Abstract A42: Using a PDX tumor bank to screen for cancer stem cell therapies (2016)

Abstract OncoMed Pharmaceuticals is focused on discovering novel therapies that target cancer stem cells (CSCs), specifically those which depend on the Notch or Wnt pathways. Since Patient Derived Xenografts (PDXs) recapitulate both tumor cell heterogeneity and maintain the histopathological characteristics of the original tumor, they represent an important preclinical model for CSC drug discovery and can be used to effectively screen for new therapeutic candidates. To this end, OncoMed has established a fully characterized PDX Tumor Bank for its monoclonal antibody discovery and developmental efforts and has used PDX models to advance seven candidates into clinical trials. The goal of this study is to: 1) review the operational steps needed to propagate PDX's; 2) define the quality controls necessary to maintain these tumors; 3) assess how the Tumor Bank has helped in the selection and advancement of these targeted biologics into the clinic; and 4) review the role of the Tumor Bank in defining biomarkers for clinical use. Tumor specimens were received from surgery and processed into fragments, cell clumps, or dissociated cells. Tumor tissue or cells were either implanted into NOG or Nod/scid mice or frozen for later implantation. Primary tumors that grew were serially transplanted to establish working stocks for drug screening experiments. Every tumor was characterized for a variety of molecular, cellular, and tumor endpoints. All pertinent data and samples were captured into a custom designed database which included lineage diagrams to easily track tumor propagation and characterization endpoints. The quality control of the established PDXs must be carefully monitored throughout the process. We have used DNA fingerprinting to ensure the identification of each tumor and subsequent passages, but the larger problem of identifying and monitoring the development of spontaneous lymphomas (both human and murine) that can infiltrate and contaminate the PDX required a rigorous monitoring strategy. The infection of mice with Lactate Dehydrogenase Elevating Virus from contaminated reagents can severely affect animal health and, therefore the screening process. Surprisingly, the misdiagnosis of tumors received from surgery was higher than expected and resulted in tumors being correctly reclassified before being used. The strategy employed to effectively screen selected targets in the Notch and Wnt pathways was to first review the molecular characterization data from our PDX models, and then select appropriate models for in vivo efficacy testing. In order to assess how the Tumor Bank has helped both in the screening process and the identification of biomarkers, we will review both pre-clinical and clinical data for selected OncoMed antibodies. As an example, one anti-CSC agent, OMP-59R5 (Tarextumab), which targets Notch2/3 was tested in ten pancreatic PDX models. Six pancreatic PDX tumors were responders to anti-NOTCH2/3 while four were non-responders. Bioinformatic analysis of the responder/non-responder data sets identified tumors that had high Notch3 gene expression as responders to OMP-59R5 treatment. Based on this preclinical data, Notch3 levels were evaluated in a Phase 1b pancreatic trial as a potential predictive biomarker. In this trial, higher response rate and longer survival was noted in patients with Notch3 high tumors receiving GEM/Nab-P/ Tarextumab (at 5-15mg/kg). These observations are being tested in a placebo-controlled, randomized Ph2 setting. The creation of a working PDX Tumor Bank across multiply human solid tumor types has allowed us to implement an effective preclinical screening program to select candidate biologics and potential predictive biomarkers for targets in the Notch and Wnt pathways. Citation Format: James Evans, Chun Zhang, Angie InKyung Park, Alayne Brunner, Min Wang, Cristina Dee-Hoskins, Roger Lopez, Xiaomei Song, Kellie Pickell, Wan-Cheng Yen, Marcus Fischer, Raymond Tam, Gilbert O'Young, Jakob Dupont, Lei Zhou, Austin Gurney, John Lewicki, Tim Hoey, Ann M. Kapoun, Belinda Cancilla. Using a PDX tumor bank to screen for cancer stem cell 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 A42.