Prostate cancer (PCa) is the leading cancer in the U.S. population and the second leading cause of cancer death in men. Therapy for locally advanced disease remains contentious and an increasing number of disparate options are available. Perhaps the most pressing issue in PCa management is the need to predict, at the time of diagnosis, which tumors will remain indolent and which will progress rapidly. The ability to fulfill that goal would eliminate the prostate-specific antigen (PSA)-mediated overdetection and overtreatment of clinically insignificant disease. PCa tends to undergo definitive treatment despite the side effects of bowel, bladder and/or sexual dysfunction. The ability to predict the """"""""bad actors"""""""" among diagnosed tumors would provide rationale for expectant management, which may be appropriate and obviate serious morbidity, but is not widely embraced in this country. Current treatment decisions are based on making a best guess at the biology of the tumor from as much indirect information as possible, i.e., PSA, digital rectal examination and biopsy. We believe that molecular imaging techniques, with their ability to interrogate receptor/enzyme/antigen/transporter concentrations and protein interaction networks, provide the best opportunity for understanding PCa biology upon diagnosis. Examples of the predictive capacity of molecular imaging techniques as applied to real clinical cases are becoming evident. More accurate staging would facilitate treatment decisions and lead to a better outcome for patients. Also in dire need is a way to detect small lesions, i.e., recurrent tumors in the surgical bed, local lymph node invasion and other subtle manifestations of the disease in men with an elevated PSA but no other obvious symptoms. The current standard of PCa staging is shifting. Metabolic imaging techniques such as magnetic resonance spectroscopy (MRS), positron emission tomography (PET) and single photon emission computed tomography (SPECT) are gaining favor over the anatomic techniques of computed tomography (CT) and MR, which merely detect enlarged tissue, revealing nothing of its underlying physiology. In particular, SPECT using the radiolabeled monoclonal antibody (mAb) [111In]capromab pendetide (Cyt-356, ProstaScint) is being used to identify candidates for salvage radiotherapy. However, intact antibodies tend to have poor pharmacokinetics for imaging. We propose to expand upon our successful low molecular weight, urea-based series of imaging agents for PCa. These compounds are inhibitors of the prostate-specific membrane antigen (PSMA), a marker for androgen-independent disease that is also expressed on solid (nonprostate) tumor neovasculature. PSMA may be prove to be a marker that can predict PCa biology - the importance of which has been alluded to above. Although we intend to focus on new, low molecular weight radiopharmaceuticals for PET (Aim 1), we will also develop the good manufacturing practice (GMP) synthesis of the one agent on which we have toxicity results and will optimize the syntheses of several related, but likely superior, compounds to approach a kit-like preparation of each (Aim 2).
In Aim 3 we will develop homo- and hetero-dimers of PSMA-binding ligands, labeled with positron- and gamma-emitting nuclides, to provide agents of enhanced affinity for tumor neovascular applications. Our proposed compounds are based on extensive structure-activity relationships - not merely of the imaging precursors or PSMA binding compounds, but on actual imaging agents already synthesized and tested in vivo - as well as on molecular modeling, including co-crystallization of several of our existing agents with PSMA. With this new array of PSMA-targeted agents we hope to provide a sensitive, noninvasive method to image not only PCa but also a variety of other solid tumors and metastases. The subtext to this proposal is to increase the chemical space of compounds that bind PSMA. Another sub-aim is to learn more about the internalization of PSMA, through use of our best compounds. Although we have achieved the rudiments of success with regard to several new imaging agents for PCa, we intend to expand upon that by synthesizing 18 new agents and evaluating them in vivo through our preclinical cancer imaging program.
The prostate-specific membrane antigen (PSMA) is an important marker of prostate cancer as well as of the neovasculature of many solid tumors. We propose to develop a new generation of molecular imaging agents that target PSMA using radiopharmaceuticals for positron emission tomography (PET) and single photon emission computed tomography (SPECT), and optimize their syntheses so we may move them to the clinic as soon as possible. In this fashion we hope to be able not only to detect minimal disease with these high- sensitivity probes, but also learn about the biology of prostate cancer (and other tumors) in patients so that we can begin to predict which tumors are indolent vs. which may progress.
|Plyku, Donika; Mena, Esther; Rowe, Steven P et al. (2018) Combined model-based and patient-specific dosimetry for 18F-DCFPyL, a PSMA-targeted PET agent. Eur J Nucl Med Mol Imaging 45:989-998|
|Campbell, Scott P; Baras, Alexander S; Ball, Mark W et al. (2018) Low levels of PSMA expression limit the utility of 18F-DCFPyL PET/CT for imaging urothelial carcinoma. Ann Nucl Med 32:69-74|
|Zukotynski, Katherine A; Valliant, John; Bénard, François et al. (2018) Flare on Serial Prostate-Specific Membrane Antigen-Targeted 18F-DCFPyL PET/CT Examinations in Castration-Resistant Prostate Cancer: First Observations. Clin Nucl Med 43:213-216|
|Woodard, Lauren E; Dennis, Cindi L; Borchers, Julie A et al. (2018) Nanoparticle architecture preserves magnetic properties during coating to enable robust multi-modal functionality. Sci Rep 8:12706|
|Coughlin, Jennifer M; Du, Yong; Rosenthal, Hailey B et al. (2018) The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: An in vivo positron emission tomography study with [18F]ASEM. Neuroimage 165:118-124|
|Werner, Rudolf A; Andree, Christian; Javadi, Mehrbod S et al. (2018) A Voice From the Past: Rediscovering the Virchow Node With Prostate-specific Membrane Antigen-targeted 18F-DCFPyL Positron Emission Tomography Imaging. Urology 117:18-21|
|Banerjee, Sangeeta Ray; Song, Xiaolei; Yang, Xing et al. (2018) Salicylic Acid-Based Polymeric Contrast Agents for Molecular Magnetic Resonance Imaging of Prostate Cancer. Chemistry 24:7235-7242|
|Liu, Guanshu; Ray Banerjee, Sangeeta; Yang, Xing et al. (2017) A dextran-based probe for the targeted magnetic resonance imaging of tumours expressing prostate-specific membrane antigen. Nat Biomed Eng 1:977-982|
|Gorin, Michael A; Rowe, Steven P; Hooper, Jody E et al. (2017) PSMA-Targeted 18F-DCFPyL PET/CT Imaging of Clear Cell Renal Cell Carcinoma: Results from a Rapid Autopsy. Eur Urol 71:145-146|
|Li, Xin; Rowe, Steven P; Leal, Jeffrey P et al. (2017) Semiquantitative Parameters in PSMA-Targeted PET Imaging with 18F-DCFPyL: Variability in Normal-Organ Uptake. J Nucl Med 58:942-946|
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