Prognostic and Theranostic Applications of Positron Emission Tomography for a Personalized Approach to Metastatic Castration-Resistant Prostate Cancer

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) represents a condition of progressive disease in spite of androgen deprivation therapy (ADT), with a broad spectrum of manifestations ranging from no symptoms to severe debilitation due to bone or visceral metastatization. The management of mCRPC has been profoundly modified by introducing novel therapeutic tools such as antiandrogen drugs (i.e., abiraterone acetate and enzalutamide), immunotherapy through sipuleucel-T, and targeted alpha therapy (TAT). This variety of approaches calls for unmet need of biomarkers suitable for patients' pre-treatment selection and prognostic stratification. In this scenario, imaging with positron emission computed tomography (PET/CT) presents great and still unexplored potential to detect specific molecular and metabolic signatures, some of whom, such as the prostate specific membrane antigen (PSMA), can also be exploited as therapeutic targets, thus combining diagnosis and therapy in the so-called "theranostic" approach. In this review, we performed a web-based and desktop literature research to investigate the prognostic and theranostic potential of several PET imaging probes, such as ¹⁸F-FDG, ¹⁸F-choline and ⁶⁸Ga-PSMA-11, also covering the emerging tracers still in a pre-clinical phase (e.g., PARP-inhibitors' analogs and the radioligands binding to gastrin releasing peptide receptors/GRPR), highlighting their potential for defining personalized care pathways in mCRPC.

Keywords: castration-resistant prostate cancer; molecular imaging; positron emission computed tomography; theranostic nanomedicine.

Figure 1

Schematic representation of PSMA molecular structure. PSMA inhibitors (PSMAi) expolit glutamate carboxypeptidase enzymatic activity of the extracellular domain of PSMA and can be labeled either with positron-emitting nuclides (e.g., ⁶⁸Ga, ⁶⁴Cu, ¹⁸F) for imaging or with beta/alpha emitting radioisotopes (e.g., ¹⁷⁷Lu, ²¹³Bi, ²²⁵Ac) for radionuclide therapy. Monoclonal antibodies (MoAbs) have also been developed: ¹¹¹In-capromab is directed towards the intracellular PSMA domain and is utilized for scintigraphic imaging, ⁸⁹Zr-DFO-J591 targets the extracellular portion of PSMA and is suitable for PET imaging (figure created with Biorender.com (accessed on 8 March 2021)).

Figure 2

A 74-year-old patient affected by mCRPC (Gleason score 5 + 4), progressing after surgery, androgen deprivation therapy (ADT) and chemotherapy, submitted to PET/CT with ⁶⁸Ga-PSMA-11 before enrollment for ¹⁷⁷Lu-RLT. Coronal fused images (A) showed highly increased tracer incorporation in abdominal lymph nodes (red arrows) and in the right iliac bone (white arrow). Note the intense physiological radiopharmaceutical uptake in salivary glands (B), white arrows), while fused axial image of the pelvis well demonstrates ⁶⁸Ga-PSMA-11 uptake in the iliac metastasis (C) white arrow).

Figure 3

Whole body Maximum Intensity Projection (MIP, A), fused coronal ⁶⁸Ga-RM2-PET/MRI (B), coronal emissive ⁶⁸Ga-RM2-PET (C), and MRI images (D) in a 74 year-old man with PCa in biochemical recurrence (PSA 8.4 ng/mL). Focal 68Ga-RM2 uptake is seen in left supraclavicular and retroperitoneal lymph nodes (red arrows). (Images courtesy of Andrei Iagaru, MD, Stanford University).

Figure 4

PET/CT GRPRs or bombesin-receptor imaging with ⁶⁴Cu-CB-TE2A-AR06, showing focal uptake of primary prostate cancer (red arrows), below urinary bladder activity, as shown by PET emissive coronal image (A), fused corresponding coronal (B) and axial slices (C) (Copyright © 2021. Wieser, Mansi, Grosu, et al. Positron emission tomography (PET) imaging of prostate cancer with a gastrin releasing peptide receptor antagonist—from mice to men. Theranostics. 2014; 4(4):412–419.65).

Figure 5

Schematic representation of the potential use of different radioconjugated nanomaterials in theranostics.