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.
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.
|Dannoon, Shorouk; Ganguly, Tanushree; Cahaya, Hendry et al. (2016) Structure-Activity Relationship of (18)F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer. J Med Chem 59:5684-94|
|Mendes, Desiree E; Wong-On-Wing, Annie; Berkman, Clifford E (2016) Phosphoramidate-based peptidomimetic inhibitors of membrane type-1 matrix metalloproteinase. J Enzyme Inhib Med Chem 31:167-71|
|Choy, Cindy J; Geruntho, Jonathan J; Davis, Austen L et al. (2016) Tunable pH-Sensitive Linker for Controlled Release. Bioconjug Chem 27:824-30|
|Choy, Cindy J; Ley, Corinne R; Davis, Austen L et al. (2016) Second-Generation Tunable pH-Sensitive Phosphoramidate-Based Linkers for Controlled Release. Bioconjug Chem 27:2206-13|
|Nedrow, Jessie R; Latoche, Joseph D; Day, Kathryn E et al. (2016) Targeting PSMA with a Cu-64 Labeled Phosphoramidate Inhibitor for PET/CT Imaging of Variant PSMA-Expressing Xenografts in Mouse Models of Prostate Cancer. Mol Imaging Biol 18:402-10|
|Novakova, Zora; Cerny, Jiri; Choy, Cindy J et al. (2016) Design of composite inhibitors targeting glutamate carboxypeptidase II: the importance of effector functionalities. FEBS J 283:130-43|
|Ganguly, Tanushree; Dannoon, Shorouk; Hopkins, Mark R et al. (2015) A high-affinity [(18)F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer. Nucl Med Biol 42:780-7|
|Ley, Corinne R; Beattie, Nathan R; Dannoon, Shorouk et al. (2015) Synthesis and evaluation of constrained phosphoramidate inhibitors of prostate-specific membrane antigen. Bioorg Med Chem Lett 25:2536-9|
|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|
|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|
Showing the most recent 10 out of 22 publications