Abstract
Next generation DNA sequencing (NGS) has provided vast quantities of data on the genomic landscape of common solid malignancies yet the discovery yield in terms of new treatment approaches has been modest. At the most fundamental level this is because we still lack a deep understanding of how complex somatic changes in the cancer genome drive the cellular phenotypes associated with cancer lethality. Our recent work in breast cancer has demonstrated that discovery mass spectrometry-based proteomics of genome annotated clinical and PDX samples (“proteogenomics”) elucidates functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies potential therapeutic targets. The advantages of patient-derived xenografts (PDX) as a source of material for proteogenomics are readily evident. Larger amounts of tumor protein required for mass spectrometry can be obtained, sample ischemia can be controlled and drug perturbation studies to study drug resistance can be easily conducted. However we still have to firmly establish that the proteome of the progenitor human tumor strongly correlates with the proteomic characteristics of the tumor that eventually emerges after engrafting into immunocompromised mice. This is critical as from the genomic perspective, engraftment does represent an evolutionary bottle neck that, at least in some cases, alters tumor clonality. The discovery potential as well as limitations of PDX for the emerging area of proteogenomics will therefore be discussed.
Citation Format: Matthew J. Ellis. The proteogenomics of breast cancer patient-derived xenografts. [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 IA01.
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