Models and Mechanisms of Fanconi Anemia-driven Cancer Formation

Dr. Krais’ research focuses on how cells undergo DNA damage repair and how issues with repair relate to cancer and its response to therapy. With his Young Investigator Award, Dr. Krais will focus his attention to Fanconi Anemia-driven cancer.  Individuals that inherit mutations in DNA damage response genes are at higher risk of cancer development. Mutations in genes encoding the Fanconi Anemia DNA repair complex often result in both severe developmental issues and in cancer.  Hematopoietic stem cell transplants (HCT) alleviate many issues with Fanconi Anemia, including blood cancers, but do not prevent solid tumors and may add to the development of those tumors.  Dr. Krais will employ a unique Fanconi Anemia mouse model to shed light on how inherited Fanconi Anemia mutations lead to accumulating genome instability and tumor formation and to seek opportunities to reactivate DNA repair and prevent cancer.

With this work, Dr. Krais hopes to answer two pressing questions: First, he will use his mouse model to discover how individuals with Fanconi Anemia receiving stem cell transplants develop cancer later in life by using long-read DNA sequencing to find the unique genetic features of these post-HCT tumors. Second, Dr. Krais already has a hypothesis that a specific type of damage arising during DNA replication in this mouse model is ultimately responsible for tumor development. He will use single molecule DNA fiber assays and multiplexed imaging to understand the role of the molecular defect he suspects. These studies will also allow Dr. Krais to test cell models where the Fanconi Amenia pathway can be reactivated, restoring DNA repair, and he hopes to develop a therapy to trigger reactivation, potentially preventing tumors in high-risk individuals. Dr. Krais will provide new insights into how Fanconi Anemia-related cancers develop, will validate a model for tumor development driven by issues in DNA damage response in other high-risk individuals, and will test new potential treatment strategies designed to stop cancer-causing genome instability at its source.