Nuclear hormone receptors (NHRs) are major regulators of hormone-responsive breast and prostate cancers, and they function as targets for endocrine therapies and as biomarkers having very significant prognostic and predictive values. The overall goal of this project is to advance positron emission tomographic (PET) imaging of specific nuclear hormone receptors and receptor function to improve the management and treatment of breast and prostate cancer patients. While some PET imaging agents have been developed by us for the estrogen receptor (ER) and the androgen receptor (AR), the current status of PET imaging of NHR levels and function in breast and prostate cancer is rather underdeveloped, and many opportunities lie ahead. Our current aims are to: (1) Develop a Progesterone Receptor (PR) PET imaging hormone-challenge test to improve prediction of success of endocrine therapy in breast Cancer. Two PR PET imaging agents, the [18F]FFNP and [18F]FPTP will be studied in xenografts and murine mammary tumor models of ER-positive endocrine-sensitive and endocrine-resistant breast cancer. Hormone treatment protocols will be developed to optimize a 1-day estradiol challenge test for ER function, based on an acute change in PR-PET, to obtain a rapid, accurate and robust prediction of breast cancer hormone responsiveness. (2) Evaluate Fluorine-18 labeled ligands for the Peroxisome Proliferator-Activated Receptor gamma (PPAR?) as PET imaging agents of predictive value for prostate cancer recurrence. PPAR? levels measured by IHC in a nested case-control human prostate cancer tissue array resource will be examined for their predictive power for risk of recurrence. The uptake efficiency and selectivity of two F-18 labeled PPAR? ligands will be studied in preclinical models of prostate cancer to develop PPAR? PET imaging protocols for suspected primary prostate cancer that can distinguish aggressive from indolent disease and improve prediction of the risk of disease recurrence. (3) Design PET imaging agents for the Estrogen Related Receptor alpha (ERR?) to develop a novel ERR? PET-Imaging test of prognostic and predictive value in hormone-responsive and unresponsive breast cancer. Fluorine-substituted analogs of high affinity ERR? ligands will be prepared and labeled with fluorine-18 rapidly, at high specific activity. Their biodistribution will then be evaluated in preclinical models of ERR?-positive breast cancers to develop ERR? as a predictive marker for novel therapies for both ER-positive and negative breast cancers.

Public Health Relevance

The choice of appropriate endocrine therapies for breast and prostate cancer can be difficult;significant time can be lost when ineffective therapies are used and major morbidity can result from excessive treatments. PET imaging agents will be developed to measure important biomarkers in these two cancers by non-invasive imaging. The successful development, evaluation, and translation of these PET biomarker imaging agents to the clinic should significantly improve the management and care of breast and prostate cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA025836-34
Application #
8685131
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Menkens, Anne E
Project Start
1984-01-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
34
Fiscal Year
2014
Total Cost
$349,318
Indirect Cost
$96,401
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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
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
Cheong, Su-Jin; Jang, DooRye; Jeong, Hwan-Jeong et al. (2011) Reduction of stimulated sodium iodide symporter expression by estrogen receptor ligands in breast cancer cells. Nucl Med Biol 38:287-94
Ackroyd, Nathan C; Katzenellenbogen, John A (2010) Pyridyl-Cyclopentadiene Re(CO)(2) Complexes as a Compact Core Systems for SPECT Ligand Development. Organometallics 29:3669-3671
Lee, Jae Hak; Zhou, Hai-bing; Dence, Carmen S et al. (2010) Development of [F-18]fluorine-substituted Tanaproget as a progesterone receptor imaging agent for positron emission tomography. Bioconjug Chem 21:1096-104
Moon, Byung Seok; Carlson, Kathryn E; Katzenellenbogen, John A et al. (2009) Synthesis and evaluation of aryl-substituted diarylpropionitriles, selective ligands for estrogen receptor beta, as positron-emission tomographic imaging agents. Bioorg Med Chem 17:3479-88
Zhou, Dong; Zhou, Haibing; Jenks, Carl C et al. (2009) Bromination from the macroscopic level to the tracer radiochemical level: (76)Br radiolabeling of aromatic compounds via electrophilic substitution. Bioconjug Chem 20:808-16
Dehdashti, Farrokh; Mortimer, Joanne E; Trinkaus, Kathryn et al. (2009) PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer. Breast Cancer Res Treat 113:509-17
Zhou, Dong; Sharp, Terry L; Fettig, Nicole M et al. (2008) Evaluation of a bromine-76-labeled progestin 16alpha,17alpha-dioxolane for breast tumor imaging and radiotherapy: in vivo biodistribution and metabolic stability studies. Nucl Med Biol 35:655-63
Kim, Dong Wook; Jeong, Hwan-Jeong; Lim, Seok Tae et al. (2008) Facile nucleophilic fluorination reactions using tert-alcohols as a reaction medium: significantly enhanced reactivity of alkali metal fluorides and improved selectivity. J Org Chem 73:957-62

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