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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 serous ovarian 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 this year despite the COVID pandemic. Thus far we have generated twenty 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 and some 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. We have identified the bromodomain containing protein BRD1 as possibly being important in the replication stress response in HGSC. We continue to work up the mechanism of action of BRD1 and other hits from our RNA sequencing in the HGSC replication stress response. Finally, we immune profiled multiple parent tumors and matched organoidimmune cell co-cultures by flow cytometry and one also by single cell RNA sequencing and demonstrated that the organoid cocultures are accurate models of the parent tumors.


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  • Medicine and Medical Research

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[A, Approved For Public Release]