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Elucidation and Pharmacological Targeting of Non-oncogene Dependencies at the Single-Cell Level

Wednesday, January 12, 2022 - 3:00pm to 4:00pm

Speaker

Andrea Califano, Ph.D.
Clyde and Helen Wu Professor of Chemical and Systems Biology
Chair, Department of Systems Biology
Director, JP Sulzberger Columbia Genome Center
Columbia University Medical Center

Andrea Califano, Dr., is a pioneer in the field of systems biology and founding chair of the Department of Systems Biology at Columbia University Irving Medical Center. A physicist by training, Dr. Califano has taken innovative, systematic approaches to identify the molecular factors that lead to cancer progression and to the emergence of drug resistance at the single-cell level. Directing the conversation about cancer research away from focusing solely on gene mutations, Dr. Califano examines the complex and tumor-specific molecular interaction networks that determine cancer cell behavior. Using information theoretic approaches, analysis of these networks can precisely pinpoint master regulator proteins that are mechanistically responsible for supporting tumorigenesis and for implementing tumor cell homeostasis. Dr. Califano and his lab have shown that master regulators represent critical drivers and tumor dependencies, despite the fact that they are rarely mutated or differentially expressed, thus establishing them as a bona fide new class of therapeutic targets.

Summary

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 34 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 drugs combinations targeting stem-like progenitor and differentiated cells in breast adenocarcinoma as well as Master Regulators of tumour-infiltrating T regulatory cells, thus potentiating the effect of immune checkpoint therapy.

Objectives

1. Illustrating the generation and interrogation of gene regulatory and signaling networks from both bulk tissue and single cell data

2. Introducing the concept of Master Regulator proteins are homeostatic regulators of cell state in both normal and transformed cells. 

3. Introducing methodologies for the pharmacological targeting of Master Regulators as a novel class of cell state dependencies

4. Extending these approaches to the single cell level, with specific examples related to the specific targeting of breast cancer stem-like progenitor cells and tumor infiltrating T regulatory cells.


The page was last updated on Wednesday, January 12, 2022 - 1:09pm