Fibulin-4 expressed in metastatic breast cancer is a target of peptide-based imaging probes and experimental therapeutics
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Updated: May 14, 2026
![Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F68356.jpg&w=3840&q=50)
Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment
Published on: April 25, 2025
Alexes C Daquinag1, Sukhen C Ghosh2, Solmaz AghaAmiri2
1Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, Houston, TX, USA.
Abstract:
There is a lack of approaches to detect and kill metastatic cells. As an agent for metastasis targeting, a cyclic peptide BLMP6 has been previously characterized. As a step toward translation, we designed AZDye555-labeled BLMP6 and demonstrated its homing to metastases of human MDA-MB-231 cells in mice. We show that 68Ga-radiolabeled BLMP6 can be used for the detection of MDA-MB-231 metastases. We designed a peptide-drug conjugate consisting of monomethyl auristatin E (MMAE) and BLMP6. We show that MMAE-BLMP6 kills MDA-MB-231 cells in cell culture and in vivo. In mouse models of lung metastases, treatment with MMAE-BLMP6 suppressed metastasis growth and improved survival. Based on BLMP6 similarity to latent transforming growth factor β binding protein 4 (LTBP4), we identified fibulin-4 as a BLMP6 target. We show that BLMP6 mimics the LTBP4 domain binding to fibulin-4 and selectively binds to fibulin-4 in vitro. Fibulin-4 knockout in cancer cells abrogated BLMP6 homing to lung metastases in mice. Fibulin-4 expression was found to be increased in invasive and metastatic human breast cancer and correlated with the binding of AZDye555-BLMP6 in human tissue sections. Our results suggest that fibulin-4 and BLMP6 may be further developed for the detection and targeting of metastatic human cancers.
Insights
A novel peptide, BLMP6, effectively targets and eliminates metastatic cancer cells by binding to fibulin-4. This peptide shows promise for detecting and treating metastatic breast cancer, improving survival rates in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Metastatic cancer cells lack effective detection and elimination strategies.
- BLMP6 is a cyclic peptide previously identified as a potential metastasis-targeting agent.
Purpose of the Study:
- To develop and evaluate BLMP6-based agents for detecting and killing metastatic cancer cells.
- To investigate the mechanism of BLMP6 targeting and its therapeutic potential.
Main Methods:
- AZDye555 and 68Ga labeling of BLMP6 for imaging metastasis.
- Development of a peptide-drug conjugate (MMAE-BLMP6) for therapeutic intervention.
- In vitro and in vivo studies using MDA-MB-231 cell lines and mouse models.
- Identification of fibulin-4 as the BLMP6 target through sequence homology and binding assays.
- Fibulin-4 knockout experiments and analysis of fibulin-4 expression in human breast cancer tissues.
Main Results:
- AZDye555-BLMP6 successfully homed to MDA-MB-231 cell metastases in mice.
- 68Ga-BLMP6 enabled detection of MDA-MB-231 metastases.
- MMAE-BLMP6 demonstrated potent killing of cancer cells in vitro and suppressed metastasis growth in vivo, improving survival.
- BLMP6 was found to mimic LTBP4 binding to fibulin-4, with selective binding observed in vitro.
- Fibulin-4 knockout abolished BLMP6 homing, confirming fibulin-4 as the target.
- Increased fibulin-4 expression in invasive/metastatic human breast cancer correlated with BLMP6 binding.
Conclusions:
- BLMP6 is a promising agent for detecting and targeting metastatic cancer.
- Fibulin-4 is a key target for BLMP6-mediated metastasis control.
- BLMP6-based strategies hold potential for future clinical development in metastatic breast cancer treatment.
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