Abstract A11: Using a patient-derived orthotopic xenograft (PDOX) model to screen drugs targeting renal cell carcinoma (RCC) metastasis: A personalized therapeutic strategy
Authors: Jessie Gills, Ravan Moret, Xin Zhang, Ashley Richman, John Nelson, Grace Maresh, Christudas Morais, Glenda Gobe, Sunil Talwar, Marc Matrana, Stephen Bardot, Li Li
Journal: Clinical Cancer Research (2016)

Abstract Renal cell carcinoma (RCC) is the most common solid tumor of the adult kidney, with a mortality of 30-40%(1). RCC is highly metastatic and potentially lethal. 25-30% of RCC patients have metastatic disease at diagnosis, and 40-50% of patients develop metastases later. The 5-year survival for metastatic RCC patients is less than 10%(2), due to its highly-resistant to current therapies. The challenge of managing RCC patients in the clinic often involves trying different drugs one after another until one works, so individualized therapy is urgently needed. Our objective was to establish a patient-derived orthotopic xenograft (PDOX) intra-renal sub-capsular injection NOD/SCID mouse model that recapitulates metastatic RCC for personalized therapeutic strategies. Two luciferase-tagged RCC cell lines (A498-Luc, 769P-Luc) were used to determine the IC50 of sunitinib, pazopanib, and everolimus using bioluminescent imaging (BLI) of in vitro cell viability assay at 48 hrs. A consented human RCC specimen (KiCa-Pt58) was obtained via radical nephrectomy and tumor cells tagged with luciferase. KiCa-Pt58-Luc cells (0.01 million) were then injected sub-capsularly into the left kidneys of NOD/SCID mice. Mice bearing kidney tumors were split into 1 control and 4 sequential treatment groups receiving 40mg/kg sunitinib, 40mg/kg pazopanib, or 5mg/kg everolimus three times per week via gavage. Tumor growth was monitored weekly by BLI. Drug responses were evaluated based on BLI data and decision made for whether to switch to the next sequence drug. At necropsy, primary tumors and mouse lungs were collected for BLI, weights, and histology. The IC50 was 6μM for sunitinib and 3.6μg/ml for pazopanib. In our PDOX model, patient tumors successfully produced primary tumor and spontaneous lung metastasis as seen in RCC patients (45/45). Selected drug dosages delivered by gavage were safe, effective and without adverse effects. Drug sequence of pazopanib switch to everolimus is the best among 4 combinations tested for primary tumor progress and lung metastasis for patient tumor KiCa-Pt58. Our unique PDOX model provides a platform for testing RCC drugs simultaneously for responses in primary tumor progression and metastasis. It could lead to the development of realistic, durable, and individualized treatments for RCC patients. Citation Format: Jessie Gills, Ravan Moret, Xin Zhang, Ashley Richman, John Nelson, Grace Maresh, Christudas Morais, Glenda Gobe, Sunil Talwar, Marc Matrana, Stephen Bardot, Li Li. Using a patient-derived orthotopic xenograft (PDOX) model to screen drugs targeting renal cell carcinoma (RCC) metastasis: A personalized therapeutic strategy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A11.