Abstract 395: Patient stratification and drug combination strategy based on drug response and genomic information from PDX clinical trials (PCTs)

Abstract

Abstract Cancer is a heterogeneous disease with various molecular lesions and drug response profiles within the same tumor type. Patient stratification in clinical trials based on molecular features has contributed to recent success of several targeted cancer drugs on molecular aberrations such as BCR-ABL translocation in CML, Her2 amplification in breast and gastric cancers, EGFR mutations and ALK fusions in lung cancer and BRAF mutation in melanoma. However, in most cancers, the molecular features which can be used for patient stratification are not as simple as a single genetic aberration. Multiple drug resistance mechanisms caused by various mutations in cancer signaling pathways can also increase the uncertainty of clinical outcomes. To increase the chance of success in human clinical studies, patient-derived xenograft (PDX) clinical trials (PCTs) have increasingly been used for predictive biomarker validation, resistance mechanism investigation and combination therapy selection. PDX tumor models have been demonstrated to have high correlations with human patients in tumor pathology, molecular characteristics and drug responses. Large scale PCTs have also shown consistency in results when compared to related human clinical trials. At GenenDesign, we have established over 1000 PDX tumor models and more than 100 resistance models against various cancer drugs. Many of these PDX models have been characterized at RNA/Exome sequence, gene expression, gene copy number and hot-spot mutation levels. We carried out our PDX clinical trials by testing multiple approved drugs and clinical drug candidates such as targeted inhibitors against FGFRs, c-Met/ALK, HER2, EGFR, cell cycle regulators, Ras/Raf pathway, PI3K/Akt pathway, as well as chemotherapy drugs in biomarker-driven multi-drug multi-arm expanded PDX clinical trials. So far, we have accumulated more than 3000 efficacy data sets and associated PD samples. Analysis of drug response and associated genomic information from PDX clinical trials yielded rich information for predictive biomarker identification and validation. At the same time, many potential resistance mechanisms were also revealed. These information can make human clinical trial better prepared, more efficient and focused. More importantly, testing of a targeted drug with multiple chemotherapies in the same models can also provide guidance on future combination selection strategy. Citation Format: Jingjing Jiang, Tengfei Yu, Ying Yan, Wei Du, Tingting Tan, Xuqin Yang, Jiali Gu, Xin K. Ye, Zhenyu Gu. Patient stratification and drug combination strategy based on drug response and genomic information from PDX clinical trials (PCTs). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 395.