The research project outlined in this proposal holds the potential for development of one or more radiolabeled Gastrin Releasing Peptide (GRP) receptor-avid radiopharmaceuticals. We propose that these radiopharmaceuticals will be effective site-directed agents, for the treatment and/or diagnosis of patients with localized, as well as metastasized breast cancer. GRP receptors are present on estrogen receptor positive (ER+) and negative (ER-) breast cancer cells found in primary and metastatic tissue. We have previously demonstrated that selected radiolabeled bombesin (BBN) analogs developed in our laboratory target the GRP receptor with high affinity and specificity. Our initial work has resulted in the development of 99mTc- and 111In-BBN analogs which demonstrate high GRP receptor specificity and prolonged retention in vivo in GRP receptor expressing tumors including the ER+, T47D human breast cancer xenograft model. Our research plan focuses on four primary areas: 1) evaluate the diagnostic capabilities of 111In-BBN analogs to target and stage ER+ and ER- human breast tumor xenografts. This will involve assessing the applicability of these diagnostic agents for use in monitoring the course of radiotherapy and chemotherapy treatment; 2) determine the internal radiation dosimetry of 111In, 90Y, 149Pm, and 177Lu-BBN analogs in xenograft models of human breast cancer; 3) evaluate the therapeutic efficacy of 90Y, 149Pm, and 177Lu-BBN analogs in xenograft models of breast cancer. This will involve the determination of a maximum tolerable dose estimate for each isotope-BBN analog evaluated with subsequent single dose and multi-dose radiotherapy trial evaluation; 4) evaluate the synergism of targeted radiotherapy and chemotherapy in the treatment of ER+ and ER-xenograft models of human breast cancer. The experimental approaches used in the proposed research will utilize scintigraphic evaluation of 111In-BBN analog pharmacokinetics and in vivo tumor targeting capabilities with correlative data obtained using a Micro-CT. In vivo breast cancer SCID mouse tumor models (T47D and MDA-MB-231 cell origin), will be the primary assessment tool for analysis of 111In, 90Y, 149Pm, and 177Lu-BBN analog efficacy in therapeutic and diagnostic applications. The approach taken in this proposal will continue our development of a unique class of highly selective diagnostic and therapeutic BBN radiopharmaceuticals that target primary and metastatic breast cancer. Utilizing this selective radiotherapeutic targeting approach, either alone or combined with other chemotherapeutics, may provide new opportunities to manage and treat breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA072942-06
Application #
6579206
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Stone, Helen B
Project Start
1997-09-03
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
6
Fiscal Year
2003
Total Cost
$215,250
Indirect Cost
Name
University of Missouri-Columbia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Winkelmann, Christopher T; Figueroa, Said Daibes; Sieckman, Gary L et al. (2012) Non-invasive microCT imaging characterization and in vivo targeting of BB2 receptor expression of a PC-3 bone metastasis model. Mol Imaging Biol 14:667-75
Figueroa, Said Daibes; Winkelmann, Christopher T; Miller, H William et al. (2008) TLD assessment of mouse dosimetry during microCT imaging. Med Phys 35:3866-74
Garrison, Jered C; Rold, Tammy L; Sieckman, Gary L et al. (2008) Evaluation of the pharmacokinetic effects of various linking group using the 111In-DOTA-X-BBN(7-14)NH2 structural paradigm in a prostate cancer model. Bioconjug Chem 19:1803-12
Prasanphanich, Adam F; Nanda, Prasant K; Rold, Tammy L et al. (2007) [64Cu-NOTA-8-Aoc-BBN(7-14)NH2] targeting vector for positron-emission tomography imaging of gastrin-releasing peptide receptor-expressing tissues. Proc Natl Acad Sci U S A 104:12462-7
Garrison, Jered C; Rold, Tammy L; Sieckman, Gary L et al. (2007) In vivo evaluation and small-animal PET/CT of a prostate cancer mouse model using 64Cu bombesin analogs: side-by-side comparison of the CB-TE2A and DOTA chelation systems. J Nucl Med 48:1327-37
Winkelmann, Christopher T; Figueroa, Said Daibes; Rold, Tammy L et al. (2006) Microimaging characterization of a B16-F10 melanoma metastasis mouse model. Mol Imaging 5:105-14
Johnson, Christopher V; Shelton, Tiffani; Smith, Charles J et al. (2006) Evaluation of combined (177)Lu-DOTA-8-AOC-BBN (7-14)NH(2) GRP receptor-targeted radiotherapy and chemotherapy in PC-3 human prostate tumor cell xenografted SCID mice. Cancer Biother Radiopharm 21:155-66
Smith, C Jeffrey; Sieckman, Gary L; Owen, Nellie K et al. (2003) Radiochemical investigations of gastrin-releasing peptide receptor-specific [(99m)Tc(X)(CO)3-Dpr-Ser-Ser-Ser-Gln-Trp-Ala-Val-Gly-His-Leu-Met-(NH2)] in PC-3, tumor-bearing, rodent models: syntheses, radiolabeling, and in vitro/in vivo studies where Dpr = 2 Cancer Res 63:4082-8
Smith, C Jeffrey; Gali, Hariprasad; Sieckman, Gary L et al. (2003) Radiochemical investigations of 177Lu-DOTA-8-Aoc-BBN[7-14]NH2: an in vitro/in vivo assessment of the targeting ability of this new radiopharmaceutical for PC-3 human prostate cancer cells. Nucl Med Biol 30:101-9
Hoffman, Timothy J; Gali, Hariprasad; Smith, C Jeffrey et al. (2003) Novel series of 111In-labeled bombesin analogs as potential radiopharmaceuticals for specific targeting of gastrin-releasing peptide receptors expressed on human prostate cancer cells. J Nucl Med 44:823-31

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