# Proteolysis-targeting chimera against BCL-XL inhibits breast cancer metastasis

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $500,180

## Abstract

Project Summary-Abstract
Metastasis is the major cause of BrCa death. Most women with metastatic BrCa (stage IV) are treated mainly
with systemic therapy such as hormone therapy (for estrogen receptor-positive BrCa), chemotherapy, targeted
therapy, and some combinations. Current treatments are very unlikely to cure metastatic BrCa, with more than
70% death rate within 5 years of diagnosis. Therapeutic targeting BrCa metastasis is largely lacking. Here we
are aiming to develop a single agent with dual targeting capability: 1) to kill metastatic cancer cells directly; 2) to
kill cancer specific regulatory T cells (Tregs) hence inducing anti-cancer immunity. With an effort to search the
potential molecular target, we decided to inhibit BCL-XL using an emerging novel PROTAC technology. With two
lead PROTAC compounds (BCL-XL-Ps) we have recently developed, we found that both compounds can
efficiently lead to the degradation of BCL-XL in vitro and in vivo. Interestingly, it appears that the BCL-XL-Ps work
in all syngeneic cancer models we have tested with the strongest suppressive efficacy in breast cancer
metastasis. Using multidisciplinary techniques, we believe BCL-XL-Ps kill metastatic cancer cells and Tregs
simultaneously as we initially expected. The current project will define the lineage-specific role of BCL-XL in
cancer cells and in Tregs. Even though the direct cancer cell killing may not be sufficient to eradicate metastatic
tumor growth as shown in the preliminary data, a portion of dead cancer cells may provide sufficient auto- or
neo-antigens for T cell activation. In addition, BCL-XL depletion in cancer cells sensitizes them to CD8-T cell
mediated killing. The BCL-XL-Ps-mediated Treg depletion and direct activation of T cells elicits a strong anti-
cancer immunity that can be harvested for cancer therapy. Simultaneous depletion of BCL-XL by BCL-XL-Ps in
cancer cells further sensitize them to CD8-T cell mediated killing. Here we will study the lineage-specific roles of
BCL-XL in cancer. The translational research is also strongly supported by clinical observations that BCL-XL
protein expression predicts shorter patient survival in breast cancer patients. Our long-term goal is to develop
the lead compound into clinic for dual targeting of cancer cells and Tregs in treating metastatic breast cancers.

## Key facts

- **NIH application ID:** 10198532
- **Project number:** 1R01CA260239-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** DAOHONG ZHOU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $500,180
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198532

## Citation

> US National Institutes of Health, RePORTER application 10198532, Proteolysis-targeting chimera against BCL-XL inhibits breast cancer metastasis (1R01CA260239-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10198532. Licensed CC0.

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