Abstract B13: Identifying new potential therapies in ovarian cancer: Establishment and characterization of a panel of low passage tumor models and in vivo evaluation of approved and investigational agents.
Authors: Wick Michael J. , Nieves Francis E. , Kelly Scott G. , Estrada Vanessa A. , Thangasamy Amalraj , Burns Jennifer M. , Tolcher Anthony W. , Patnaik Amita , White Allan J. , Drengler Ronald L. , Papadopoulos Kyriakos P. 
Published: June 2012

Background: Ovarian cancer is the leading cause of death from gynecologic malignancies in Western countries. Standard treatment for ovarian cancer consists of tumor debulking followed by platinum/taxane therapy. While the rate of initial response to treatment is high, the majority of patients develop recurrent, chemoresistant disease. Secondary chemotherapy treatment provides benefit to only 10–30% of these patients, demonstrating the need for identifying additional useful therapies. To assist in identifying new therapies for ovarian cancer, we collected tumor tissue from chemo-naïve and pretreated patients and established, developed and characterized a panel of low passage ovarian tumor models. We then utilized these models to demonstrate antitumor activity of a novel targeted therapy.

Methods: For each model, tissue was collected and implanted into immune-deficient mice and progress monitored. Each established model was confirmed by histologic comparison to the corresponding patient clinical sample and linked to their available treatment and outcome data. Additional characterization, including mutation profiling and standard drug sensitivity studies, was performed on each model and results compared with clinical information. An investigator-initiated study was performed evaluating activity of the Smac (second mitochondrial-derived activator of caspases) mimetic TL32711 in a subset of these models. Single agent tumor growth inhibition and delay were evaluated and study endpoints included mean and individual tumor volumes of approximately 1 cm3 or up to sixty days following treatment initiation.

Results: Twenty low passage ovarian models have been established and characterized. Activating mutations identified in some models include: PI3KCA (6%), TP53 (19%), FBXW7 (6%), RAS (13%) and BRAF (6%). In vivo response to platinum and/or taxane agents correlated ≥70% with donor patient outcome at the time of sample collection and models demonstrated variable sensitivity to evaluated secondary chemotherapies. Single agent TL32711 showed statistically significant (p&lt;0.05) treatment-dependent tumor growth inhibition and notable tumor growth delay in evaluated models.

Conclusion: We have generated a panel of characterized patient-derived low passage ovarian tumor models with differential mutation status and drug sensitivity profiles. Using these models we have identified a preclinically active agent towards ovarian cancer. Expansion of this panel of ovarian tumors is planned and should further enhance its utility in identifying agents potentially useful for treatment of ovarian cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B13.