# Elucidating the mechanisms that are responsible for the stability of cancer cell state

> **NIH NIH U54** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $500,484

## Abstract

PROJECT SUMMARY
Precision cancer medicine is predicated on the identification of pharmacologically actionable tumor
dependencies. Mutated oncogenes represent one such class of dependencies and are a hallmark of targeted
therapy. However, most tumor patients (~75%) do not present with actionable alterations. CaST, thus,
proposes to investigate a new class of tumor dependencies that is comprised of master regulator proteins
(MRs) that control the regulatory logic of tumor cells. These regulatory modules are referred to as tumor
checkpoints, and the aberrant activity of tumor checkpoints is both necessary and sufficient to govern the
pathophysiological state of tumor cells, i.e. they maintain tumor homeostasis and effect tumor plasticity. MRs
are much more conserved across patients than the individual genetic alterations contributing to tumor etiology.
Tumor checkpoints, thus, represent the Achilles' heel of cancer.
A key goal of this project is to systematically dissect tumor checkpoints across tumor samples from publicly
available repositories and generate a comprehensive, functionally annotated inventory of ~400 tumor
checkpoint MRs. This Cancer Homeostasis Protein Database (CHoPD) is the focus of a novel reductionist
approach to elucidating tumor homeostasis and plasticity as described in three aims (1) Elucidating key tumor
checkpoints and associated MRs across all individual tumor samples in TCGA and related resources to
develop CHoPD. Annotation of these proteins will include the upstream genetic alterations and signals
responsible for their aberrant activity and their downstream genetic programs. Specific tumor signatures will be
used to interrogate tumor-specific regulatory models with an integrated collection of analytical, network-based
tools. These analyses will avoid the current lineage-based subtype classification in favor of one based on
tumor homeostasis. (2) Elucidating the logic and regulatory architecture of tumor checkpoints responsible for
tumor homeostasis and plasticity by decoding their autoregulatory activity, modeling their modular structure
(i.e. protein-protein and protein-DNA complexes), and establishing the existence of critical control entry points,
whose genetic or drug induced modulation may lead to checkpoint collapse. This will be accomplished by
combining protein structure data, genetic and epigenetic data, as well as high-resolution time-series generated
with perturbational assays, using small molecules and genetic perturbations. (3) Elucidating the interaction of
tumor checkpoints in different tumor compartments, such as tumor cell niches, which represent alternative
homeostatic states, and the interactions between tumors and their stromal and immune microenvironments.
This will be accomplished by isolating individual cells representing individual tumor and microenvironment
niches and studying the interactions between their coupled checkpoints using the tools and methodologies
developed in Aims 1 and 2.

## Key facts

- **NIH application ID:** 9976484
- **Project number:** 5U54CA209997-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** BARRY H HONIG
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $500,484
- **Award type:** 5
- **Project period:** — → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976484

## Citation

> US National Institutes of Health, RePORTER application 9976484, Elucidating the mechanisms that are responsible for the stability of cancer cell state (5U54CA209997-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976484. Licensed CC0.

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