Alexander Sobeck

Program: Cancer Biology

Current advisor: Priyanka Verma, PhD

Undergraduate university: University of Michigan-Ann Arbor, 2022

Enrollment year: 2024

Research summary
Investigating ADAR1 as a synthetic lethal target in Cyclin E1-amplified serous ovarian cancers

High-grade serous cancers (HGSCs) represent one of the largest and most lethal subtypes of ovarian cancer accounting for roughly 70-80% of all deaths. Nearly 20% of HGSCs are associated with an amplification of CCNE1, an oncogene that encodes the protein Cyclin E1. Cyclin E1-amplified ovarian cancers display poorer patient prognosis since they are resistant to platinum-based therapies, the current standard of care. Hence there is a need for new therapeutic strategies for treating Cyclin E1-amplified HGSCs. Increased expression of Cyclin E1 aberrates the cell cycle by permitting the G1 to S transition to proceed more rapidly. This induces replication-coupled DNA damage and transcription replication conflicts that contribute to genomic instability. Using a targeted CRISPR screen to deplete genes that maintain genomic stability, I discovered that depleting Adenosine Deaminase Acting on RNA 1 (ADAR1) significantly reduced the proliferation of Cyclin E1-high cells as compared to normal cells. ADAR1 is an RNA binding protein that deaminates adenosine to inosine on double-strand (ds) RNA structures to prevent an autoimmune response. Cyclin E1-high cells harbor more dsRNA stemming from their higher burden of R-loops. Thus, I hypothesize that ADAR1 loss is synthetic lethal in Cyclin E1-high cells via R-loop induced autoimmune response. This project seeks to define the mechanistic basis of synthetic lethality between ADAR1 loss and high Cyclin E1 expression. This knowledge will provide a critical foundation to assess ADAR1 as a targeted therapeutic strategy for Cyclin E1-amplified serous ovarian cancers.

Graduate publications