Abstract IA10: Renal cancer tumorgrafts: A validated model to evaluate novel targeted therapies

Abstract

Abstract Renal cell carcinoma (RCC) is diagnosed in over 50,000 Americans annually and in the metastatic setting remains largely incurable. The development of new drugs is hampered by the lack of suitable preclinical animal models reproducing the characteristics of human tumors. To date, we have implanted tumors from over 700 kidney cancer patients orthotopically in mice. Our models include common tumor types, such as clear cell and papillary, but also rare tumor types such as translocation carcinomas and fumarate hydratase (FH)-deficient renal tumors from HLRCC patients. We have shown that tumor fragments implanted orthotopically into NOD/SCID mice result in tumors that reproduce: (i) histology, (ii) gene expression, (iii) DNA copy number alterations and (iv) mutations. Tumorgraft (TG)-bearing mice also reproduce paraneoplastic syndromes (paraneoplastic hypercalcemia). Furthermore, TGs recapitulate the treatment responsiveness of RCC in patients. We performed pharmacokinetic studies to determine appropriate administration regimens resulting in comparable exposures. TGs responded to drugs effective against RCC in patients (sunitinib and sirolimus, which accounts for 70% of the circulating drug after temsirolimus administration) and were resistant to ineffective drugs (erlotinib). TGs provide a superb platform to evaluate promising novel therapeutics. Data will be presented on the application of our TG platform to the evaluation of a first-in-class inhibitor of arguably the most important driver of RCC, the HIF-2 transcription factor. TGs were used to assess activity, validate a putative pharmacodynamic biomarker, identify biomarkers of sensitivity, and to assess the development of resistance. By leveraging a large and diverse TG platform, preclinical drug testing may be rigorously conducted, the most promising agents may be identified, and future clinical development may be effectively informed. Citation Format: Andrea Pavia-Jimenez, Wenfang Chen, Haley Hill, Alana Christie, Qurratulain Yousuf, Noelle Williams, Xian-Jin Xie, Payal Kapur, James Brugarolas. Renal cancer tumorgrafts: A validated model to evaluate novel targeted therapies. [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 IA10.