Abstract 5650: Functional proteomics for precise cancer diagnosis and therapy using the MSK Quantitative Cancer Proteomics Atlas

Abstract

Abstract The advent of molecular biology and molecular profiling in clinical medicine has transformed our understanding of the molecular basis of human cancer. As a result, we are increasingly improving the classification of human tumors based on their specific genetic and molecular mechanisms of pathogenesis. However, currently only a small number of mutant alleles guide treatment decisions, while most observed mutations remain of unknown pathologic and clinical significance. In addition, even for recently approved drugs, such as those targeting activated kinase signaling, clinical efficacy is highly varied, with no currently satisfactory means to identify molecular markers of response and resistance. To address this need, and broadly enable transformative future advances in precision oncology and patient outcomes, we have now developed the Quantitative Cancer Proteomics Atlas (QCPA). This technology permits highly multiplexed, quantitative analysis of the expression and biochemical activity of hundreds of proteins, covering most recurrently mutated and known pathogenic pathways in cancer cells, and designed to be applied to clinically accessible patient specimens. QCPA enables concomitant measurement of cellular concentration and stoichiometry of regulatory post-translational modification of key proteins mediating aberrant survival and proliferation. The activation status of these proteins is then used as a proxy to infer regulatory status of relevant biochemical pathways. These sentinel proteins include 467 known effectors of kinase regulatory signaling, apoptosis, stress response, and proliferation. QCPA measurements can be made using conventional parallel reaction monitoring mass spectrometry, or using an improved method termed accumulated ion monitoring (Cifani & Kentsis 2017). We established analytical metrics of QCPA assays in cancer cell lines, and demonstrated sensitivity and quantification accuracy amenable to measure endogenous chemically modified proteins from microgram specimens. We then demonstrated the ability of QCPA profiling to detect differential biochemical activities in response to defined stimuli in vitro. Next, we deployed QCPA profiling to reveal functional differences between primary human acute myeloid leukemia specimens and CD34+ myeloid progenitors, measuring specific activation of biochemical pathways in cancer cells. Finally, we tested the clinical utility of functional proteomic profiling by determining molecular markers of response and resistance to ERK pathway inhibitors in patient specimens. Thus, QCPA functional proteomic profiling provides a tool to achieve precise diagnosis and rational targeted cancer therapies. Citation Format: Paolo Cifani, Ahmet Dogan, David B. Solit, Alex Kentsis. Functional proteomics for precise cancer diagnosis and therapy using the MSK Quantitative Cancer Proteomics Atlas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5650.