Functional proteomics and molecular pharmacology of pediatric and young-onset cancers
To answer these questions, we are developing functional genomics and mass spectrometry proteomics approaches to decipher the mechanisms of genomic plasticity and adaptive signaling. Using protein engineering techniques, we rationally design and develop precisely targeted cancer therapeutic agents.
We leverage proteomics to develop improved biologic therapies, computational modeling to define oncogenic mechanisms, and innovative mouse models to determine biological functions and guide clinical trials of improved treatments, particularly for children and young adults with refractory cancers.
Our current research is focused on developmental cancer biology and developmental therapeutics. Our past research identified molecular mechanisms and therapeutic strategies to interfere with oncogenic kinase signaling, transcriptional and chromatin, and post-transcriptional protein regulation, as well as diagnostic biomarkers of leukemias, solid tumors, and inflammatory conditions. Recently, our group has identified new mechanisms of aberrant gene control and dysregulation of cell death, differentiation and stem cell quiescence in blood cancers, mechanisms of site-specific oncogenic mutations and DNA damage repair signaling in solid tumors, and improved epigenetic, drug delivery and macromolecular therapeutics for cancer. Based on over two decades of research in functional proteomics and genomics, we continue to develop and apply improved proteomic and genomic methods to define oncogenic mechanisms and develop improved therapies, thereby translating laboratory discoveries into rational therapeutic strategies and clinical trials for patients.
1) Leveraging improved methods in functional genomics and proteomics that our group developed, we revealed developmental mechanisms of site-specific oncogenic mutations in solid tumors that affect children and young adults, molecular and cellular mechanisms, therapeutic targets and rational combination strategies to overcome therapy resistance, and synthetic lethal strategies to pharmacologically target developmental oncogenic mutators in childhood and young-adult human cancers.
2) Our lab has used functional genomic and proteomic approaches to elucidate molecular mechanisms of pathogenesis of acute leukemias with the goal of identifying improved therapeutic strategies, particularly for refractory leukemias of children and young adults. This work led to the development of rational combination strategies to overcome adaptive therapy resistance, mechanisms of leukemia stem cell quiescence, mechanisms, and therapies of signaling-mediated control of oncogenic gene expression, and first-in-class transcriptional coactivator inhibitors.
3) Our research in mass spectrometry proteomics has focused on developing improved methods for quantitative biological proteomics and translational platforms for the discovery of improved biomarkers and therapeutic targets in human disease and cancer in particular. This has enabled comprehensive mapping of cancer proteomes, including methods for detection of chemical modifications and non-canonical proteoforms, and improved approaches for the incorporation of molecular profiling into clinical medicine, as implemented in the Quantitative Cell Proteomics Atlas. More recently, we implemented proteomic barcoding as a platform for macromolecular screening and delivery, established the scalable ProteomeGenerator framework for integrative proteogenomics, and led the development of a modular platform for therapeutic drug delivery using trifunctional bio-orthogonal macromolecular conjugates (BMC).
4) We continue to apply and advance methods in biophysical theory and computational biology to understand fundamental properties of living systems and develop precisely targeted therapeutic agents. This includes statistical mechanics and molecular dynamics, computational genomics, systems biology, and a project to develop new physics of life to understand biological molecules, development, and disease.
We are a group of physicians and scientists in the Molecular Pharmacology Program at the Sloan Kettering Institute and Department of Pediatrics and the Tow Center for Developmental Oncology at the Memorial Sloan-Kettering Cancer Center. We study the biology of cancers that affect children and young adults ranging from embryonal tumors in infants, leukemias and brain tumors in children, and sarcomas in young adults. Scientists in our group use inter-disciplinary experimental tools as they work to understand the fundamental causes of cancer and to develop definitive therapies for their control.
We are interested in understanding the principles of disorganization of genomes and proteomes of refractory leukemias and solid tumors, and determining the molecular mechanisms of response and adaptation of tumor cells to targeted therapies.
