MP72-14 IDENTIFYING THE SPATIO-FUNCTIONAL ORIGINS OF DRUG RESISTANCE WITH RAPID TUMOR XENOGRAFTS

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II1 Apr 2018MP72-14 IDENTIFYING THE SPATIO-FUNCTIONAL ORIGINS OF DRUG RESISTANCE WITH RAPID TUMOR XENOGRAFTS Nicholas Power, Matthew Lowerison, Yaroslav Fedyshyn, Karla Williams, Ann Chambers, James Lacefield, Paul Boutros, and Hon Leong Nicholas PowerNicholas Power More articles by this author , Matthew LowerisonMatthew Lowerison More articles by this author , Yaroslav FedyshynYaroslav Fedyshyn More articles by this author , Karla WilliamsKarla Williams More articles by this author , Ann ChambersAnn Chambers More articles by this author , James LacefieldJames Lacefield More articles by this author , Paul BoutrosPaul Boutros More articles by this author , and Hon LeongHon Leong More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2298AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Treatment of patients with advanced cancers increasingly relies on expensive agents targeting specific molecular or cellular aberrations. Pre-existing and acquired drug resistance typically renders these therapies ineffective, leading to lethal disease. The genome and microenvironment of cancers vary spatially, allowing drug resistance to emerge in any tumor region. To quantify this spatio-functional heterogeneity in response to therapy, we developed an approach based on tumor-implantation into the chorioallantoic membrane of chick embryos (PDXovo). METHODS Various cores were obtained from the primary tumor and metastases from patients with metastatic renal cell carcinoma at the time of nephrectomy (N=6). Each of these cores (5-6 for the primary tumor and 1-3 for metastases) were subdivided into 3 mm sized fragments and were implanted into the chorioallantoic membrane of chick embryos at Day 9 of embryonic development. Two days later, PDXs were treated topically with vehicle or Sunitinib (10 uM final in DMSO) every day until Day 17 of embryonic development. At endpoint (Day 19), all PDXs were submitted to high-frequency ultrasound imaging to quantitate differences in tumor blood perfusion and tumor volume between treatment groups. After imaging, PDXs were individually submitted to total exome sequencing. RESULTS We apply this approach to 1548 tumor regions from six renal cell carcinoma patients, achieving a 93.6% engraftment rate. We quantify the spatial heterogeneity in response of these models to sunitinib, an anti-angiogenic therapy, and predict clinical resistance using ultrasound imaging. Combining functional and somatic genomics of the primary tumor and metastases revealed some mutational features associated with sunitinib resistance both at baseline and after treatment. CONCLUSIONS These studies establish a rapid and efficient new method of surveying functional tumor heterogeneity in the context of drug resistance. Within 8-10 days of drug challenge, various regions of the primary tumor and metastases can be determined to be resistant or sensitive to targeted therapy, with no outright identifiable molecular signature correlated to drug resistance. This phenotype-based readout was superior to various prognostic scoring criteria systems and point towards PDX based methods to predict de novo drug resistance in patients with metastatic renal cell carcinoma. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e957 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Nicholas Power More articles by this author Matthew Lowerison More articles by this author Yaroslav Fedyshyn More articles by this author Karla Williams More articles by this author Ann Chambers More articles by this author James Lacefield More articles by this author Paul Boutros More articles by this author Hon Leong More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...