Radiopharmaceuticals for Imaging Nuclear Receptors in Breast and Prostate Cancers

Summary

Principal Investigator: John A Katzenellenbogen
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 1984-01-01 - 2018-05-31
more information: NIH RePORT

Top Publications

  1. pmc Linkage effects on binding affinity and activation of GPR30 and estrogen receptors ERalpha/beta with tridentate pyridin-2-yl hydrazine tricarbonyl-Re/(99m)Tc(I) chelates
    Chinnasamy Ramesh
    Department of Chemistry and Biochemistry MSC 3C, New Mexico State University, P O Box 30001, Las Cruces, New Mexico 88003, USA
    J Am Chem Soc 128:14476-7. 2006
  2. pmc Small-animal PET of steroid hormone receptors predicts tumor response to endocrine therapy using a preclinical model of breast cancer
    Amy M Fowler
    Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology, St Louis, MO, USA
    J Nucl Med 53:1119-26. 2012
  3. ncbi Reduction of stimulated sodium iodide symporter expression by estrogen receptor ligands in breast cancer cells
    Su Jin Cheong
    Department of Nuclear Medicine, Cyclotron Research Center, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk 561 756, South Korea
    Nucl Med Biol 38:287-94. 2011
  4. ncbi Development of [F-18]fluorine-substituted Tanaproget as a progesterone receptor imaging agent for positron emission tomography
    Jae Hak Lee
    Department of Chemistry, University of Illinois at Urbana Champaign, 61801, USA
    Bioconjug Chem 21:1096-104. 2010
  5. ncbi Synthesis and evaluation of aryl-substituted diarylpropionitriles, selective ligands for estrogen receptor beta, as positron-emission tomographic imaging agents
    Byung Seok Moon
    Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
    Bioorg Med Chem 17:3479-88. 2009
  6. pmc Bromination from the macroscopic level to the tracer radiochemical level: (76)Br radiolabeling of aromatic compounds via electrophilic substitution
    Dong Zhou
    Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    Bioconjug Chem 20:808-16. 2009
  7. pmc Evaluation of a bromine-76-labeled progestin 16alpha,17alpha-dioxolane for breast tumor imaging and radiotherapy: in vivo biodistribution and metabolic stability studies
    Dong Zhou
    Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA
    Nucl Med Biol 35:655-63. 2008
  8. pmc PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer
    Farrokh Dehdashti
    Division of Nuclear Medicine, Edward Mallinckrodt Institute of Radiology, St Louis, MO 63110, USA
    Breast Cancer Res Treat 113:509-17. 2009
  9. ncbi Facile nucleophilic fluorination reactions using tert-alcohols as a reaction medium: significantly enhanced reactivity of alkali metal fluorides and improved selectivity
    Dong Wook Kim
    Department of Nuclear Medicine, Research Institute of Clinical Medicine, Chonbuk National University School of Medicine, Jeonju, Jeonbuk 561 712, Korea
    J Org Chem 73:957-62. 2008
  10. pmc Synthesis and biological evaluation of two agents for imaging estrogen receptor β by positron emission tomography: challenges in PET imaging of a low abundance target
    Jae Hak Lee
    Department of Chemistry, University of Illinois at Urbana Champaign, 600 South Mathews Avenue, Urbana, IL, 61801, USA
    Nucl Med Biol 39:1105-16. 2012

