Novel Receptor-Targeting Theranostic Peptides for Prostate Cancer

Summary

Principal Investigator: Yubin Miao
Abstract: DESCRIPTION (provided by applicant): Prostate cancer is the most commonly diagnosed cancer in males and the second leading cause of cancer- related death among men in the United States. Unfortunately, no curative treatment exists for metastatic prostate cancer. Early diagnosis of prostate cancer followed by prompt surgical removal provides patients the best opportunities for cures or prolonged survivals. Current ProstaScint(R) SPECT (single photon emission computed tomography) and [18F] FDG (2-[18F] fluoro-2-deoxy-D-glucose) PET (positron emission tomography) imaging have limited use by lack of specificity. Novel receptor-targeting diagnostic and therapeutic agents are urgently needed to improve the detection accuracy and enhance the therapeutic efficacy of prostate cancer. Our strategy to improve the detection accuracy and enhance the therapeutic efficacy of prostate cancer focuses on developing novel theranostic (diagnostic &therapeutic) 177Lu-labeled gonadotropin-releasing hormone (GnRH) peptides to target the GnRH receptors (GnRHRs). GnRHR is a distinct target in this project for developing effective prostate cancer-specific imaging probes due to its over-expression on human prostate cancer cells and specimens, and dramatic low expression on healthy prostate cells and no expression on most normal tissue cells. Recently, we have firstly identified a novel GnRH peptide {111In-DOTA-Ahx-(D-Lys6-GnRH)} as an imaging probe for human prostate cancer detection. Very recently, we found that the introduction of D- Phe dramatically improved the GnRHR binding affinity of DOTA-D-Phe-Ahx-(D-Lys6-GnRH) (7.6 nM) by 4.8- fold as compared to DOTA-Ahx-(D-Lys6-GnRH) (36.1 nM). In this project, we will perform structure-activity relationship (SAR) studies to identify more potent 177Lu-labeled GnRH peptides for prostate cancer imaging and therapy based on the unique DOTA-D-Phe-Ahx-(D-Lys6-GnRH) construct. Specifically, we will synthesize and evaluate 8 novel GnRH peptides with neutral hydrocarbon and amino acid linkers in vitro and in vivo. We hypothesize that the GnRH peptides can specifically bind the GnRH receptors and target theranostic radionuclide (177Lu) to human prostate cancer cells for prostate cancer imaging and therapy. Our positive preliminary results strongly support our hypothesis and research design. Importantly, we have assembled a strong multidisciplinary research team with established expertise that is uniquely suited to carry out this exciting translational project. The success of this project will provide a new insight into the design of novel theranostic agents for prostate cancer detection and treatment, as well as open the avenue of treating human prostate cancer with low-energy beta-radiation (177Lu), high-energy beta-radiation (90Y) and alpha- radiation {212Pb/212Bi and 213Bi} in the future (future directions), providing patients with personalized therapeutic agents to meet individual need (i.e. tumor size or metastases). Identification of novel theranostic peptides promoted by this project will pave the way for evaluation of this novel class of peptides in US FDA-approved clinical trials in the future, enhancing the opportunities of cures to patients with metastatic prostate cancer.
Funding Period: 2013-08-01 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. pmc Influences of hydrocarbon linkers on the receptor binding affinities of gonadotropin-releasing hormone peptides
    Haixun Guo
    College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA
    Bioorg Med Chem Lett 23:5484-7. 2013
  2. pmc Introduction of D-phenylalanine enhanced the receptor binding affinities of gonadotropin-releasing hormone peptides
    Jie Lu
    College of Pharmacy, University of New Mexico, 2502 Marble NE, MSC09 5360, Albuquerque, NM 87131, United States
    Bioorg Med Chem Lett 24:725-30. 2014

