Date of Award
6-2024
Document Type
Thesis (Ph.D.)
Department or Program
Cancer Biology
First Advisor
Bonnie W. Lau, M.D. Ph.D.
Second Advisor
Kelli B. Pointer, M.D. Ph.D.
Abstract
The overall survival rate of pediatric cancer has continued to increase with new advancements in the field, however, it remains suboptimal for individuals with childhood cancer predisposition syndromes, such as Fanconi anemia. Patients with Fanconi anemia often have limited therapeutic options due to their hypersensitivity to the effect of interstrand crosslinking agents. Furthermore, the patients who do successfully respond to their cancer treatment experience significant late effects and chronic health conditions due to the treatment’s toxicity. This suggests that more targeted therapeutics are necessary to treat pediatric cancer while minimizing the toxicity to surrounding healthy tissue. This thesis aims to investigate targeting the DNA damage pathway in the context of two cancers that commonly arise in patients with Fanconi anemia: acute myeloid leukemia and sonic hedgehog (SHH) medulloblastoma. First, I present the development of a novel humanized murine model of Fanconi anemia-mutated AML that recapitulates both human disease and a humanized immune system. Utilizing this model, I demonstrate the efficacy of exploiting the underlying DNA damage repair deficits seen in Fanconi anemia-mutated AML through immune checkpoint blockade. I then exploit the DNA damage repair deficiencies in Fanconi anemia-mutated AML through the inhibition of a critical component of the DNA damage repair pathways, poly (ADP-ribose) polymerase 1 (PARP1) and investigate the efficacy of combining PARP inhibitors and immune checkpoint blockade in vivo. Finally, I shift my focus to indirectly targeting the DNA damage response pathways with sonic hedgehog inhibitors for the treatment of SHH medulloblastoma. I demonstrate the anti-tumor efficacy of the sonic hedgehog inhibitors both alone and in combination with radiation therapy in pediatric medulloblastoma. The combined works of this thesis further establish the rationale for exploiting the DNA damage response indirectly through immune checkpoint inhibitors and SHH inhibitors and directly through PARP inhibitors both alone and in combination with the indirect approaches in the context of both Fanconi anemia-mutated and Fanconi anemia wild type pediatric cancers.
Original Citation
Huang T, Leung B, Huang Y, Price L, Gui J, Lau BW. A murine model to evaluate immunotherapy effectiveness for human Fanconi anemia-mutated acute myeloid leukemia. Palaniyandi S, ed. PLOS ONE. 2024;19(1):e0292375. doi:10.1371/journal.pone.0292375
Recommended Citation
Price, Laura M., "Exploiting DNA damage repair for the treatment of pediatric tumors that arise in Fanconi anemia" (2024). Dartmouth College Ph.D Dissertations. 306.
https://digitalcommons.dartmouth.edu/dissertations/306
