Effective management of breast cancer requires early diagnosis, accurate staging, prediction of the responsiveness to endocrine therapy, and early determination of therapeutic response. The role of the estrogen receptor (ER) as a predictive marker in breast cancer is well recognized, as is the effectiveness of hormonal agents such as the antiestrogen tamoxifen or aromatase inhibitors such as letrozole for treating certain cancers. The overall goal of this project-to improve the diagnosis and treatment of hormone- responsive breast cancer-is organized around three specific aims: (1) Develop Imaging Agents Specific for ERa and ERft: The ERa subtype in breast tumors is generally found together with the more recently discovered ERp subtype, which is thought to have a restraining effect on the proliferative drive of ERa. Thus, it is important to determine both ERa and ERp levels in breast tumors by imaging. We have selected two clinically promising ERp-selective ligands for labeling with F-18 or Br-76 for PET imaging of ERp in breast tumors. We will also prepare an ERa ligand with enhanced characteristics for imaging, using a diaryliodonium salt approach for introducing F-18 into phenols. (2) Develop Tc-99m Labeled Breast Tumor Imaging Agents: To make imaging of ER in breast tumors more readily accessible and less expensive, we will prepare ER ligands labeled with Tc-99m. The large radiometal will be accommodated in a manner that does not interfere with receptor binding by using recently developed methods to place a tricarbonyltechnetium organometallic unit into the interior of a non-steroidal ligand, producing compact metal- integrated ligands that have high affinity for the ER. This approach for integrated ligand design could be of general utility for nuclear receptor radiopharmaceutical development. (3) Develop ER-Guided Radiotherapeutic Agents: Estrogens labeled with Auger-emitting radionuclides have promise as ER-guided radiotherapy agents, because ER binds to gene regulatory sites in chromatin. To develop such an agent, we have selected for labeling with bromine radioisotopes an ER ligand that has both very high affinity and very low non-specific binding ER ligands, giving it the long target tissue retention needed for radiotherapy. The work we propose on the three components of this project should lead to improved methods for breast cancer diagnosis and therapy. Relevance: The estrogen receptor is a well recognized prognostic factor and therapeutic target for breast cancer.
The aim of this project is to develop specialized radioactive agents (radiopharmaceuticals) to image this receptor non-invasively and to direct radiotoxic isotopes specifically to receptor-containing cancers. These agents could improve the selection of patients for individualized and optimized hormone therapy, sparing them the morbidity associated with standard radiation and chemotherapy which would provide them with no further benefit.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Menkens, Anne E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois Urbana-Champaign
Schools of Arts and Sciences
United States
Zip Code
Zhou, Dong; Kim, Sung Hoon; Chu, Wenhua et al. (2017) Evaluation of aromatic radiobromination by nucleophilic substitution using diaryliodonium salt precursors. J Labelled Comp Radiopharm 60:450-456
Fowler, Amy M; Clark, Amy S; Katzenellenbogen, John A et al. (2016) Imaging Diagnostic and Therapeutic Targets: Steroid Receptors in Breast Cancer. J Nucl Med 57 Suppl 1:75S-80S
Bosch, Ana; Li, Zhiqiang; Bergamaschi, Anna et al. (2015) PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci Transl Med 7:283ra51
Yasui, Norio; Mayne, Christopher G; Katzenellenbogen, John A (2015) Preparation of o-Fluorophenols from Nonaromatic Precursors: Mechanistic Considerations for Adaptation to Fluorine-18 Radiolabeling. Org Lett 17:5540-3
Paterni, Ilaria; Bertini, Simone; Granchi, Carlotta et al. (2015) Highly selective salicylketoxime-based estrogen receptor ? agonists display antiproliferative activities in a glioma model. J Med Chem 58:1184-94
Chan, Szeman Ruby; Fowler, Amy M; Allen, Julie A et al. (2015) Longitudinal noninvasive imaging of progesterone receptor as a predictive biomarker of tumor responsiveness to estrogen deprivation therapy. Clin Cancer Res 21:1063-70
Zhou, Dong; Chu, Wenhua; Peng, Xin et al. (2015) Facile purification and click labeling with 2-[(18)F]fluoroethyl azide using solid phase extraction cartridges. Tetrahedron Lett 56:952-954
Paterni, Ilaria; Granchi, Carlotta; Katzenellenbogen, John A et al. (2014) Estrogen receptors alpha (ER?) and beta (ER?): subtype-selective ligands and clinical potential. Steroids 90:13-29
Zhou, Dong; Lin, Mai; Yasui, Norio et al. (2014) Optimization of the preparation of fluorine-18-labeled steroid receptor ligands 16alpha-[18F]fluoroestradiol (FES), [18F]fluoro furanyl norprogesterone (FFNP), and 16beta-[18F]fluoro-5alpha-dihydrotestosterone (FDHT) as radiopharmaceuticals. J Labelled Comp Radiopharm 57:371-7
Lee, Jae Hak; Peters, Olaf; Lehmann, Lutz et al. (2012) Synthesis and biological evaluation of two agents for imaging estrogen receptor ýý by positron emission tomography: challenges in PET imaging of a low abundance target. Nucl Med Biol 39:1105-16

Showing the most recent 10 out of 63 publications