Prostate-specific membrane antigen as a target for cancer imaging and therapy

Abstract

The prostate-specific membrane antigen (PSMA) is a molecular target whose use has resulted in some of the most productive work toward imaging and treating prostate cancer over the past two decades. A wide variety of imaging agents extending from intact antibodies to low-molecular-weight compounds permeate the literature. In parallel there is a rapidly expanding pool of antibody-drug conjugates, radiopharmaceutical therapeutics, small-molecule drug conjugates, theranostics and nanomedicines targeting PSMA. Such productivity is motivated by the abundant expression of PSMA on the surface of prostate cancer cells and within the neovasculature of other solid tumors, with limited expression in most normal tissues. Animating the field is a variety of small-molecule scaffolds upon which the radionuclides, drugs, MR-detectable species and nanoparticles can be placed with relative ease. Among those, the urea-based agents have been most extensively leveraged, with expanding clinical use for detection and more recently for radiopharmaceutical therapy of prostate cancer, with surprisingly little toxicity. PSMA imaging of other cancers is also appearing in the clinical literature, and may overtake FDG for certain indications. Targeting PSMA may provide a viable alternative or first-line approach to managing prostate and other cancers.

Figure 1

Homodimer of human PSMA (crystal structure) tethered to the biological membrane. One monomer shown in semitransparent surface representation with individual domains of the extracellular part colored green (protease domain; amino acids 57 – 116 and 352 – 590), blue (apical domain; amino acids 117 – 351), and yellow (C-terminal; amino acids 591 – 750); the second monomer is colored gray. N-linked sugar moieties are colored cyan, and the active-site Zn²⁺ ions are shown as red spheres. Left panel: residing at the plasma membrane of astrocytes /schwann cells, PSMA catabolizes N-acetylaspartyl glutamate (NAAG), the most prevalent peptidic neurotransmitter in the mammalian nervous system. N-acetylaspartate and glutamate, the reaction products, are selectively transported into glial cells, metabolized and reused for NAAG synthesis in neurons. Right panel: PSMA (or folate hydrolase) at the plasma membrane of enterocytes in the proximal jejunum sequentially hydrolyzes the C-terminal γ-glutamate tail of dietary folates, finally leaving folate-monoglutamate, which can then be transported transcellularly into the blood stream [Adapted from Barinka C et al.].

Figure 2

The hydrophobic pocket accessory to the S1 site. The active site bound DCIBzL is in stick representation. The dissected substrate-binding cavity of PSMA is shown in semi-transparent surface representation (gray). The side chains of amino acids delineating the “accessory hydrophobic pocket” are shown in stick representation and colored cyan. The active-site Zn⁺² and S1 bound Cl⁻ are colored blue and represented as a transparent sphere, respectively and water molecules are shown as red spheres. Adapted from Barinka C et al.

Figure 3

PET/CT volume-rendered composite images of [¹⁸F]DCFPyL in a mouse bearing PSMA+ PC3 PIP and PSMA− PC3 flu tumors at (A) 0–30 minutes; (B) 30–60 minutes and (C) 3–3.5 hours post-injection. By 30 minutes radiochemical uptake was evident within the PSMA+ PC3 PIP tumor and kidneys. Radioactivity receded from kidneys faster than from tumor, and was not evident within kidneys by 3.5 hours post-injection. Radioactivity within bladder was due to excretion. At no time was radioactivity clearly visualized within the isogenic, PSMA-PC3 flu tumor. Adapted from Chen Y et al.]

Figure 4

Long linker strategy for attachment of radiometals and other bulky substituents to PSMA-targeted, small-molecule agents. Tri-partite construct including the chelator, linker and targeting moiety (A). A minimal linker length of approximately 20Å enables productive binding of the construct to PSMA through externalization of the bulky substituent (B).

Figure 5

Near-infrared fluorescence) (NIRF) imaging with YC-27 Left panels show animals that underwent surgery with assistance of the Pearl imaging system to assure negative margins after receiving the PSMA-targeted NIRF agent, YC-27, while those on the right did not. Note re-growth of tumor as soon as seven days Post-operatively in the absence of NIR guidance (red circle, right panels) [Adapted from Neuman BP et al].

Figure 6

Compound Gd3 MR Imaging of human PSMA+ PC3 PIP and PSMA– PC3 flu tumor xenografts in male NOD/SCID mice. Enhancement (ΔR₁%) maps in PSMA+ PC3 PIP and PSMA– PC3 flu tumors are superimposed upon T₂-weighted images during 40–160 min after a single bolus injection of Gd3 (A). ΔR₁% maps in PSMA+ PC3 PIP and PSMA– PC3 flu tumors of a trimeric Gd contrast agent without a PSMA-targeting moiety (B). [Adapted from Banerjee SR et al].

Figure 7

Maximum intensity projection images of patients with metastatic prostate cancer imaged with [¹⁸F]DCFBC (A) and [¹⁸F]DCFPyL (B). In both images, arrows demarcate sites of metastatic lymph nodes in the pelvis or retroperitoneum and arrowheads demonstrate sites of bone metastases (cervical spine in [A] and thoracic spine and left femoral head in [B]]. Note the markedly reduced blood pool activity and overall higher tumor-to-background ratio with [¹⁸F]DCFPyL.

Figure 8

⁶⁸Ga-PSMA PET/CT following therapy with [¹⁷⁷Lu]PSMA I&T. Patient presented with PSA=35.9 ng/mL and a PET scan showing multiple, intense mediastinal, abdominal and pelvic lymph node metastases, as well as lesions in the thoracic spine and local recurrence in the prostate fossa (A). Ten months later, after three cycles of peptide radioligand therapy (PRLT) PSA decreased to 1.0 ng/mL with significant regression of previously noted disease (B). Three foci of radioactivity superimposed upon the thorax are due to retention of radioactivity within the Port-A-Cath^® device in B. Images courtesy Dr. Richard Baum, Zentralklinik Bad Berka, DE.

Figure 9

Axial FDG PET/CT (A) and axial [¹⁸F]DCFPyL PET/CT (B) images of a patient with metastatic clear cell renal cell carcinoma involving the posterior aspect of the right iliac bone. Both images are set to the same quantitative scale, highlighting the increased tumor uptake achieved with [¹⁸F]DCFPyL in this case.