PSMA is an important biomarker for prostate cancer prognosis and an appropriate target for therapy due to its restricted expression mainly on late-stage, androgen-independent and metastatic prostate cancer cells. While currently there is only one clinical PSMA targeted agent for SPECT imaging (the antibody-based Prostascint), high-affinity small-molecule inhibitors to PSMA have not been fully exploited for targeting and imaging prostate cancer. The overall objective of this application is to optimize a novel imaging probe for the in vivo detection of PSMA positive prostate tumors. Our central hypothesis for the proposed work is that structural modifications made to the core and linker components of peptidomimetic PSMA inhibitors will improve tumor uptake and clearance properties of imaging probes constructed from these small-molecules. The rationale for undertaking the proposed research is that optimized PSMA imaging constructs will serve as the foundation for translating this research into a clinically relevant imaging modality for the diagnosis and post-treatment assessment of prostate cancer. Additionally, demonstrating the effectiveness of our prostate tumor imaging probes in vivo will serve as initial validation steps for the subsequent development of radiotherapeutic agents based on the general design. The PIs will test the central hypothesis and accomplish the overall objective of this application by pursuing the following specific aims: 1) refine the structure of peptidomimetic inhibitors of PSMA for enhanced affinity and lipophilicity;2) optimize the current design of the prostate cancer positron emission tomography (PET) imaging agent;and 3) develop single photon emission computed tomography (SPECT) imaging agents for prostate cancer based on PSMA targeting agents. The proposed work is expected to yield the following outcomes. First, novel 2nd-generation PSMA-targeting agents designed to exploit auxiliary binding sites remote from the catalytic center of PSMA are expected to exhibit both improved affinity towards PSMA and increased lipophilicity to ameliorate the rapid renal clearance observed with these types of agents. Secondly, PET imaging agents for prostate cancer detection with improved pharmacokinetics will be developed. Thirdly, versatile SPECT imaging agents for prostate cancer will be developed with the potential for substituting the imaging radionuclide with a therapeutic radionuclide. The high-affinity small-molecule targeting platform upon which these agents are based is unique compared to other targeting molecules because they have demonstrated irreversible or slowly-reversible binding to the prostate tumor biomarker PSMA. These unique characteristics make these compounds a more attractive targeting platform for prostate tumor binding with enhanced translational potential. It is expected that the proposed work will result in optimized prostate cancer imaging agents, which is important because better detection agents are essential for assisting clinicians in staging prostate cancer, developing personalized therapy, and monitoring treatment.

Public Health Relevance

The overall objective of this application is to optimize a novel imaging probe for prostate cancer for the in vivo detection of prostate tumors. The proposed work is important, in that it will demonstrate the feasibility of developing a clinically-relevant detection agent for prostate cancer for assisting clinicians in staging prostate cancer, developing personalized therapy, and monitoring treatment. 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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Menkens, Anne E
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Washington State University
Schools of Arts and Sciences
United States
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Liu, Tiancheng; Mendes, Desiree E; Berkman, Clifford E (2014) Prolonged androgen deprivation leads to overexpression of calpain 2: implications for prostate cancer progression. Int J Oncol 44:467-72
Duong, Hong-Quan; Yi, Yong Weon; Kang, Hyo Jin et al. (2014) Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine. Int J Oncol 44:959-69
Wu, Lisa Y; Johnson, Jacqueline M; Simmons, Jessica K et al. (2014) Biochemical characterization of prostate-specific membrane antigen from canine prostate carcinoma cells. Prostate 74:451-7
Liu, Tiancheng; Mendes, Desiree E; Berkman, Clifford E (2014) Functional prostate-specific membrane antigen is enriched in exosomes from prostate cancer cells. Int J Oncol 44:918-22
Martin, Stacy E; Ganguly, Tanushree; Munske, Gerhard R et al. (2014) Development of inhibitor-directed enzyme prodrug therapy (IDEPT) for prostate cancer. Bioconjug Chem 25:1752-60
Kasten, Benjamin B; Liu, Tiancheng; Nedrow-Byers, Jessie R et al. (2013) Targeting prostate cancer cells with PSMA inhibitor-guided gold nanoparticles. Bioorg Med Chem Lett 23:565-8
Liu, Tiancheng; Mendes, Desiree E; Berkman, Clifford E (2013) From AR to c-Met: androgen deprivation leads to a signaling pathway switch in prostate cancer cells. Int J Oncol 43:1125-30
Nedrow-Byers, Jessie R; Moore, Adam L; Ganguly, Tanushree et al. (2013) PSMA-targeted SPECT agents: mode of binding effect on in vitro performance. Prostate 73:355-62
Blank, Brian R; Alayoglu, Pinar; Engen, William et al. (2011) N-substituted glutamyl sulfonamides as inhibitors of glutamate carboxypeptidase II (GCP2). Chem Biol Drug Des 77:241-7
Liu, Tiancheng; Nedrow-Byers, Jessie R; Hopkins, Mark R et al. (2011) Spacer length effects on in vitro imaging and surface accessibility of fluorescent inhibitors of prostate specific membrane antigen. Bioorg Med Chem Lett 21:7013-6

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