824P Real-world-data (RWD) on platinum (Pt) outcomes after PARP inhibitors (PARPi) progression in high grade serous ovarian cancer (HGSOC) patients (p)

Abstract Background Vaccination against human papillomavirus (HPV) has proven to be effective against severe cervical lesions and genital warts, whereas no previous study has provided real-world data on the HPV vaccine effectiveness against high-grade vulvovaginal lesions. Methods A cohort of all women aged 17–26 years, living in Denmark during 2006–2019 was followed in nationwide registers for individual-level information about HPV vaccination and first diagnoses of vulvar and vaginal high-grade intraepithelial lesions or worse (HSIL+). The cumulative incidence of vulvar and vaginal HSIL+, respectively, was estimated with the Aalen-Johansen estimator and Cox proportional hazards regression was used to estimate hazard ratios (HRs) for vulvar and vaginal lesions separately comparing women vaccinated at age <16 years and at age 17–26 years with unvaccinated women. Results The cohort consisted of 514,537 women, of which 50.6% were vaccinated at baseline (<16 years), 31.8% were vaccinated during follow-up (17–26 years) and 17.6% remained unvaccinated. The cumulative incidence was less than 0.6‰ for vulvar HSIL+ and less than 0.2‰ for vaginal HSIL+. Adjusted analyses showed reduced hazard rates for both vulvar (HR = 0.22, 95% CI = 0.13 to 0.38) and vaginal HSIL + (HR = 0.16, 95% CI = 0.04 to 0.55) for women vaccinated at age ≤16 years compared to unvaccinated women. For women vaccinated at 17–26 years, the reductions in hazard rates were smaller for vaginal HSIL+ and close to zero for vulvar HSIL+. Conclusion HPV vaccination before 17 years of age reduces the risk of vulvar and vaginal HSIL+ based on real-world data.

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Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

10.1101/621623 ◽

2019 ◽

Cited By ~ 2

Author(s):

Elaine Sanij ◽

Katherine M. Hannan ◽

Shunfei Yan ◽

Jiachen Xuan ◽

Jessica E. Ahern ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Dna Damage Response ◽

Parp Inhibitors ◽

Rna Polymerase I ◽

High Grade ◽

Replication Forks ◽

Serous Ovarian Cancer ◽

Damage Response ◽

Polymerase I

AbstractHigh-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has a dismal prognosis. PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi by complex mechanisms including HR restoration and stabilisation of replication forks is a major challenge in the clinic. Here, we demonstrate CX-5461, an inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress at rDNA leading to activation of DNA damage response and DNA damage involving MRE11-dependent degradation of replication forks. CX-5461 cooperates with PARPi in exacerbating DNA damage and enhances synthetic lethal interactions of PARPi with HR deficiency in HGSOC-patient-derived xenograft (PDX)in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi and destabilises replication forks irrespective of HR pathway status, overcoming two well-known mechanisms of resistance to PARPi. Importantly, CX-5461 exhibits single agent efficacy in PARPi-resistant HGSOC-PDX. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. Therefore, CX-5461 is a promising therapy alone and in combination therapy with PARPi in HR-deficient HGSOC. CX-5461 is also an exciting treatment option for patients with relapsed HGSOC tumors that have poor clinical outcome.

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PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22168506 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8506

Author(s):

Kristie-Ann Dickson ◽

Tao Xie ◽

Christian Evenhuis ◽

Yue Ma ◽

Deborah J. Marsh

Keyword(s):

Ovarian Cancer ◽

Cell Line ◽

Ovarian Cancer Cell Line ◽

Acquired Resistance ◽

Parp Inhibitors ◽

Ovarian Cancer Cells ◽

High Grade ◽

Serous Ovarian Cancer ◽

Cancer Genes ◽

Chemical Structures

Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes BRCA1 or BRCA2 that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known BRCA status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of BRCA1. In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours.

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