# Investigating the HSF1 Cancer Network

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $406,031

## Abstract

PROJECT SUMMARY/ABSTRACT
Background:
 Cancer cells contend with many obstacles such as metabolic derangements and proteotoxic stress that
would normally hamper cell survival and proliferation. Medical interventions impose additional impediments for
tumor cell survival. Adaptation to these pressures is essential for cancer survival and proliferation. This
proposal is on heat shock factor 1 (HSF1) and understanding how HSF1 is recruited in cancer to support
tumorigenesis. HSF1 is the master transcriptional regulator of the heat shock response, a powerful
cytoprotective response that drives expression of chaperone proteins. We have recently shown that cancers
co-opt HSF1 for efficient growth and that activation of HSF1 is strongly associated with poor clinical outcome.
In addition, we have shown that the HSF1 transcriptional network in cancer is distinct from the HSF1 program
in heat shock and involves many non-heat shock genes, supporting a rich biological role for HSF1 outside heat
shock. A more complete view of the regulation of the HSF1 cancer network and its role in cancer biology is
needed.
Objective/Hypothesis:
 There appear to be two distinct but related states of HSF1 activation: one driven by thermal stress (heat
shock) but also one driven by the pressure of high rates of cellular proliferation (cancer). The regulation of
HSF1 in the two distinct states must therefore be different – via distinct signaling pathways and distinct protein
regulators. In addition, the HSF1 cancer network governs such a potent adaptive response that it may play an
important role in helping tumor cells adapt to targeted therapeutics and in developing resistance.
Specific Aims:
 Aim 1: To test the prediction that the HSF1 interactome is different in heat shock and in cancer and to
characterize the effects of these HSF1 partner proteins on the activity of HSF1 in cancer. Aim 2: To test the
prediction that HSF1 and HSP90 (one of the principal chaperones HSF1 regulates) are important for the ability
of cancer cells to develop resistance to targeted therapeutics.
Study design:
 I will use a genetically defined panel of cancer lines and affinity purification based approaches to
identify the HSF1 interactome in cancer and heat shock and will rigorously validate identified candidate
regulators for each state. I will explore if HSF1 and a principal chaperone that it regulates, HSP90, can modify
the emergence of resistance to targeted therapeutics for BRAF V600E using melanoma cell lines systems,
engineered resistant lines and high complexity DNA bar code libraries that allow us to assess changes in
clonal dynamics.
Cancer relevance:
 Identifying the cellular systems that allow cells to withstand and adapt to the challenges of the
malignant state is of critical importance for understanding the development and evolution of cancer. Interfering
with the mechanisms that support these adaptations may provide a broadly applicable anti-cancer strategy.

## Key facts

- **NIH application ID:** 9984309
- **Project number:** 5R01CA194005-05
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Sandro Santagata
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $406,031
- **Award type:** 5
- **Project period:** 2016-08-11 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984309

## Citation

> US National Institutes of Health, RePORTER application 9984309, Investigating the HSF1 Cancer Network (5R01CA194005-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9984309. Licensed CC0.

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