Breast cancer is the most common type of cancer and the leading cause of cancer death among women. In the United States, around 300,000 women are diagnosed each year.
The main cause of death in breast cancer is distant metastases, where cancer cells are found in organs such as the brain, lungs and liver. These might be detected at diagnosis, but they can also arise following initially successful treatment of the primary tumor. Therefore, the early and accurate detection of metastases is important for optimizing treatment and monitoring for disease relapses.
However, there are currently limitations to the use of existing clinical imaging modalities when it comes to the diagnosis of small high-risk breast cancer and micrometastases – metastases smaller than 2 mm.
Magnetic resonance imaging (MRI) holds potential as a powerful tool for visualizing tumors but existing contrast agents have a number of drawbacks. Enhancement with Gd (III) chelates is non-specific and is unable to provide information on tumor aggressiveness. It also provides insufficient contrast to detect small tumors and micrometastases.
And, attempts to create alternative contrast agents using nanoparticles loaded with Gd (III) chelates resulted in slow and incomplete clearance from the body in animal studies, raising concerns about potential toxic side effects.
But researchers from the Case Western Reserve University in Cleveland, Ohio believe they may have found an alternative.
Zoning in on cancer
The team, led by Zhuxian Zhou, created a “tumor-homing” peptide that targets fibronectin, conjugated to a contrast agent containing Gd (III) chelates. In a study in mice, they showed that this agent binds to fibrin-fibronectin complexes in tumors, while binding very little in healthy tissue. And, the contrast agent was readily excreted from the body, with little long-term retention.
Increased production of fibronectin, which goes on to form fibrin-fibronectin complexes, in the tumor extracellular matrix is associated with a number of poor prognostic factors such as increased invasiveness, angiogenesis and metastatic potential. Therefore, fibronectin is potentially a very useful biomarker for identify high-risk breast cancer and micrometastases.
So in a recent paper (Zhou et al. 2015), the researchers turned their attention to the efficacy of the agent, known as CREKA-Tris(Gd-DOTA)3, in detecting micrometastases in breast cancer.
A model of efficacy
The team created a mouse model of metastatic breast cancer by inoculating mice via the heart with human breast cancer cells that were fluorescently labeled. They then administered CREKA-Tris(Gd-DOTA)3 before performing MRI and overlaid the two images – allowing them to see the overlap between the fluorescently labeled cells and those detected via MRI.
They showed that the CREKA-based MRI was able to detect metastatic tumors in multiple sites including the bone marrow, adrenal glands, lungs and lymph nodes. And CREKA-Tris(Gd-DOTA)3 resulted in robust contrast enhancement when compared with other contrast agents.
Furthermore, they showed that the method was able to detect micrometastases, down to a size of less than 0.5mm which is well below the resolution offered by current imaging methods.
The team, who reported their findings in Nature Communications, say that the results show the potential of the contrast-agent technique to address current limitations in cancer imaging.
The method could play a role in both accurately differentiating high-risk tumors as well as the detection of micrometastases during the clinical management of the disease, they say.
They add that CREKA-based MRI could be used for breast-cancer screening in high-risk populations and as a non-invasive way to monitor disease progression and treatment responses.
Furthermore, the technique could be modified to use for other cancers, such as prostate cancer, they suggest. The researchers say that they will be carrying out safety tests on the contrast agent over the coming years before hopefully progressing to trials in patients.
For their animal experiments, the researchers used a Bruker Biospec MRI scanner. The Bruker Biospec range uses an innovative modular design, making it adaptable to virtually any application in small-animal imaging.
The UltraShield Refrigerated magnet technology is available in field strengths from 4.7 to 21 Tesla, while bore sizes range from 11 to 40 cm, making it suited to investigations on all animals in preclinical imaging.
- Cardoso F, Harbeck N, Fallowfield L, et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012; 23 (suppl 7): vii11-vii19. doi: 10.1093/annonc/mds232.
- Breastcancer.org. U.S. Breast Cancer Statistics. Available at: http://www.breastcancer.org/symptoms/understand_bc/statistics. Accessed: June 2016.
- Zhou Z, Wu X, Kresak A, et al. Peptide targeted tripod macrocyclic Gd(III) chelates for cancer molecular MRI. Biomaterials 2013; 34 (31): 7683–7693.
- Zhou Z, Qutaish M, Han Z, et al. MRI detection of breast cancer micrometastases with a fibronectin-targeting contrast agent. Nature Communications 2015; 6: 7984. doi: 10.1038/ncomms8984.
- Bruker.com Biospec MRI https://www.bruker.com/products/mr/preclinical-mri/biospec/overview.html
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