Abstract C034: Beyond genomics: Integrative multi-omics in cancer research

Abstract The treatment of cancer increasingly leverages genomic testing to tailor therapies to a patient's tumor profile. While this approach has achieved significant success, challenges and unmet needs remain. Integrating genomics with other "omics," particularly proteomics - an approach called proteogenomics that encompasses cataloguing the functional output of genes - enhances our understanding of cancer's biological complexity and offers functional validation of molecular pathways and therapeutic targets. Recent studies by the National Cancer Institute’s (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) illustrate how proteogenomics can provide a more complete picture of patient’s tumor, address mechanisms of treatment response, resistance, or toxicity, and support biomarker discovery[1]. The NCI has released comprehensive proteogenomic datasets from over 1,500 patients and 10 primary sites with clinical annotations and imaging data as a rich resource for hypothesis generation and validation[2]. Technological advances are transitioning proteomics from a discovery science to a translational tool, potentially informing clinical decisions. Mass spectrometry platforms now offer increased sensitivity, throughput, improved quantification, reduced sample input requirements, and the ability to process biospecimens collected during routine clinical care. Analyzing post-translational modifications (PTMs), such as phosphorylation, glycosylation, acetylation, and ubiquitination, provides pathway insights unattainable from genomic data alone[3]. Direct measurement of protein PTMs, particularly phosphorylation, enables the assessment of pathway activity and signaling networks driven by genomic changes. Kinase inference algorithms that utilize global phosphoproteomic data can inform precision oncology by identifying deregulated kinases as potential therapeutic targets. Single-cell and near single-cell spatial proteomics technologies reveal critical information about the tumor microenvironment and its evolution during cancer development and therapy. For proteomics to achieve clinical relevance, several challenges must be addressed, including technical limitations related to the amount and type of input biospecimen. Demonstrating the utility of proteogenomic approaches within clinical contexts requires prioritizing correlative studies that provide evidence of meaningful improvement in patient outcomes during clinical trials. Regulatory approvals should be addressed by developing standardized protocols that ensure analytical and clinical validity. Regulatory agencies must establish guidelines and pathways for approval. Achieving these objectives will necessitate collaboration and data sharing across multidisciplinary research networks and well-powered, well-annotated patient cohorts. [1] Jaehnig, Eric J et al. Cell Rep Med, 2025. [2] Li, Yize et al. Cancer Cell, 2023. [3] Joshi, Sunil K et al. Annu Rev Pharmacol Toxicol, 2024. Citation Format: Ana I. Robles. Beyond genomics: Integrative multi-omics in cancer research [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C034.