Targeting CD146 with a 64Cu-labeled antibody enables in
vivo immunoPET imaging of high-grade gliomas |
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Authors: | Yunan Yang Reinier Hernandez Jun Rao Li Yin Yazhuo Qu Jinrong Wu Christopher G England Stephen A Graves Christina M Lewis Pu Wang Mary E Meyerand Robert J Nickles Xiu-wu Bian Weibo Cai |
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Institution: | aDepartment of Radiology, University of Wisconsin-Madison, Madison, WI, 53705;;bDepartment of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China, 400038;;cDepartment of Medical Physics, University of Wisconsin-Madison, Madison, WI, 53705;;dUniversity of Wisconsin Carbone Cancer Center, Madison, WI, 53705 |
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Abstract: | Given the highly heterogeneous character of brain malignancies and the associated
implication for its proper diagnosis and treatment, finding biomarkers that
better characterize this disease from a molecular standpoint is imperative. In
this study, we evaluated CD146 as a potential molecular target for diagnosis and
targeted therapy of glioblastoma multiforme (GBM), the most common and lethal
brain malignancy. YY146, an anti-CD146 monoclonal antibody, was generated and
radiolabeled for noninvasive positron-emission tomography (PET) imaging of
orthotopic GBM models. 64Cu-labeled YY146 preferentially accumulated
in the tumors of mice bearing U87MG xenografts, which allowed the acquisition of
high-contrast PET images of small tumor nodules (∼2 mm). Additionally,
we found that tumor uptake correlated with the levels of CD146 expression in a
highly specific manner. We also explored the potential therapeutic effects of
YY146 on the cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT)
properties of U87MG cells, demonstrating that YY146 can mitigate those
aggressive phenotypes. Using YY146 as the primary antibody, we performed
histological studies of World Health Organization (WHO) grades I through IV
primary gliomas. The positive correlation found between CD146-positive staining
and high tumor grade (χ2 = 9.028; P = 0.029)
concurred with the GBM data available in The Cancer Genome Atlas (TCGA) and
validated the clinical value of YY146. In addition, we demonstrate that YY146
can be used to detect CD146 in various cancer cell lines and human resected
tumor tissues of multiple other tumor types (gastric, ovarian, liver, and lung),
indicating a broad applicability of YY146 in solid tumors.About 23,000 new cases of brain and central nervous system
tumors are expected to be diagnosed in 2015 in the United States alone (1). More importantly, 15,320 patients will likely die of
brain cancer by the end of the year, the majority of them due to malignant tumors types
(1, 2).
Glioblastoma multiforme (GBM) is the most common brain malignancy, accounting for more
than 45% of all primary malignant brain tumors. Incidence rates of GBM increase with
age, peaking at ages between 75 and 84; as a result, the number of glioblastoma cases is
expected to increase in the United States due to population aging (3). Amid the significant efforts devoted to find effective
therapeutic strategies for the treatment of GBM, it remains an incurable disease with a
dismal 5-y survival rate of only 5%.Recent understanding of the complex molecular mechanisms underlying GBM’s
pathogenesis has revealed the considerable heterogeneity inherent to the disease and has
led to the emergence of several promising, patient-tailored therapies (3, 4). However, these
therapies benefit only a specific subset of patients and almost invariably need the
implementation of combinatorial regimes that simultaneously target several
tumor-associated pathways to avoid tumor recurrence and rapid development of resistance.
Therefore, it is critical to find new relevant GBM molecular signatures that allow for
better patient stratification into specific molecular subtypes and the design of
effective targeted therapeutic agents. The creation of The Cancer Genome Atlas (TCGA),
and with it the availability of invaluable cancer genome data, has been instrumental in
creating the opportunity for researchers to explore the genomic profile of several
malignancies and identify new targets that might allow the emergence of novel
diagnostics and therapeutic paradigms. GBM was the first malignancy incorporated to TCGA
for which extensive genomic and matched phenotypical and clinical data are
available.We identified CD146 as a promising diagnosis and therapeutic target for GBM. Subsequent
analysis of the TCGA data revealed a statistically significant correlation between the
expression of CD146 and decreased disease-free survival and overall survival in
glioblastoma patients (). Thus, we
devoted our efforts to validate CD146 as a target for noninvasive diagnosis and
stratification of GBMs and to evaluate its potential as a therapeutic target. CD146,
also known as MCAM, Mel-CAM, MUC18, or S-endo1, was first identified as a tumor
progression and metastasis marker in malignant melanomas (5, 6). The major roles of CD146 have
been associated with intercellular and cell-matrix adhesion. However, its involvement in
several other processes, including development, cell migration, signal transduction,
stem cell differentiation, immune response, angiogenesis, and, more recently, induction
of epithelial-mesenchymal transition (EMT), has also been documented (7, 8). Despite the
copious body of data describing the expression of CD146 in a myriad of cancers,
noninvasive in vivo molecular imaging of CD146 expression has remained unexplored.Open in a separate window
CD146 clinical relevance in glioblastoma multiforme patients. Clinical data were
obtained from TCGA. (A) The table summarizes the demographics
of the analyzed patient cohort. A Kaplan–Meier plot showing a
significant difference in (B) disease-free survival (DFS) and
(C) overall survival between CD146(+) and CD146(−)
GBM patients. P values were determined by the log-rank
test.
Molecular imaging techniques such as positron emission tomography (PET) and fluorescence
imaging are becoming indispensable tools to study tumor biology in a clinical setting
(9). ImmunoPET, which combines the excellent
sensitivity and quantification capabilities of PET with monoclonal antibodies’
(mAbs’) exquisite binding affinity and specificity for their cognate antigen, is
one of the most valuable techniques (10, 11). In this study, we used an improved method to
produce YY146, an mAb against human CD146, which we implemented as an immunoPET agent
for noninvasive in vivo imaging of CD146 expression in an orthotopic GBM mouse model. We
further investigated how CD146 expression associates with several stem cell-like and
mesenchymal cell traits in tumor cells and determined the ability of YY146 to actuate
preferentially on cell subpopulations presenting these aggressive phenotypes. Finally,
histological analysis of different WHO grade human brain tumor tissue samples confirmed
the clinical relevance of CD146 for diagnosis and stratification of high-grade glioma
patients and suggested its feasibility as a target for YY146-based targeted therapies
(e.g., YY146 alone or in combination with other drugs, radioimmunotherapy, antibody-drug
conjugates, etc.). |
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Keywords: | CD146 epithelial-mesenchymal transition positron emission tomography glioblastoma multiforme cancer stem cells |
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