN Loss and Microsatellite Instability 17.5 WRN Background 17.6 Validation of the MSI/WRN Synthetic Lethal Relationship 17.7 Mechanistic Underpinnings of WRN Dependency 17.8 Perspectives References