38350087

Exploring Theranostic Avenues in Adrenocortical Carcinoma Using Chemokine Receptor and Prostate-Specific Membrane Antigen-Directed PET/CT

Stefanie Hahner,* Takahiro Higuchi, ¿¿ Sebastian E. Serfling, ¡ Samuel Samnick, ¡ Carmina Teresa Fuss,* Britta Heinze,* Andreas K. Buck, ¡ Andreas Schirbel, ; Martin Fassnacht,* and Rudolf A. Werner, MD1§

Abstract: We report on an adrenocortical carcinoma (ACC) patient, which has exhausted previous treatment options and was scheduled for prostate- specific membrane antigen (PSMA)- and C-X-C motif chemokine receptor 4 (CXCR4)-targeted PET/CT. We identified PSMA-avid pulmonary metas- tases exhibiting modest radiotracer accumulation, while chemokine receptor PET/CT provided intense uptake. This dual-tracer molecular imaging ap- proach revealed that chemokine receptor PET appears to be more suitable in patients with advanced ACC, indicating that CXCR4-directed radioligand therapy may be considered in such patients suffering from end-stage dis- ease. Given its dismal prognosis, chemokine receptor-directed theranostics may therefore extend the therapeutic armamentarium as last-line option in advanced ACC.

Key Words: adrenocortical carcinoma, theranostics, PSMA, prostate- specific membrane antigen, C-X-C motif chemokine receptor 4, CXCR4 (Clin Nucl Med 2024;49: 369-370)

Received for publication November 22, 2023; revision accepted December 7, 2023.

From the *Division of Endocrinology and Diabetes, Department of Medicine I, Uni- versity Hospital, University of Würzburg; ¡ Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany; ¿ Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan; and §The Russell H. Morgan Department of Radiology and Radiolog- ical Sciences, Johns Hopkins School of Medicine, Baltimore, MD. M.F. and R.A.W. equally contributed to the study.

Conflicts of interest and sources of funding: This study was partially supported by the Okayama University “RECTOR” Program, KAKENHI grant (22H03027) from the Japan Society for the Promotion of Science (T.H.), and the German Research Foundation (453989101, R.A.W., T.H .; 507803309, R.A.W.). This work was supported by the Deutsche Forschungsgemeinschaft (DFG AL 203/1-1 and CRC/Transregio 205 “The Adrenal: Central Relay in Health and Disease”). R.A.W. and A.K.B. have received speaker honoraria from Novartis/AAA and PentixaPharm. R.A.W. reports advisory board work for Novartis/AAA and Bayer. A.K.B. is a member of the advisory board of PentixaPharm. All other authors declare no conflict of interest.

Correspondence to: Rudolf A. Werner, MD, Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany. E-mail: werner_r1@ukw.de.

Copyright C 2024 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0363-9762/24/4904-0369

DOI: 10.1097/RLU.0000000000005083

REFERENCES

1. Shu Q, Deng M, Chen Y, et al. Imaging aldosterone-producing adrenocortical carcinoma with 68Ga-pentixafor PET/CT. Clin Nucl Med. 2022;47:e572-e573.

2. Chifu I, Heinze B, