Despite the expanding arsenal of new targeted agents to treat castrate-resistant prostate cancer (CRPC), the disease remains incurable, with nearly half of men with this form of prostate cancer (PCa) developing bone metastases at two years. Metastatic bone disease carries a one year survival rate on the order of 40%. New targeted therapies vary widely in mechanism, from those that inhibit androgen production, such as the CYP enzyme inhibitor abiraterone acetate, to those that focus on metastatic bone deposits, such as the ?-particle emitter, 223RaCl2. The recent Phase III, placebo-controlled ALSYMPCA trial, which studied 223RaCl2 in men with CRPC and symptomatic bone metastases, demonstrated such a clear survival benefit that the trial was discontinued early. Nevertheless, 223RaCl2 only increased median overall survival from 11.2 to 14 months. Here, we intend to build on this initial clinical success with ?-emitter therapy by generating targeted compounds that emit ?-particles specific for both bone-localized and soft tissue-localized tumors. Alpha particles are helium nuclei that have a short but highly lethal range and have proved much more effective than -particle emitters in the context of molecularly targeted radiotherapy for cancer. A goal of developing ?-emitters is to minimize damage to adjacent, surrounding tissue, which is currently unattainable by standard external beam therapy. They have been employed clinically for treatment of PCa previously, but as antibody conjugates, which tend to have limited access to solid tumors. Here we will extend our program in the development of low molecular weight radiopharmaceuticals for PCa that target the prostate-specific membrane antigen (PSMA) to molecular radiotherapeutics - specifically for the synthesis and optimization of compounds for ?-emitter therapy. We have shown in clinical studies that our agents are capable of targeting both bone and soft tissue. Because PSMA is internalized upon ligand binding, fluorescent versions of our compounds localize to the perinuclear area, near the primary target for radiation therapy - cellular DNA. Preliminary dosimetry studies suggest effective treatment can be achieved with acceptable levels of radioactivity deposited to normal tissues, including kidney. We believe that treatment of metastatic CRPC is an unmet medical need for which molecular radiotherapy - particularly with targeted ?-emitters - is ideally suited. We will take a graded approach across three aims that can be summarized as: (1) synthesis of PSMA binding agents that incorporate the ?-emitter, 211At; (2) biological characterization of compounds meeting affinity and stability criteria; and, (3) radiotherapy of suitable leads in relevant mouse models of PCa and comparison of relative biological effectiveness of the top lead, and its 131I-labeled analog, to the emerging clinical PSMA-targeted radiotherapeutic, the humanized anti-PSMA antibody, 177Lu-J591. The goal is to have a lead compound at the end of this funding period ready to progress through the necessary steps for translation to patients with CRPC and biochemical-only recurrence.
The prostate-specific membrane antigen (PSMA) is over-expressed in prostate cancer, particularly of the hormone-independent, aggressive variety as found in metastatic disease, and within solid tumor neovasculature. In this dual-PI project we will leverage our combined knowledge of targeting PSMA with low- molecular-weight imaging agents (Pomper) and ?-particle emitter radiotherapy (Zalutsky) to test PSMA- targeted ?-emitters in relevant animal models of prostate cancer and micrometastasis. We will employ synthetic strategies to optimize cell kill and macro to micro dosimetry estimates - specifically designed by us to assess ?-emitters (Sgouros) - to find a compound worthy of clinical translation to patients with castrate- resistant disease and biochemical-only recurrence, i.e., the lead compound must kill tumor cells while leaving normal tissues unharmed.
|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|
|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|
|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|
|Vaidyanathan, Ganesan; Kang, Choong Mo; McDougald, Darryl et al. (2018) Brush border enzyme-cleavable linkers: Evaluation for reducing renal uptake of radiolabeled prostate-specific membrane antigen inhibitors. Nucl Med Biol 62-63:18-30|
|Pozzi, Oscar R; Zalutsky, Michael R (2017) Radiopharmaceutical chemistry of targeted radiotherapeutics, part 4: Strategies for211At labeling at high activities and radiation doses of211At ?-particles. Nucl Med Biol 46:43-49|
|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|
|Banerjee, Sangeeta R; Foss, Catherine A; Horhota, Allen et al. (2017) 111In- and IRDye800CW-Labeled PLA-PEG Nanoparticle for Imaging Prostate-Specific Membrane Antigen-Expressing Tissues. Biomacromolecules 18:201-209|
|Tosoian, Jeffrey J; Gorin, Michael A; Rowe, Steven P et al. (2017) Correlation of PSMA-Targeted 18F-DCFPyL PET/CT Findings With Immunohistochemical and Genomic Data in a Patient With Metastatic Neuroendocrine Prostate Cancer. Clin Genitourin Cancer 15:e65-e68|
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