Abstract A01: A comprehensive collection of patient derived xenografts of human melanoma with clinical, genomic, and biological characterization
Authors: Clemens Krepler, Katrin Sproesser, Marilda Beqiri, Min Xiao, Patricia Brafford, Wei Xu, Bradley Garman, Jennifer Wargo, Michael A. Davies, Dennie T. Frederick, Keith T. Flaherty, David Hoon, Joseph J. Bennett, Michael Guarino, Nicholas J. Petrelli, David Elder, Xiaowei Xu, Giorgos Karakousis, KATHERINE L. NATHANSON, Lynn Schuchter, Meenhard Herlyn
Journal: Clinical Cancer Research (2016)

Abstract Advanced melanoma has seen dramatic changes in standard of care in the last years and many novel targeted small molecules and immune checkpoint inhibitors are in development. More than 200 clinical trials are currently ongoing for metastatic melanoma. Thus, accurate pre-clinical models to predict clinical responses are urgently needed. We have established a large bank of live tumor tissue (n=500) with more than 300 models expanded as PDX. Melanoma tumor tissue is uniquely suited to establish patient-derived xenograft (PDX) models, since only one tumor cell can initiate tumor growth. Thus, our success rate is at 90% using NSG mice and matrigel for s.c. implantation of minced tissue chunks. We have opted for such a large number of models due to the genomic and clinical heterogeneity of melanoma based on available TCGA data. Although almost half of all melanomas harbor BRAF V600 hotspot mutations, followed in frequency by NRAS and NF1 mutations, many driver mutations are only found in a small subset and many mutations are occurring concurrently in various confirmations. We used a custom targeted capture of 108 genes previously implicated in melanoma, and performed massively parallel sequencing on currently 200 PDX. Samples were then clustered into groups based on deleterious mutations which were detected in all but a very small subset of samples. The biological relevance of these multiple genomic subsets was then tested against latency, growth rate, and spontaneous metastasis in PDX. Further, clinical information such as age, gender, history, and response to therapies provided additional parameters to classify this collection into meaningful subgroups. In conclusion, this collection of melanoma PDX recapitulates the breadth of advanced melanoma in the clinic and therefore a comprehensive resource for precision medicine testing in an increasingly scattered therapy landscape. Citation Format: Clemens Krepler, Katrin Sproesser, Marilda Beqiri, Min Xiao, Patricia Brafford, Wei Xu, Bradley Garman, Jennifer Wargo, Michael A. Davies, Dennie T. Frederick, Keith T. Flaherty, David Hoon, Joseph J. Bennett, Michael Guarino, Nicholas J. Petrelli, David Elder, Xiaowei Xu, Giorgos Karakousis, KATHERINE L. NATHANSON, Lynn Schuchter, Meenhard Herlyn. A comprehensive collection of patient derived xenografts of human melanoma with clinical, genomic, and biological characterization. [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 A01.