Despite the abundant ongoing research efforts, cancer remains one of the most challenging diseases to treat globally. Due to the heterogenous nature of cancer, one of the major clinical challenges in therapeutic development is the cancer’s ability to develop resistance. It has been hypothesized that cancer stem cells are the cause for this resistance, and targeting them will lead to tumor regression. A pentaspan transmembrane glycoprotein, CD133 has been suggested to mark cancer stem cells in various tumor types, however, the accuracy of CD133 as a cancer stem cell biomarker has been highly controversial. There are numerous speculations for this, including differences in cell culture conditions, poor in vivo assays, and the inability of current antibodies to detect CD133 variants and deglycosylated epitopes. This review summarizes the most recent and relevant research regarding the controversies surrounding CD133 as a normal stem cell and cancer stem cell biomarker. Additionally, it aims to establish the overall clinical significance of CD133 in cancer. Recent clinical studies have shown that high expression of CD133 in tumors has been indicated as a prognostic marker of disease progression. As such, a spectrum of immunotherapeutic strategies have been developed to target these CD133 pos cells with the goal of translation into the clinic. This review compiles the current therapeutic strategies targeting CD133 and discusses their prognostic potential in various cancer subtypes.
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.
We have developed a novel antibody that was able to detect CD133 by both IHC and flow cytometry. Using HA10 as an IHC reagent, we found that CD133 is a marker for a very rare cell type in both healthy prostate and adenocarcinoma sections. Our preliminary investigation also suggests that there may be an association between CD133 and non-AR driven prostate cancer with neuroendocrine differentiation.
Prostate cancer is one of the most frequently diagnosed malignancies and the second leading cause of cancer related death among American men. Aggressive variant prostate cancer (AVPC) accounts for approximately 33% of all prostate cancer-related deaths and is characterized by visceral metastasis, minimal responses to current therapies, and poor overall prognosis. The current disease monitoring strategy for AVPC is positron emission tomography - computed tomography (PET/CT) with [18F]-fluorodeoxyglucose (FDG), which is not specific to prostate cancer cells and thus is inadequate in many cases. As such, novel targeted imaging agents are urgently needed for earlier detection and better monitoring of AVPC. The transmembrane glycoprotein, CD133, is overexpressed in AVPC and we have identified a single chain variable fragment, termed HA10, which preferentially recognizes a glycosylation-independent epitope on CD133. Further characterization of HA10 revealed that it was able to identify CD133 in cells, patient tissue samples, and in vivo xenograft models using fluorescent imaging. The purpose of this study was to investigate the performance of the radioimmunoconjugate, 89Zr-HA10, for µPET/CT imaging in preclinical models of prostate cancer. HA10 was conjugated to p-SCN-Deferoxamine (DFO) and then radiolabeled with [89Zr]Zr-oxalate at room temperature. Parental (CWR-R1) and CD133-transduced (CWR-R1CD133) prostate cancer cell lines were implanted subcutaneously into male athymic nu/nu mice. Mice were administered 180 µCi of 89Zr-HA10 via tail vein injection and µPET/CT imaging was conducted at 24, 48, 72, and 144 hours post-injection. The 89Zr-HA10 construct was successfully labeled with a radiochemical purity >99% as determined by radio-thin layer chromatography. Specificity of 89Zr-HA10 was demonstrated for CD133-positive tumors with strong tumoral uptake detection from 24-72 hours. Furthermore, the margins of the CD133-positive tumors were clearly defined following 3D reconstruction of the µPET/CT images. These studies suggest that 89Zr-HA10 is a promising immunoPET imaging agent for AVPC and potentially other CD133-positive cancer subtypes. Moreover, the use of 89Zr-HA10 as a radiotracer will facilitate a more selective strategy for diagnosis and disease monitoring of these patients compared to the conventional FDG radiotracer. Further studies seek to evaluate the potential of 89Zr-HA10 to detect small metastatic lesions in vivo. Citation Format: Paige Glumac, Aaron LeBeau. Targeted immunoPET imaging of prostate cancer using a novel CD133 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1150.
<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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.</p>Results:<p>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 [<sup>89</sup>Zr]Zr-HA10 IgG revealed a mean %ID/g of 24.30 ± 3.19 in CD133-positive metastatic lesions as compared with 11.82 ± 0.57 in CD133-negative lesions after 72 hours (<i>P</i> = 0.0069). <i>Ex vivo</i> biodistribution showed similar trends as signals were increased by nearly 3-fold in CD133-positive tumors (<i>P</i> < 0.0001).</p>Conclusions:<p>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 CD133-expressing tumors, resulting in a noninvasive PET imaging approach to more effectively detect and monitor AVPC.</p></div>
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