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Elucidation and Pharmacologic targeting of non-oncogene dependencies at the single cell level
We have developed network-based methodologies for the systematic identification, validation, and pharmacological targeting of a new class of therapeutic targets. These targets comprise Master Regulator proteins, whose concerted activity within a Regulatory Checkpoint module is responsible for the mechanistic implementation and maintenance of cell transcriptional state, in both transformed and non-transformed cells. By leveraging these methodologies, we have developed NY CLIA certified tests (OncoTreat and OncoTarget) that leverage large-scale drug-perturbation assays to systematically identify drugs and drug combinations whose mechanism of action is specifically effective in abrogating tumour checkpoint activity, on an individual patient basis. These tests have shown >80% success rate in 35 drug arms in PDX models established from patients who had failed multiple lines of therapy. We will first introduce the methodological advances supporting the development of these methodologies and then demonstrate their extension to elucidating drugs capable of targeting the master regulator dependencies of transcriptionally distinct tumour subpopulations, at the single cell level. Specifically, we will discuss identification and pre-clinical validation of drug combinations targeting seven distinct subpopulations in Diffuse Midline Glioma, as well as Master Regulators of tumour-infiltrating T regulatory cells, whose pharmacologic targeting synergizes with immune checkpoint therapy.
About the speaker
Dr Andrea Califano is the Clyde and Helen Wu Professor of Chemical and Systems Biology at Columbia University Irving Medical Center, with appointments in Biochemistry & Molecular Biophysics, Biomedical Informatics, and Medicine. Recently, he became the President of the Chan Zuckerberg Biohub New York. After earning his Ph.D. in physics from the University of Florence in 1986, Dr Califano joined IBM’s TJ Watson Research Center, where he later directed the Computational Biology Center. He co-founded First Genetic Trust Inc. in 2000 and joined Columbia in 2003.
Dr Califano is a leader in the reverse engineering of gene regulatory networks, contributing to numerous clinical trials, including pioneering N-of-1 studies for personalized cancer treatment. He serves on several prestigious scientific boards, including the National Cancer Institute and St. Jude Children’s Hospital, and has chaired numerous international conferences. His accolades include membership in the National Academy of Medicine, fellowships in AACR, ISCB, AAAS, and IEEE, and multiple awards for his contributions to cancer research. He also co-founded DarwinHealth Inc., where he serves as Chief Scientific Advisor.
The Causal Analysis of Biomedical Data Lecture Series is supported by the Luxembourg National Research Fund (FNR) RESCOM Program.
