Early detection of metastasis in patients with breast cancer, which is critical for designing effective targeted therapies, has unfortunate limitations with prevalent screening methods. A study published in Nature Communications has shown promise for extending the detection limit of the current clinical imaging technology
Zheng-Rong Lu, PhD
Zheng-Rong Lu, PhD
Early detection of metastasis in patients with breast cancer, which is critical for designing effective targeted therapies, has unfortunate limitations with prevalent screening methods.1A study2published inNature Communicationshas shown promise for extending the detection limit of the current clinical imaging technology.
Existing approaches like X-ray mammography, F-2-deoxy-D-glucose (FDG)-positron emission tomographycomputed tomography, ultrasound, and contrast-enhanced magnetic resonance imaging (MRI) are not cancer specific and fail to detect micrometastases. In the study, Zhou et al designed molecular imaging with high specificity and sensitivity, based on deregulated fibronectin expression in cancer cells.2
The researchers used the fibronectin content as a prognostic biomarker for molecular imaging and differential diagnosis of high-risk breast cancer and micrometastases, because increased fibronectin content in tumors has been associated with growth and angiogenesis.3,4They developed a peptide made up of 5 amino acids: CREKA-Tris(Gd-DOTA)3 (Gd-DOTA [4,7,10-tris(carboxymethyl]-1,4,7,10-tetraazacyclododecyl gadolinium), which binds specifically to fibrinfibronectin complexes in the tumor extra cellular matrix (ECM). No binding with ECM of normal tissue was observed.
The team further used this penta-peptide to develop a CREKA-targeted contrast agent that also binds to fibrinfibronectin complexes in the tumor ECM, producing robust and prolonged tumor contrast enhancement compared with a nontargeted control, in a primary mouse tumor model.5
“We showed that we can detect very tiny tumors of just a few hundred cells with this technique,” said primary investigator, Zheng-Rong Lu, PhD, M. Frank and Margaret Domiter Rudy Professor of biomedical engineering at Case Western Reserve University, Cleveland. Zheng-Rong feels that study pushed imaging boundaries, revealing smaller cancers than can be detected with current clinical imaging modalities.
“Our imaging technology has the potential to differentiate aggressive tumors from low-risk tumors. These are two things that potentially can make a big impact on clinical practice and also the management of cancer.”
Contrast-enhanced MRI with small molecular Gd(III) chelates normally has low sensitivity for molecular imaging due to low expression levels of biomarkers. Fibronectin and its complexes, however, have high levels of expression in high-risk breast cancers and distant metastases. This allows sufficient binding of the targeted contrast agent, CREKA-Tris(Gd-DOTA), to the tumor ECM. Robust enhancement for effective molecular MRI of micrometastasis is therefore possible. The authors further noted effective imaging of metastases and micrometastases in different distant organs such as the lung, liver, lymph node, adrenal gland, and bone, validating the effectiveness of molecular MRI with CREKA Tris(Gd-DOTA).
The team has previously demonstrated the safety profile of the CREKA-Tris(Gd-DOTA)3 contrast agent. They documented rapid clearance of the unbound Gd(III)-based contrast agent from the body via renal filtration, precluding potential unintended toxic side effects due to delayed excretion. The rapid clearance also minimizes background signal for tumor-specific contrast-enhanced MRI.6
“MRI has a wide array of diagnostic applications and shows promise in breast cancer detection and treatment monitoring,” said Richard Conroy, PhD, director of NIBIB Division of Applied Science and Technology. “The technique used by researchers in this study enables very early detection of metastatic spread, which would allow adaptation of treatment more quickly and hopefully lead to better outcomes in the future.”
The molecular MRI imaging with CREKA-Tris(Gd-DOTA)3 developed by Zhou et al has the potential to facilitate early detection of high-risk breast cancer and micrometastasis in the clinic, providing physicians a tool for differential diagnosis of high-risk tumors. In addition to monitoring tumor progression and disease response, the technique also has the potential to be used for breast cancer screening in high-risk patient populations.
1. Chaffer, CL and Weinberg, RA. A perspective on cancer cell metastasis.Science. 2011;331:1559-1564.
2. 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.
3. Van Obberghen-Schilling E, Tucker RP, Saupe F et al. Fibronectin and tenascin-C: accomplices in vascular morphogenesis during development and tumor growth.Int. J. Dev. Biol. 2011;55:511-525.
4. Von Au A, Vasel M, Kraft S et al. Circulating fibronectin controls tumor growth.Neoplasia. 2013;15;925-938.
5. Zhou Z., Wu X., Kresak A., et al. Peptide targeted tripod macrocyclic Gd(III) chelates for cancer molecular MRI.Biomaterials. 2013;34:7683-7693.
6. Thomsen, HS. Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide.Eur. Radiol. 2006;16:2619-2262.