This year, breast cancer (BC) will attack approximately 210,000 and will take the lives of 40,000 women in the U.S. Standard screening with breast self-examination and mammography, recommended to minimize BC morbidity and mortality, miss 10-20% (up to 40% in young women) of breast cancers. Moreover, if an abnormality is found, an invasive diagnostic procedure is required to determine if the breast contains hyperplasia, atypia, or cancer. Approximately 80% of invasive procedures detect a benign process. BC cells express a gene product, cell surface receptor VPAC1, so named because the endogenous growth hormones Vasoctive Intestinal Peptide (VIP) and Pituitary Adenylate Cylcase Activating Peptide (PACAP) bind to VPAC1 receptors with affinity. We have labeled two VIP analogs with Tc-99m (Tc-99m- TP3654, EC50, 15 nM and Tc-99m-TP3652, EC50, 0.8 nM) and shown in a pilot clinical study that these agents correctly and unequivocally imaged all tumors which overexpress VPAC1 receptors, including precancerous lesions in the breast, supporting our hypothesis that potent analogs of VIP and PACAP candetect cancer at an early stage. We have prepared two additional analogs (Tc-99m-TP3871, EC50, 0.45 Nm and Tc-99m-TP3475, EC50, 1.5 nM) with improved receptor affinity and more favorable structural conformation for better in vivo stability. Furthermore, we have labeled VIP analog (TP3654) with p+ emitter Cu-64, which improved BC uptake by 85-fold. These results, compounded by the high resolution and sensitivity of PET, have prompted us to undertake a systematic investigation to develop a PET molecular imaging technique that will 1) target early BC, 2) distinguish between hyperplastic ductal epithelium (normal image) and atypical hyperplasia and invasive cancer (positive image), 3) minimize the number of unnecessary invasive procedures, and 4) permit clinicians to treat precancerous mastopathy (atypia and in situ cancer) or invasive cancer with preventive or therapeutic agents, respectively, to decrease morbidity and mortality associated with progressing disease. The study will 1) systematically evaluate four analogs for critical imaging parameters, 2) determine the specificity of a lead agent in differentiating pre- and invasive BC from normal breast tissue ex vivo by autoradiography and RT-PCR, 3) perform preclinical toxicity studies in animals, and 4) examine its ability to correctly identify tumors which over express VPAC1 receptors by PET imaging.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109231-04
Application #
7355546
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Farahani, Keyvan
Project Start
2005-04-01
Project End
2012-02-29
Budget Start
2008-03-01
Budget End
2012-02-29
Support Year
4
Fiscal Year
2008
Total Cost
$404,031
Indirect Cost
Name
Thomas Jefferson University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Thakur, Mathew L; Zhang, Kaijun; Berger, Adam et al. (2013) VPAC1 receptors for imaging breast cancer: a feasibility study. J Nucl Med 54:1019-25
Thakur, Mathew L; Devadhas, Devakumar; Zhang, Kaijun et al. (2010) Imaging spontaneous MMTVneu transgenic murine mammary tumors: targeting metabolic activity versus genetic products. J Nucl Med 51:106-11
Amirkhanov, Nariman V; Zhang, Kaijun; Aruva, Mohan R et al. (2010) Imaging human pancreatic cancer xenografts by targeting mutant KRAS2 mRNA with [(111)In]DOTA(n)-poly(diamidopropanoyl)(m)-KRAS2 PNA-D(Cys-Ser-Lys-Cys) nanoparticles. Bioconjug Chem 21:731-40
Petruzzi, Nicholas; Shanthly, Nylla; Thakur, Mathew (2009) Recent trends in soft-tissue infection imaging. Semin Nucl Med 39:115-23
Mukherjee, Archana; Wickstrom, Eric; Thakur, Mathew L (2009) Imaging oncogene expression. Eur J Radiol 70:265-73
Thakur, Mathew L (2009) Genomic biomarkers for molecular imaging: predicting the future. Semin Nucl Med 39:236-46
Amirkhanov, Nariman V; Dimitrov, Ivan; Opitz, Armin W et al. (2008) Design of (Gd-DO3A)n-polydiamidopropanoyl-peptide nucleic acid-D(Cys-Ser-Lys-Cys) magnetic resonance contrast agents. Biopolymers 89:1061-76
Zhang, Kaijun; Aruva, Mohan R; Shanthly, Nylla et al. (2008) PET imaging of VPAC1 expression in experimental and spontaneous prostate cancer. J Nucl Med 49:112-21
Zhang, Kaijun; Aruva, Mohan R; Shanthly, Nylla et al. (2007) Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP) receptor specific peptide analogues for PET imaging of breast cancer: In vitro/in vivo evaluation. Regul Pept 144:91-100
Tian, Xiaobing; Aruva, Mohan R; Zhang, Kaijun et al. (2007) 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. J Nucl Med 48:1699-707

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