Abstract A013: TAp63-Regulated Oncogenic LncRNAs (TROLLs) as novel therapeutic targets in high grade serous ovarian cancer

Abstract High-grade serous ovarian cancer (HGSOC) is the most common and malignant type of ovarian cancer. Even though roughly 85% of patients achieve remission after initial surgical debulking and chemotherapy, four out of five HGSOC patients will experience disease recurrence, resulting in a 5-year survival rate of 43%. HGSOC tumors are frequently mutated in p53 (>95%) and have hyperactivation of the AKT pathway (∼45%). Our laboratory has identified and characterized two TAp63 Regulated Oncogenic Long non-coding RNAs (TROLL-2 and TROLL-3) whose transcription is induced by mutant p53 and expression levels correlate with ovarian cancer's grade and phosphorylation of AKT. In-depth analysis demonstrated that TROLL-2 and TROLL-3 directly activate AKT in tumor cells, thus linking p53 alterations to AKT activity. The use of AKT inhibitors in the clinic is limited because of frequent adverse effects, likely due to the constitutive expression of AKT in all cells. TROLL-2 and TROLL-3 expression is limited to tumor cells and provides a more specific target for decreasing AKT activation, potentially minimizing off-target effects. Reduction of TROLL-2 and TROLL-3 has been optimized using antisense oligonucleotides (ASOs) in an ex vivo perfusion platform for 3D culture of microtumors derived from primary patient tissue and xenograft models. Samples show maximum reduction of proliferation (EdU) and phosphorylation of AKT when TROLL-2 and TROLL-3 ASOs are used concurrently. Primary ovarian patient tissues were orthotopically implanted into NSG mice to generate ovarian PDXs (patient-derived xenografts) as translationally relevant in vivo models. Furthermore, to reduce the dosage and clearance of ASOs, ASOs encapsulated into metal-organic frameworks (ASO@MOFs) are undergoing in vivo and ex vivo testing. Inhibition of AKT is a promising mechanism for HGSOC by combinatorically enhancing cell death at two critical stages of HGSOC treatment: (1) in conjunction with PARP inhibitors at the post-chemotherapy maintenance phase and (2) re-sensitization of platinum-resistant tumors to carboplatin. Our data provides preclinical rationale for the implementation of ASOs targeting TROLL-2 and TROLL-3 as a relevant translational therapy and novel method to exploit the specificity of TROLL-2 and TROLL-3 expression in HGSOC thus bolstering susceptibility to PARP inhibitors or platinum treatment via the downregulation of AKT activity. Citation Format: Ashley Lui, Marco Napoli, Julia Nowak, Mayayi Izzo, Jaden Baldwin, Christina Carr, Angie Rivera, Gregory Sawyer, Erin George, Michelle Teplensky, Elsa R. Flores. TAp63-Regulated Oncogenic LncRNAs (TROLLs) as novel therapeutic targets in high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A013.