Towards Targeted Treatment for Pediatric Cancer: Inhibition of the replication stress response as a novel therapeutic approach

Abstract

Decades of data support replication stress as a therapeutic target, however, toxic side effects often encountered during chemotherapy treatment and long-term health consequences often limit the practical applicability of these compounds. With the advent of small molecule inhibitors, a more targeted and possibly less toxic approach to treating pediatric solid malignancies has emerged. In chapter 2 of this thesis, we conduct a Target Actionability Review (TAR) to evaluate specific targets within the replication stress response. The TAR methodology aims to match targeted anti-cancer drugs with specific cancer subtypes based on preclinical studies. In our study, we create a comprehensive, structured, and critically evaluated overview of literature related to targeting replication stress in pediatric solid malignancies. In addition, we underscore the importance of robust preclinical studies and highlight emerging targets such as PARP, which is explored in more detail in chapter 3. The development of novel therapeutic approaches for pediatric cancer is often challenged by the fact that there are very few patients available to participate in clinical studies. Not only does this create a certain degree of hesitancy to fund pediatric-specific (pre)clinical drug development, but the execution of robust clinical trials also remains difficult. The existence of a drug target applicable in a wider range of tumor types could help mitigate these challenges and aid in the development of safe therapeutics for children with cancer. In chapter 3 PARP is explored as a broader pediatric target and potential biomarkers and therapeutic combinations are suggested. In the remaining chapters of this thesis, we dive deeper into targeting replication stress and investigate CHK1 as a therapeutic target in neuroblastoma. Neuroblastoma is a malignancy of the sympathetic nervous system and is the most common extracranial solid tumor found in children. Although most high-risk neuroblastoma tumors initially respond to treatment, relapse and therapy resistance remain major clinical obstacles. Approximately 50% of high-risk patients eventually succumb to the disease, thus there is an absolute need for more effective therapeutic approaches for these patients. While neuroblastoma is characterized by a paucity in targetable somatic mutations, a remarkable number of tumors are driven by chromosomal aberrations such as hemizygous loss of chromosome 11q or amplification of MYCN. Although these abnormalities are very different from one another on a genomic level, they both induce replication stress, offering a targetable vulnerability. In chapter 4, we establish chromosome 11q loss and MYCN amplification as therapeutic biomarkers for CHK1 inhibition and in chapter 5 we elucidate the mechanism driving CHK1 inhibitor sensitivity in MYCN amplified neuroblastoma. Additionally, both chapters propose novel therapeutic combinations that could extend the clinical applicability of CHK1 inhibition in neuroblastoma. Lastly, in chapter 6, we discuss our main findings and their future implications. Altogether, the discussion highlights our insights and brings our findings into context with other published research with the hope of helping the development of safe and effective therapeutics for children with cancer.