Detail Information

Publications11

  1. pmc Linkage effects on binding affinity and activation of GPR30 and estrogen receptors ERalpha/beta with tridentate pyridin-2-yl hydrazine tricarbonyl-Re/(99m)Tc(I) chelates
    Chinnasamy Ramesh
    Department of Chemistry and Biochemistry MSC 3C, New Mexico State University, P O Box 30001, Las Cruces, New Mexico 88003, USA
    J Am Chem Soc 128:14476-7. 2006
    ..These results suggest that in vitro assays will facilitate the development of targeted imaging agents for intracellular receptors and the feasibility of targeting GPR30 and ERalpha/beta for diagnostic tumor imaging...
  2. pmc Small-animal PET of steroid hormone receptors predicts tumor response to endocrine therapy using a preclinical model of breast cancer
    Amy M Fowler
    Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology, St Louis, MO, USA
    J Nucl Med 53:1119-26. 2012
    ....
  3. ncbi Reduction of stimulated sodium iodide symporter expression by estrogen receptor ligands in breast cancer cells
    Su Jin Cheong
    Department of Nuclear Medicine, Cyclotron Research Center, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk 561 756, South Korea
    Nucl Med Biol 38:287-94. 2011
    ....
  4. ncbi Development of [F-18]fluorine-substituted Tanaproget as a progesterone receptor imaging agent for positron emission tomography
    Jae Hak Lee
    Department of Chemistry, University of Illinois at Urbana Champaign, 61801, USA
    Bioconjug Chem 21:1096-104. 2010
    ..Its high target tissue uptake efficiency and selectivity, and prolonged retention, suggest that it has excellent promise as a PET imaging agent for PR-positive breast tumors...
  5. ncbi Synthesis and evaluation of aryl-substituted diarylpropionitriles, selective ligands for estrogen receptor beta, as positron-emission tomographic imaging agents
    Byung Seok Moon
    Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
    Bioorg Med Chem 17:3479-88. 2009
    ..023%; ERbeta, 6.25%). The absolute ERbeta binding affinities, however, were not sufficient to merit further consideration for developing these ligands as PET imaging agents...
  6. pmc Bromination from the macroscopic level to the tracer radiochemical level: (76)Br radiolabeling of aromatic compounds via electrophilic substitution
    Dong Zhou
    Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    Bioconjug Chem 20:808-16. 2009
    ....
  7. pmc Evaluation of a bromine-76-labeled progestin 16alpha,17alpha-dioxolane for breast tumor imaging and radiotherapy: in vivo biodistribution and metabolic stability studies
    Dong Zhou
    Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA
    Nucl Med Biol 35:655-63. 2008
    ..Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. They can be used as targets for diagnostic imaging and radiotherapy...
  8. pmc PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer
    Farrokh Dehdashti
    Division of Nuclear Medicine, Edward Mallinckrodt Institute of Radiology, St Louis, MO 63110, USA
    Breast Cancer Res Treat 113:509-17. 2009
    ....
  9. ncbi Facile nucleophilic fluorination reactions using tert-alcohols as a reaction medium: significantly enhanced reactivity of alkali metal fluorides and improved selectivity
    Dong Wook Kim
    Department of Nuclear Medicine, Research Institute of Clinical Medicine, Chonbuk National University School of Medicine, Jeonju, Jeonbuk 561 712, Korea
    J Org Chem 73:957-62. 2008
    ..The protic medium also suppresses formation of byproducts, such as alkenes, ethers, and cyclic adducts...
  10. pmc Synthesis and biological evaluation of two agents for imaging estrogen receptor β by positron emission tomography: challenges in PET imaging of a low abundance target
    Jae Hak Lee
    Department of Chemistry, University of Illinois at Urbana Champaign, 600 South Mathews Avenue, Urbana, IL, 61801, USA
    Nucl Med Biol 39:1105-16. 2012
    ..While ERα levels can be measured by positron emission tomography (PET) using 16α-[(18)F]fluoroestradiol (FES), no effective agent for imaging ERβ by PET has yet been reported...

Research Grants30

  1. Small-Molecule Disruptors of the Nuclear Hormone Receptor/Coactivator Interaction
    ALEXANDER ALPHONSE PARENT; Fiscal Year: 2013
    ..By binding to the surface of the receptor, coactivator binding inhibitors or CBIs offer a new approach to endocrine-related cancer therapy, one that should remain viable after current antagonists fail. ..
  2. Comparative Mechanisms of Cancer Chemoprevention
    Roderick H Dashwood; Fiscal Year: 2013
    ..This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet. ..
  3. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013
    ..The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied. ..
  4. Development of VN/14-1 and Related Analogs for Breast Cancer Therapy
    VINCENT COLLINS OFUKA NJAR; Fiscal Year: 2013
    ..The studies would also lead to the identification of biomarkers that would be useful in clinical trials. ..