Screening of cancer tissue arrays identifies CXCR4 on adrenocortical carcinoma: correlates with expression and quantification on metastases using 64Cu-plerixafor PET

Abstract

Expression of the chemokine receptor CXCR4 by many cancers correlates with aggressive clinical behavior. As part of the initial studies in a project whose goal was to quantify CXCR4 expression on cancers non-invasively, we examined CXCR4 expression in cancer samples by immunohistochemistry using a validated anti-CXCR4 antibody. Among solid tumors, we found expression of CXCR4 on significant percentages of major types of kidney, lung, and pancreatic adenocarcinomas, and, notably, on metastases of clear cell renal cell carcinoma and squamous cell carcinoma of the lung. We found particularly high expression of CXCR4 on adrenocortical cancer (ACC) metastases. Microarrays of ACC metastases revealed correlations between expression of CXCR4 and other chemokine system genes, particularly CXCR7/ACKR3, which encodes an atypical chemokine receptor that shares a ligand, CXCL12, with CXCR4. A first-in-human study using 64Cu-plerixafor for PET in an ACC patient prior to resection of metastases showed heterogeneity among metastatic nodules and good correlations among PET SUVs, CXCR4 staining, and CXCR4 mRNA. Additionally, we were able to show that CXCR4 expression correlated with the rates of growth of the pulmonary lesions in this patient. Further studies are needed to understand better the role of CXCR4 in ACC and whether targeting it may be beneficial. In this regard, non-invasive methods for assessing CXCR4 expression, such as PET using 64Cu-plerixafor, should be important investigative tools.

Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma

“…For CXCR4, suitable radioligands are available and have been successfully tested in lymphoproliferative malignancies (19)(20)(21). Two of these radioligands, 64 Cu-plerixafor and 68 Ga-Pentixafor, can also reliably assess the expression of CXCR4 in vivo in patients affected by ACC or aldosterone producing adenoma, respectively (4,38). Bluemel et al went a step further towards a potential theranostic use of CXCR4 and compared the performance of 68 Ga-pentixafor PET/CT with 18 F-FDG PET/ CT in 30 patients with advanced ACC (3).…”

“…They are an active component of the tumor microenvironment, driving tumor-specific immune responses and promoting invasion, metastasis, stemness and resistance to chemo-and radiotherapy (1,2). Recently, expression of CXCR4 was reported in primary tumors and metastatic lesions of patients with ACC both at protein level in vitro and in vivo using radiolabeled CXCR4 ligands (3,4).…”

“…Its ligand CXCL12 (SDF-1) is highly abundant in tissues that are common sites of metastasis such as lymph nodes, lung or bone, suggesting a specific chemokine-mediated trafficking-pattern of circulating tumor cells (6,9,10). CXCR7, an atypical chemokine receptor with a ten times higher affinity for CXCL12 compared to CXCR4, was detected at protein level in ACC metastases and correlated with CXCR4 expression (4). CXCR7 can generate CXCL12 gradients for CXCR4 but also acts as a CXCL12 "scavenger", as it is constantly recycled to the cell membrane after ligand binding (11,12).…”

CXCR4 and its ligand CXCL12 display opposite expression profiles in feline mammary metastatic disease, with the exception of HER2-overexpressing tumors

“…As in our study, expression differed in intensity and staining pattern but we obtained 82% of positive PT (93/113 animals). In human breast primary tumors, heterogeneity of expression pattern is often found and the positivity rate, is highly diverse [ 29 , 30 , 35 – 42 ]. This variability can be explained by the different IHC and scoring methods but also by the diversity of CXCR4 primary antibodies used.…”

CXCR4 Based Therapeutics for Non-Small Cell Lung Cancer (NSCLC)

“…Two promising directions that are being pursued in this regard are (1) the generation of radioactively-labeled small CXCR4 inhibitors for utilization in diagnostics and therapeutics of high CXCR4 expressing tumors [ 64 , 65 ], and (2) the usage of CXCR4 inhibitors to overcome tumor immune suppression in general and resistance to ICIs in particular [ 66 , 67 , 68 , 69 ]. With regards to the first direction, two groups have shown that labeling of the CXCR4 antagonist pentixafor with radioactive isotopes (68Ga and 64Cu) enabled the specific and accurate in vivo detection of high CXCR4 expressing tumors in the lung [ 64 , 65 ]. These findings are highly intriguing not only because they may, in the future, facilitate the selection of patients with high CXCR4 expressing tumors for anti-CXCR4 based therapeutics, but also because they open the way for labeling of CXCR4 antagonists with therapeutic radioactive isotopes such as 177Lu and 90Y for endoradiotherapy [ 70 ].…”