Targeting poly (ADP ribose) polymerase (PARP) in endometrial cancer

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Project Summary/Abstract Endometrial cancer (EC) is the most common gynecologic malignancy with poor outcomes for those with serous histology. Chemotherapy resistance is common in recurrent disease and very few targeted therapies are available. However, there is growing evidence that some serous or molecularly serous-like ECs have evidence for homologous recombination (HR) deficiency (HRD). Here we show that EC patient derived xenograft (PDX) models also revealed a higher frequency of HRD in serous EC, as determined by a genomic score of HRD (based on telomeric allelic imbalance, large state transitions, and loss of heterozygosity). Serous EC were also more sensitive to rucaparib, a poly (ADP ribose) polymerase (PARP) inhibitor (PARPi), in an ex vivo 3D culture system. To confirm the dependence of an HRD-high EC on HR DNA repair, SN38 was used to provoke single- and double-strand DNA breaks concurrently with rucaparib and indeed, the observed synergy was consistent with a deficiency of HR repair. Further validation of HRD was demonstrated in an in vivo PDX study showing the combination of rucaparib plus a novel formulation of SN38 (PLX038A) resulted in a marked and unparalleled regression of tumors. Remarkably, four of eight mice had undetectable tumors. However, several questions require investigation to facilitate the clinical use of PARPis and/or the combination with PLX038A. It is unknown whether the HRD score of other ECs (e.g serous-like, regardless of histology) will predict response to a PARPi and if the genetic HRD score can be improved by including another omics data to more accurately predict response to a PARPi. To test the hypothesis that an HRD score in ECs can predict response to a PARPi and the synergy with SN38 is dependent on HR deficiency, the following aims are planned. We propose to i) predict PARPi sensitivity using the genomic HRD score and a novel mRNA signature of PARPi response, ii) determine the efficacy of rucaparib alone and in combination with SN38 in a larger cohort of EC PDXs ex vivo and in vivo, and iii) evaluate a dual-omics score in relation to PARPi response in fresh surgical specimens of primary patient tumors ex vivo. The data generated from this application will be used to justify clinical use of PARPis in a molecularly defined subset of ECs. In addition, since rucaparib + PLX038 is currently in phase 1 trials (NCT04209595) with plans to open a phase 2 trial in ovarian cancer, these data will support an expansion cohort in EC.