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Background: BRCA1/2 mutant tumors cells are deficient for homologous recombination (HR)-mediated DNA repair and are particularly sensitive to PARP inhibitors (PARPi). PARPi have proved efficacy in breast, ovarian, prostate, and pancreatic cancers, particularly in HR-deficient tumors, while their activity is limited in HR-proficient tumors. However, PARPi resistance is inevitable and therapeutic resistance resulting from restoration of HR repair is a pressing clinical problem. Identifying combination treatments to sensitize tumors cells to PARPi and/or overcome PARPi resistance is critical to expand the benefit of these therapies. The Polo-like kinase 1 (PLK1), a serine threonine kinase, is a master regulator of mitosis, overexpressed in many cancers. PLK1 is also involved in the DNA damage response through the promotion of HR-mediated DNA repair and the recovery from the G2/M checkpoint. PLK1 roles in HR repair suggest that PLK1 inhibition may reverse PARPi resistance. Methods: To test the effect of PLK1 and PARP inhibitors combination, we used onvansertib, a highly selective, ATP-competitor PLK1 inhibitor currently in clinical development and the FDA-approved PARPi olaparib. The antitumor effect of the single and combined drug treatments was tested in 2 BRCA1 mutated high-grade serous ovarian cancer (HGSOC) patient derived (PDX) models resistant to olaparib. Orthotopically PDX transplanted mice were treated for 4 weeks and followed for survival. Results: The combination of onvansertib and olaparib was well tolerated and showed strong anti-tumor activity in both PDX models. The combination significantly increased mice survival in comparison to vehicle, olaparib and onvansertib, and showed that onvansertib can re-sensitize PARPi-resistant tumors to olaparib. Median survival increased by 2.7-fold and 8.1-fold respectively in the 2 PDX models in the combination group versus vehicle and the Kaplan Meyer survival curves of mice treated with the combination showed a statistically survival advantage versus control and single agent treated mice. Pharmacodynamic analyses showed an increase in mitotic, apoptotic and DNA damage markers in tumors treated with the combination versus vehicle. Conclusions: The combination of the PLK1 inhibitor onvansertib and the PARPi olaparib showed potent anti-tumor activity in olaparib-resistant BRAC1 mutant HGSOC PDX models. Additional studies are ongoing to further assess the potential of the combination in BRCA wild-type and mutant ovarian, prostate, pancreatic and breast cancer preclinical models. Citation Format: Michela Chiappa, Federica Guffanti, Alessandra Decio, Alessandro Aliverti, Francesca Ricci, Eugenio Scanziani, Federica Camin, Ilaria Craparotta, Maria Chiara Barbera, Marco Bolis, Maya Ridinger, Giovanna Damia. Combining PARP inhibition with the polo-like kinase 1 (PLK1) inhibitor onvansertib overcomes PARP inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3237.

INTRODUCTION and AIM Pancreatic ductal adenocarcinoma is a lethal disease with an overall survival rate of 5% and a median survival time of less than 6 months. Current systemic treatments offer only a modest benefit in symptom control and survival, thus surgery remains the most effective treatment. The exploitation of new therapeutics is an urgent need, but the research is braked by the limited value of the current preclinical models as predictors of patients response. The aim of our study is to develop patient-derived primary pancreatic ductal adenocarcinoma xenografts (PDAC-PDX) growing into the pancreas of recipient mice that retain features of the patient’s tumors and mimic the biological heterogeneity of human pancreatic cancer. METHODS Cancer specimens from patients undergoing cephalic duodenopancreatectomy were transplanted in NSG mice and orthotopically propagated by their re-implantation into the pancreas of SCID mice. Tumor burden was measured by abdominal palpation and by non invasive magnetic resonance imaging (MRI). PDAC-PDXs were characterized histologically, for mutational status (KRAS, TP53 and SMAD4), and responsiveness to gemcitabine. Gemcitabine was administered alone or combined with nab-paclitaxel, to mice bearing tumor in their pancreas; drugs were given intravenously on days 1 and 8 of each 21-day cycle to copy as much as possible patient’s recommendations. To determine the antitumor effects of the treatments, changes in tumor growth over time were evaluated by MRI and plasma level of Ca19-9. RESULTS Surgically resectable pancreatic adenocarcinoma (histologically confirmed) engrafted successfully in 5 cases (out of 11) and retained the molecular, morphological and biological features of the original patient tumors. Mutational landscape of the PDAC-PDXs reflect the clinical scenario: 80% are mutated in KRAS (G12D, G12R), 80% carry a TP53 mutation (I162F, R213*, Y220C, R248Q) and 20% show the deletion of SMAD4. Histological features recapitulate the human disease, the PDAC-PDXs exhibit a robust amount of host derived stroma with collagen deposition, constant through generations (up to five). Orthotopic growing PDAC-PDXs were marginal responsive to gemcitabine treatment, while significant response (stable disease and regression) was observed with the gemcitabine and nab-paclitaxel combination regimen, which was more efficacious than paclitaxel (equimolar dose). CONCLUSION PDAC-PDXs growing orthotopically in the pancreas of mice provide a valuable tool for the preclinical exploitation of novel therapeutics for pancreatic cancer. . Supported by Associazione Italiana per la Ricerca sul Cancro (AIRC 5 per mille n. 12182) and Fondazione “Eugenio Morandi” ONLUS per lo studio e la cura dei tumori del pancreas. Citation Format: Alessia Anastasia, Andrea Resovi, Carmen Ghilardi, Roberta Avigni, Edoardo Micotti, Lucia Minoli, Eugenio Scanziani, Carlo Corbellini, Eugenio Morandi, Dorina Belotti, Raffaella Giavazzi, MariaRosa Bani. Patient-derived tumor xenografts as pharmacological model of human pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3857. doi:10.1158/1538-7445.AM2017-3857

TIR8 (also known as SIGIRR) is a member of the interleukin-1/Toll-like receptor family with inhibitory activity on inflammatory reactions and high expression in intestinal mucosa. Here, we report that Tir8-deficient mice exhibited a dramatic intestinal inflammation in response to dextran sulfate sodium salt (DSS) administration in terms of weight loss, intestinal bleeding, and mortality and showed increased susceptibility to carcinogenesis in response to azoxymethane and DSS. Increased susceptibility to colitis-associated cancer was associated to increased permeability and local production of prostaglandin E2, proinflammatory cytokines, and chemokines. Thus, these results are consistent with the hypothesis that TIR8, by negatively regulating intestinal inflammation, plays a nonredundant role in the control of the protumor activity of chronic inflammation in the gut. [Cancer Res 2007;67(13):6017–21]