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PET Imaging of CCND1 mRNA in Human MCF7 Estrogen Receptor–Positive Breast Cancer Xenografts with Oncogene-Specific [⁶⁴Cu]Chelator-Peptide Nucleic Acid-IGF1 Analog Radiohybridization Probes

¹ Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; ² Department of Medicine (Hematology/Oncology), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ³ Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania; and ⁴ Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania

Correspondence: For correspondence or reprints contact: Eric Wickstrom, PhD, Biochemistry and Molecular Biology, Thomas Jefferson University, 219 Bluemle Life Science Building, 233 South 10th St., Philadelphia, PA 19107-5541. E-mail: eric{at}tesla.jci.tju.edu

Treatment of breast cancer is hampered by a large unmet need for rapid, sensitive, specific staging and stratification of palpable and nonpalpable abnormalities. Mammography and physical examination miss many early breast cancers, yet detect many benign lesions. Cyclin D1, encoded by CCND1 messenger RNA (mRNA), and insulin-like growth factor 1 receptor (IGF1R) are key regulators of cell proliferation that are overexpressed in most breast cancers. Therefore, we hypothesized that malignant breast masses could be imaged and quantitated externally by PET with a dual-specificity probe that targets both CCND1 mRNA and IGF1R. Methods: We designed a CCND1-specific peptide nucleic acid (PNA) hybridization sequence (CTGGTGTTCCAT), separated by a C-terminal spacer to a cyclized IGF1 peptide analog (D-Cys-Ser-Lys-Cys), for IGF1R-mediated endocytosis. On the N-terminus we attached a chelator (1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl [DO3A]) for the positron-emitting nuclide ⁶⁴Cu. We administered the [⁶⁴Cu]CCND1-IGF1 analog radiohybridization probes, as well as sequence controls, by tail vein to immunocompromised female NCr mice bearing human MCF7 estrogen-dependent, receptor-positive xenografts. We imaged the mice by PET and CT 4 and 24 h later, and measured tissue distribution of the radiohybridization probes. Results: We observed 8 ± 2-fold higher PET intensity in the center of the breast cancer xenografts than in the contralateral tissues at 24 h after injection of the [⁶⁴Cu]CCND1-IGF1 analog radiohybridization probe. IGF1 blocking yielded significantly weaker images (P < 0.05) relative to the tumor-free side at 24 h after injection, as did a PNA mismatch probe, a peptide mismatch probe, and free ⁶⁴CuCl₂. Conclusion: These results are consistent with our hypothesis for radiohybridization PET of overexpressed CCND1 mRNA, dependent on IGF1R-mediated endocytosis, in suspect masses. Early noninvasive detection of initial cancerous transformation, as well as invasive or recurrent breast cancer, with dual-specificity radiohybridization probes, might enable molecularly targeted staging, stratification, and choice of therapy.

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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