Research Grants

  1. Mayo Clinic Breast Cancer SPORE
    JAMES NEWELL INGLE; Fiscal Year: 2013
  2. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
  3. Probe Optimization for Prostate Cancer Detection
    CLIFFORD BERKMAN; Fiscal Year: 2013
  4. Center for Molecular Imaging Research at MGH/HMS
    Ralph Weissleder; Fiscal Year: 2013
  5. WINCART: Weaving an Islander Network for Cancer Awareness, Research and Training
    Sora P Tanjasiri; Fiscal Year: 2013
  6. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
  7. MSKCC Center for Molecular Imaging in Cancer
    STEVEN MARK LARSON; Fiscal Year: 2013
  8. M. D. Anderson Cancer Center SPORE in Multiple Myeloma
    ROBERT ZYGMUNT ORLOWSKI; Fiscal Year: 2013
  9. Engineered HGF-NK1 antagonists for Met-targeted cancer imaging and therapy
    Jennifer R Cochran; Fiscal Year: 2013
  10. Characterization of Pathways Controlling Cancer at the Level of Gene Regulation
    Phillip A Sharp; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Influences of hydrocarbon linkers on the receptor binding affinities of gonadotropin-releasing hormone peptides
    Haixun Guo
    College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA
    Bioorg Med Chem Lett 23:5484-7. 2013
    ..The cellular and biological results provided an insight into the design of new GnRH peptides in the future...
  2. pmc Introduction of D-phenylalanine enhanced the receptor binding affinities of gonadotropin-releasing hormone peptides
    Jie Lu
    College of Pharmacy, University of New Mexico, 2502 Marble NE, MSC09 5360, Albuquerque, NM 87131, United States
    Bioorg Med Chem Lett 24:725-30. 2014
    ....

Research Grants30

  1. Mayo Clinic Breast Cancer SPORE
    JAMES NEWELL INGLE; Fiscal Year: 2013
    ..abstract_text> ..
  2. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
    ..The program represents an integrated effort to improve screening with the overall aim of averting deaths from breast cancer while minimizing harms. ..
  3. Probe Optimization for Prostate Cancer Detection
    CLIFFORD BERKMAN; Fiscal Year: 2013
    ..It is expected that the simplicity of the designs for these agents will not be prone to the same technological and regulatory issues associated with the development of biological targeting agents such as antibodies. ..
  4. Center for Molecular Imaging Research at MGH/HMS
    Ralph Weissleder; Fiscal Year: 2013
    ....
  5. WINCART: Weaving an Islander Network for Cancer Awareness, Research and Training
    Sora P Tanjasiri; Fiscal Year: 2013
    ....
  6. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
    ..The Career Development Component is structured with the purpose of creating independently funded investigators who will, in the future, become leaders in the field. ..
  7. MSKCC Center for Molecular Imaging in Cancer
    STEVEN MARK LARSON; Fiscal Year: 2013
    ..In summary, we have shaped ICMIC-3 to closely adhere to the goals of PAR 09-157. ..
  8. M. D. Anderson Cancer Center SPORE in Multiple Myeloma
    ROBERT ZYGMUNT ORLOWSKI; Fiscal Year: 2013
    ..abstract_text> ..
  9. Engineered HGF-NK1 antagonists for Met-targeted cancer imaging and therapy
    Jennifer R Cochran; Fiscal Year: 2013
    ..Upon completion of this proposal, we will have evaluated the potential of engineered NK1 proteins as molecular imaging and therapeutic agents in pre-clinical models, an important step on the path to clinical translation. ..
  10. 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. ..
  11. Reducing Cervical Cancer in Appalachia
    Electra D Paskett; Fiscal Year: 2013
    ..Future work of this Center will focus on moving this type of multi-level observational and interventional community-based research, into other areas where health disparities exist in relation to cancer withinour region. ..
  12. Targeting aggressive prostate cancer with novel theranostic nanomedicine
    Jer Tsong Hsieh; Fiscal Year: 2013
    ..Sun's and Hsieh's laboratory for evaluating the application of molecular imaging and therapy. ..
  13. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
    ..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..
  14. Mechanisms and Markers of Prostate Cancer Metastases
    ROBERT LOUIS VESSELLA; Fiscal Year: 2013
    ..It also conducts pre-clinical xenograft studies and provides statistical support to the overall P01 program. Core B is the Administrative Core which provides overall administrative support to the investigators. ..