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- Title
Therapeutic Targeting of DNA Repair Pathways in Pediatric Extracranial Solid Tumors: Current State and Implications for Immunotherapy.
- Authors
Zhao, Sophia J.; Prior, Daniel; Heske, Christine M.; Vasquez, Juan C.
- Abstract
Simple Summary: Survival for many pediatric cancers has improved over recent decades. However, for pediatric patients with solid tumors that fail to respond to standard therapies, or relapse after initial response, outcomes generally remain poor, indicating a need for novel and improved treatments. Many cancers have an impaired ability to repair DNA damage, which in excess can become toxic to cells. As such, one potential approach for these challenging cancers is to target the DNA damage repair pathways of cancer cells, with the goal of inducing a lethal amount of DNA damage. This article reviews the current research efforts into targeting DNA damage repair pathways in pediatric extracranial solid tumors. It reviews the biology of DNA damage repair pathways, the biology of several extracranial pediatric cancers, the preclinical research investigating targeting the DNA damage repair in pediatric cancers, and the clinical trials using these agents in patients. This article also reviews the ability to harness a patient's immune system to kill cancer cells, and the research that has been done investigating ways in which DNA damage can activate the anti-tumor immune response. DNA damage is fundamental to tumorigenesis, and the inability to repair DNA damage is a hallmark of many human cancers. DNA is repaired via the DNA damage repair (DDR) apparatus, which includes five major pathways. DDR deficiencies in cancers give rise to potential therapeutic targets, as cancers harboring DDR deficiencies become increasingly dependent on alternative DDR pathways for survival. In this review, we summarize the DDR apparatus, and examine the current state of research efforts focused on identifying vulnerabilities in DDR pathways that can be therapeutically exploited in pediatric extracranial solid tumors. We assess the potential for synergistic combinations of different DDR inhibitors as well as combinations of DDR inhibitors with chemotherapy. Lastly, we discuss the immunomodulatory implications of targeting DDR pathways and the potential for using DDR inhibitors to enhance tumor immunogenicity, with the goal of improving the response to immune checkpoint blockade in pediatric solid tumors. We review the ongoing and future research into DDR in pediatric tumors and the subsequent pediatric clinical trials that will be critical to further elucidate the efficacy of the approaches targeting DDR.
- Subjects
TUMORS in children; IMMUNOTHERAPY; CANCER chemotherapy; IMMUNE checkpoint inhibitors; DNA repair; DNA damage; BRAIN tumors; IMMUNOMODULATORS
- Publication
Cancers, 2024, Vol 16, Issue 9, p1648
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16091648