Abstract LB216: Static and microfluidic platforms for novel therapeutic testing in high-grade serous ovarian cancer

Abstract

Abstract Background: High-Grade Serous Ovarian Cancer (HGSOC) is the most lethal OC type because of its silent progression and lack of specific markers for early detection. In this context, the timely initiation of effective treatment is imperative to prevent disease progression extending life expectancy. However, responses to treatment can vary significantly among individuals, presenting clinical challenges in selecting effective treatments, necessitating the interpretation of molecular and genomic data of the patient on a case-by-case basis. The aim of this study is to establish a highly sensitive platform, implemented with microfluidic technology, to predict patient drug responses with the goal of assisting oncologists in shaping effective treatments. Moreover, validating this platform through a retrospective study, enabling the development of innovative drugs. Methods: In this work, patient-derived ovarian cancer organoids (PDOs) were engineered for drug screening and twenty FDA approved drugs were assessed on seven PDOs derived from both primary tumors and ascites. The fidelity of PDOs in reproducing the histopathology of the primary tumour was confirmed by immunohistochemistry. Proteomics and repeated screening on high- and low-passage PDOs confirmed the reliability of the platform over time. Furthermore, to bridge the gap between static systems and the dynamic of human tumours, a microfluidic platform was employed and using fluorescence microscopy the patients' drug sensitivity was predicted (PMID: 37143603). Results: PDOs were able to replicate patients' response to the drug in a retrospective study and surprisingly, in some cases, to predict resistance to certain drugs administered on the basis of strong, clinically validated predictive biomarkers, which proved ineffective in the clinic. The platform could predict innovative therapeutic strategies as demonstrated by inhibiting the activity of Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (Pin1), a novel druggable target for OC (PMID: 22322860, 29746956, 30697729). The Pin1 inhibitor (VS10) is effective in a subset of patients resistant to platinum-based chemotherapy and synergize with doxorubicin. Finally, a microfluidic platform fluorescence based, which improved drug penetration in PDOs was developed for efficient and faster drug screening. Conclusions: This study underscores the significance of utilizing engineered PDOs to develop predictive and easy to use platforms that can truly aid oncologists in devising patient-specific treatments while circumventing the use of drugs that, despite strong recommendations, may prove ineffective. Furthermore, these platforms have demonstrated their effectiveness in the development of innovative therapeutics, such as Pin1 inhibitors, which have been proven both effective and safe in animal models, underscoring the need for clinical studies. Acknowledgments: AIRC IG23566 Citation Format: Enrico Cavarzerani, Gloria Saorin, Matteo Mauceri, Isabella Caligiuri, Michele Bartoletti, Vincenzo Canzonieri, Flavio Rizzolio. Static and microfluidic platforms for novel therapeutic testing in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB216.