Exploitation of CD133 for the Targeted Imaging of Lethal Prostate Cancer

Abstract

Purpose: Aggressive variant prostate cancer (AVPC) is a nonandrogen receptor-driven form of disease that arises in men in whom standard-of-care therapies have failed. Therapeutic options for AVPC are limited, and the development of novel therapeutics is significantly hindered by the inability to accurately quantify patient response to therapy by imaging. Imaging modalities that accurately and sensitively detect the bone and visceral metastases associated with AVPC do not exist.Experimental Design: This study investigated the transmembrane protein CD133 as a targetable cell surface antigen in AVPC. We evaluated the expression of CD133 by microarray and IHC analysis. The imaging potential of the CD133-targeted IgG (HA10 IgG) was evaluated in preclinical prostate cancer models using two different imaging modalities: near-infrared and PET imaging.Results: Evaluation of the patient data demonstrated that CD133 is overexpressed in a specific phenotype of AVPC that is androgen receptor indifferent and neuroendocrine differentiated. In addition, HA10 IgG was selective for CD133-expressing tumors in all preclinical imaging studies. PET imaging with [ 89 Zr]Zr-HA10 IgG revealed a mean %ID/g of 24.30 AE 3.19 in CD133positive metastatic lesions as compared with 11.82 AE 0.57 in CD133-negative lesions after 72 hours (P ¼ 0.0069). Ex vivo biodistribution showed similar trends as signals were increased by nearly 3-fold in CD133-positive tumors (P < 0.0001).Conclusions: To our knowledge, this is the first study to define CD133 as a targetable marker of AVPC. Similarly, we have developed a novel imaging agent, which is selective for CD133expressing tumors, resulting in a noninvasive PET imaging approach to more effectively detect and monitor AVPC.

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

“…The pentaspan transmembrane glycoprotein CD133 is the most frequently used cell surface antigen to detect CSCs from various solid tumors including prostate tumors [21] and to isolate prostate stem cells from a population of primary human prostate cancer cell lines [22]. In addition, it is overexpressed in aggressive androgen-independent prostate cancer [23]. The enzyme ALDH1A1 has also been considered a cancer stem marker in prostate cancer [24].…”

Imaging Fibroblast Activation Protein Alpha Improves Diagnosis of Metastatic Prostate Cancer with Positron Emission Tomography

“…Therefore, targeting the tumor microenvironment could increase imaging sensitivity and have greater utility compared with current agents. Our group has previously shown that non-specific PET radiotracers have limited function in preclinical prostate cancer models (29). CAFs are the major cell population in the tumor stroma and are critical to tumor growth beyond 1 to 2 mm, indicating that CAF-targeted imaging could have improved sensitivity for small tumors (32).…”

“…To radiolabel the B12 IgG and IC IgG, the DFO-B12 IgG conjugate (272 mL, 2.2 mg/mL, 600 mg mAb) or DFO-IC IgG conjugate (600 mg mAb) in 0.5 mol/L HEPES (pH 7.5) was added to the neutralized [ 89 Zr]Zr-oxalate solution and incubated at room temperature with rotation for 1 hour. The labeled product was purified using a size-exclusion PD-10 column preequilibrated with PBS buffer and evaluated via radioactive TLC for purity using standard methods as described previously (29). Size-exclusion HPLC analysis with a radioactive detector was not performed on any of the radiolabeled products.…”

Radiotracer zur Diagnose des Prostatakarzinoms: Etablierte und neue Verfahren

“…In einer Androgenrezeptor (AR) unabhängigen Form des PCa (aggressive Variante des PCa, AVPC), für das derzeit keine diagnostischen Tracer zur Verfügung stehen, erwies sich CD133 als vielversprechender Marker. Dies gilt sowohl auf mRNA-als auch auf Proteinebene für AR-negative/neuroendokrin-positive (AR -/ NE + ) Patienten und könnte in einem präklinischen Modell des PCa erfolgreich eingesetzt werden [130]. Kürzlich wurden sowohl das scFv-Antikörperfragment HA10 als auch eine humane IgG-HA10-Version in voller Länge gegen CD133 entwickelt.…”

“…Beide wurden mit einem Nahinfrarot-Farbstoff und 89 Zr markiert und in subkutanen und metastatischen AVPC-Mausmodellen untersucht. Dies ist der erste beschriebene Ansatz zur Bildgebung der AVPC mit großem Potenzial als Theranostikum bei diesem malignen Subtyp eines PSMA-negativem PCa [130].…”