Stalled Replication Fork Protection Defects as a Predictor of Therapeutic Response
Abstract
The major goals of this award are to study prevalence and mechanisms of stalled replication fork protection defects in high grade serousovarian cancer (HGSC) using patient derived organoid models. The goals of the three Aims included generating and characterizing the organoids, profiling the DNA damage repair capacity of the organoids, and determining if there is synergy between DNA damage repair defect therapies and immune therapies. Progress has been made in all aims in the short time since the award began. Thus far we have generated twelve HGSC organoid cultures and validated them as being matches to their parent tumors. We also profiled the DNA damage repair capacity of these cultures and demonstrated that the majority were proficient in homologous recombination but deficient in stalled replication fork protection and that these fork protection defects correlated with sensitivity to specific DNA damage repair therapies. We are following all patients from whom organoids are generated and comparing the organoid outcomes with the patient outcomes. In addition, we have tested for activation of the replication stress response in various tumors after single or combination DNA damage repair therapies. We have not identified a common mechanism within ATR signaling which is an overarching signaling pathway in replication stress. However, the speed of progression of tumor cells through the cell cycle may dictate response to DNA damage therapies. In addition, after performing bulk RNA sequencing analysis on a subset of these organoids after treatment with replication stress inducing agents, we have identified the protein IKZF3 as possibly being important in the replication stress response in HGSC. We continue to work up the mechanism of action of IKZF3 and other hits from our bulk RNA sequencing in the HGSC replication stress response.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2020
- Accession Number
- AD1112049
Entities
People
- Sarah Hill
Organizations
- Dana–Farber Cancer Institute