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Stalled Replication Fork Protection Defects as a Predictor of Therapeutic Response

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[Technical Report, Annual Report]

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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 theDNA 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 this year despite the COVID pandemic induced supply chain issues. Thus far we have generated 34 HGSC organoidcultures and validated them as being matches to their parent tumors. We also profiled the DNA damage repair capacity of these cultures and demonstratedthat the majority were proficient in homologous recombination and some deficient in stalled replication fork protection and that these fork protection defectscorrelated with sensitivity to specific DNA damage repair therapies. We are following all patients from whom organoids are generated and comparing theorganoid outcomes with the patient outcomes. In addition, we have tested for activation of the replication stress response in various tumors after single orcombination DNA damage repair therapies. We have not identified a common mechanism within ATR signaling which is an overarching signaling pathway inreplication stress. We have identified the bromodomain containing protein BRD1 as possibly being important in the replication stress response in HGSC. Wecontinue to work up the mechanism of action of BRD1 and have now found it to be critical in the HGSC replication stress response. It is a relevant therapeutictarget.

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[A, Approved For Public Release]