The long-range goal of this research is the development of radiolabeled somatostatin-receptor ligands for positron emission tomography (PET) imaging and targeted radiotherapy of cancer. Our studies have yielded significant discoveries that have contributed to the development of PET and therapeutic radiopharmaceuticals, principally, the labeling of somatostatin analogs with 64Cu (T1/2 = 12.7 h;+ (17.8%);- (38.4%)). One key finding has been that 64Cu from 64Cu-TETA-octreotide was delivered to tumor cell nuclei, whereas 111In from 111In-DTPA-octreotide was found primarily in lysosomes and cytoplasm. As our group and others have previously demonstrated enhanced therapeutic efficacy of 64Cu (and 67Cu) radiopharmaceuticals, these findings may be relevant to mechanisms of cell killing with copper radionuclides. We are currently addressing two hypotheses relevant to imaging and therapy with 64Cu. Our first hypothesis is that a 64Cu- labeled SSTr2 antagonist will display optimal receptor targeting properties and stable chelation of 64Cu, and therefore will be an improved radiopharmaceutical for PET imaging of SSTr2-positive tumors (aim 1). Recently, somatostatin antagonists have been reported to be superior to somatostatin agonists for in vivo targeting of SSTr2-expressing tumors. We propose to utilize the most promising somatostatin antagonist, sst2-ANT, conjugated to CB-TE2A, which complexes copper more stably in vivo than any other chelator investigated thus far. Our second hypothesis is that the tumor suppressor protein p53 is involved in the trafficking of 64Cu to tumor cell nuclei, and this may enhance tumor cell killing (Aims 2, 3 and 4). Using SSTr2-transfected HCT116 cells, we propose studies to evaluate cell killing with 64Cu-labeled internalizing somatostatin agonists compared to the weakly internalizing 64Cu-labeled antagonist in p53 WT (HCT116 +/+) and null cells (HCT116 -/-) grown in culture (aim 2), and as tumors in mice (aim 4). Preliminary data with 64Cu- CB-TE2A- sst2-ANT show low levels of internalization, although the number of cell surface receptors that the antagonist bound was >10-fold higher than for the agonist. Comparing the 64Cu-labeled agonist vs antagonist in SSTr2-transfected HCT116+/+ and -/- cell lines, both in vitro and in vivo (aim 2 and 4), will determine the importance of internalization with respect to cell killing. Experiments proposed for Aim 3 will elucidate the copper protein binding partner for p53. These studies will have implications for microdosimetry, as well as future studies to capitalize on treating tumors expressing WT p53. The proposed research has clinical relevance for the potentially enhanced therapeutic efficacy of 64Cu and 67Cu radiopharmaceuticals and development of future PET oncological imaging radiopharmaceuticals. In addition, this research will provide answers to basic questions regarding the effect of p53 status on cell killing by receptor-mediated targeted radiotherapy, as well as questions regarding basic biochemistry of p53-mediated copper trafficking to the cell nucleus.
ABSTRACT: Copper-64 (T1/2 = 12.7 h;+ (17.8%);- (38.4%)) radiopharmaceuticals have made an important impact in the area of positron emission tomography (PET) imaging of cancer. In addition to the PET imaging capabilities of 64Cu, this radionuclide also has been shown to be effective for targeted radiotherapy of cancer. This proposal describes research to further develop 64Cu radiopharmaceuticals for cancer imaging and therapy, as well as investigate mechanisms of copper radionuclide trafficking in cells and their impact on tumor cell killing.
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|Cai, Zhengxin; Ouyang, Qin; Zeng, Dexing et al. (2014) 64Cu-labeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging: in silico through in vivo studies. J Med Chem 57:6019-29|
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|Beaino, Wissam; Guo, Yunjun; Chang, Albert J et al. (2014) Roles of Atox1 and p53 in the trafficking of copper-64 to tumor cell nuclei: implications for cancer therapy. J Biol Inorg Chem 19:427-38|
|Zeng, Dexing; Guo, Yunjun; White, Alexander G et al. (2014) Comparison of conjugation strategies of cross-bridged macrocyclic chelators with cetuximab for copper-64 radiolabeling and PET imaging of EGFR in colorectal tumor-bearing mice. Mol Pharm 11:3980-7|
|Guo, Yunjun; Parry, Jesse J; Laforest, Richard et al. (2013) The role of p53 in combination radioimmunotherapy with 64Cu-DOTA-cetuximab and cisplatin in a mouse model of colorectal cancer. J Nucl Med 54:1621-9|
|Nguyen, Kim; Parry, Jesse J; Rogers, Buck E et al. (2012) Evaluation of copper-64-labeled somatostatin agonists and antagonist in SSTr2-transfected cell lines that are positive and negative for p53: implications for cancer therapy. Nucl Med Biol 39:187-97|
|Wadas, Thaddeus J; Wong, Edward H; Weisman, Gary R et al. (2010) Coordinating radiometals of copper, gallium, indium, yttrium, and zirconium for PET and SPECT imaging of disease. Chem Rev 110:2858-902|
|Anderson, Carolyn J; Ferdani, Riccardo (2009) Copper-64 radiopharmaceuticals for PET imaging of cancer: advances in preclinical and clinical research. Cancer Biother Radiopharm 24:379-93|
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