How do developmental processes give rise to cancer, and how do malignant cells adapt to survive treatment? Our laboratory investigates these questions in leukemias and solid tumors affecting children and young adults, with a particular focus on refractory disease. We connect studies of genome plasticity, protein function, and cell-state regulation to the development of precisely targeted therapies.
How do developmental processes initiate cancer? We investigate the mechanisms that generate cancer-causing mutations, including developmentally regulated somatic mutators that produce site-specific alterations in the genome. Our research examines how these processes intersect with DNA damage repair and contribute to the pathogenesis of childhood and young-adult solid tumors. We combine functional genomics and proteomics with computational approaches and mouse models to define their biological functions and therapeutic vulnerabilities. A central objective is to identify dependencies associated with oncogenic mutators and exploit them through synthetic-lethal strategies by targeting functions that these cancer cells require for survival.
How do malignant cells persist and adapt? We study how cancer cells coordinate signaling, gene expression, and chromatin regulation to sustain malignant states and resist treatment. In acute leukemias, our work examines the regulatory mechanisms governing differentiation, cell death, and stem-cell quiescence, alongside the adaptive responses that limit targeted therapies. Functional genomic and proteomic approaches allow us to connect changes in molecular regulation with cellular behavior. We use these insights to investigate transcriptional coactivator inhibition and rational treatment combinations that disrupt oncogenic programs and counter mechanisms of resistance.
How can mechanistic discoveries guide better treatments? We develop experimental tools both to understand cancer biology and to act on that understanding. Quantitative mass spectrometry and integrative proteogenomics reveal protein regulation, chemical modifications, and non-canonical proteoforms that can inform biomarker and therapeutic-target discovery. Biophysical modeling and protein engineering support the design of agents that interfere with disease-associated molecular interactions, while proteomic barcoding and modular macromolecular conjugates provide platforms for screening and drug delivery. By integrating these technologies with disease models and clinical collaboration, we aim to translate molecular mechanisms into testable therapeutic strategies and guide the development of clinical trials for refractory cancers.
Please visit https://alexkentsis.net for more information about our research.