# Role of necrosis in the evolution of highly metastatic and chemo-resistant breast cancers

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $678,482

## Abstract

High-grade, fast-growing breast cancers often display necrosis, usually within the tumor interior, 
where perfusion, nutrients, and oxygen are limited. Recent studies indicate that necrosis is not 
just an indicator of aggressive disease, but also a regulator of the aggressive phenotype, by 
impairing cancer drug delivery, promoting genomic evolution, and instigating metastasis to distant 
organs. However, we currently lack an understanding of the molecular mechanisms regulating necrosis 
development and consequently, there are no therapies to prevent the development of necrosis and its 
downstream effects on tumor aggression. For this application, we have developed animal models that 
enable the robust dissection of the tumor-host ecosystem in the necrotic interior. Our studies 
reveal that a secreted protein, angiopoietin-like 7 (Angptl7), is produced by tumor cells adjacent 
to the necrotic core and is a regulator of tumor core vasculature development. Importantly, when 
Angptl7 is suppressed genetically, tumor necrosis, tumor growth, and metastatic dissemination are 
each drastically reduced. Thus, necrosis development is not inevitable but rather is preventable by 
Angptl7 suppression. In the proposed work, we will combine studies using innovative animal models 
and breast cancer patient blood and tissue samples to test the hypothesis that the development of 
necrosis is a driving force for the evolution of highly metastatic and drug-resistant breast tumor 
cells. In Aim 1, we will use mouse models to test the hypothesis that Angptl7-induced necrosis 
limits delivery of chemotherapeutics to the tumor core, and that Angptl7 suppression synergizes 
with neoadjuvant chemotherapeutics to improve drug delivery and improve tumor killing. In Aim 2, we 
will use tissue from a large population-based cohort of early-stage breast cancer patients to 
determine how dilated blood vessels, an indicator of Angptl7-induced necrosis, influences risk of 
local and distant metastatic dissemination to predict benefit from adjuvant therapy. In Aim 3, we 
will apply genomic sequencing and circulating tumor DNA analysis in an innovative rat model for 
liquid biopsy studies to define the genomic signatures associated with Angptl7-induced necrosis.  
We will then determine the prognostic impact of a circulating tumor DNA signature of necrosis in 
human clinical samples. This work will define necrosis development as an engine for tumor 
diversification and aggression, and the clinical contexts both in early stage and metastatic 
settings where necrosis prevention could benetits patients with breast cancer and tumor types.

## Key facts

- **NIH application ID:** 10912796
- **Project number:** 5R01CA277045-02
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Kevin Jon Cheung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $678,482
- **Award type:** 5
- **Project period:** 2023-08-23 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912796

## Citation

> US National Institutes of Health, RePORTER application 10912796, Role of necrosis in the evolution of highly metastatic and chemo-resistant breast cancers (5R01CA277045-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10912796. Licensed CC0.

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