# Centers for Cancer Systems Therapeutics (CaST)

> **NIH NIH U54** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $2,041,589

## Abstract

PROJECT SUMMARY
The quantitative, model driven approaches that constitute the underpinning of systems biology are emerging
as an increasingly critical methodological repertoire for a truly “precise” implementation of precision cancer
medicine. This is especially relevant in view of the increasing limitations of current approaches based on the
oncogene addiction paradigm. Even though pharmacological inhibition of oncogenes harboring activating
alterations has emerged as a valuable rationale for targeted therapy, >75% of all adult malignancies lack any
actionable alteration or present with undruggable ones and inhibitors of canonical oncogenes have shown
lackluster response in the clinic. Most critically, following initial and at times remarkable response, targeted
therapy almost invariably leads to relapse to drug-resistant disease. Systematic treatment of hundreds of cell
lines with hundreds of compounds has shown that, with few notable exceptions, mutations are far from
representing optimal predictors of targeted agent sensitivity. This is not surprising, as drug sensitivity clearly
represents a complex polygenic phenotype, requiring equally complex and tumor-specific models. This center
proposal encompasses studies across multiple levels of granularity, representing the full complexity of the
tumor phenotype: from tumor/microenvironment interactions to single cell plasticity, supporting tumors
reprograming to distinct isogenic states associated with progression or drug resistance. Specifically, three
complementary directions will be pursued: First, elucidation of the regulatory module architecture (tumor
checkpoint) and specific proteins within these modules (master regulators) that comprise the dysregulated
mechanisms presiding over tumor homeostasis (I.e., a cell's ability to maintain its tumor state independent of
mutational landscape and endogenous/exogenous signal heterogeneity). This will be accomplished by
developing model-based approaches to analyze omics data representing distinct compartments of the tumor,
ranging from tumor bulk, to stroma/tumor compartments, to single cells, following physiologic, genetic, and
pharmacologic perturbations. Second, study the mechanisms by which tumor state can be altered to induce
progression or drug resistance by adopting and extending approaches for the study of physiologic
differentiation and reprograming. This analysis will integrate subclonal genomic characterization, using
innovative computational models, with single cell data from primary tumors and patient derived xenografts to
elucidate the mechanisms presiding over tumor plasticity. Finally, using the mechanistic regulatory frameworks
emerging from these studies to elucidate actionable tumor dependencies leading to irreversible collapse of
tumor homeostasis in vitro and in vivo. This will be accomplished by assembling and experimentally validating
both probabilistic and kinetic models of tumor checkpoint regulation, assembled from time-serie...

## Key facts

- **NIH application ID:** 9976471
- **Project number:** 5U54CA209997-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** ANDREA CALIFANO
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,041,589
- **Award type:** 5
- **Project period:** 2016-08-08 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976471

## Citation

> US National Institutes of Health, RePORTER application 9976471, Centers for Cancer Systems Therapeutics (CaST) (5U54CA209997-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9976471. Licensed CC0.

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