Characterization of Telomere Maintenance in Tumor Models of Dyskeratosis Congenita
Awardee: Judy Wong
Institution: University of British Columbia
Award Amount: $66,440
Funding Period: February 1, 2021 - January 31, 2022
Summary:
Work in my laboratory and others had shown that telomere maintenance defects in the bone marrow failure syndrome dyskeratosis congenita (DC) contributed to an increased risk of developing cancers. Our long-term collaboration with the Inherited Bone Marrow Failure Syndrome (IBFMS) clinical group at the National Cancer Institute provided us with the opportunity to model and study the cancer development process in DC. Using primary patient materials collected by the IBFMS group, my laboratory will develop DC cancer models in the laboratory and study how these DC tumors overcome the innate genetic restrictions on telomere maintenance and achieve immortal growth. The long term goal of this project is to provide new screening paradigm and to stratify treatment options for DC tumors, an unmet clinical need in the battles against the spectrum of disorders associated with this Bone Marrow Failure Syndrome.
Final Report Lay Summary:
Dyskeratosis congenita (DC) was the first telomere maintenance disorder identified in humans. DC is an inherited disease of bone-marrow failure, with symptoms that include hematopoietic, epithelial and mucosal epithelial dysfunctions. In addition, DC patients have an increased risk of developing cancers from epithelial origin, believed to be a direct consequence of accelerated telomere attrition. With advancement in the clinical management of DC mortality due to hematopoietic system failure, DC patients are now faced with an estimated hundreds-fold increase in their risk of developing cancer, with HPV-negative Head and Neck Cancer (predominantly at the tongue) being the most prominent cancer type (Haematologica, 2018). My laboratory has ongoing interests in modeling the cancer development process in DC, using primary patient materials collected from the NIH National Cancer Institute’s Inherited Bone Marrow Failure Syndrome cohort study. With funding from the UPennMDBR award, we have optimized the sequential viral infection protocol for the delivery of oncogenic elements, and successfully created four X-DC tumor models and two corresponding controls. Currently, we are conducting mouse xenograft studies using these cell models to further characterize the in vivo behavior of these XDC tumors. Our project successfully optimized the in vitro transformation protocol and established viable DC tumor models for future research towards informed patient screening guidelines and the development for novel, targeted therapeutics.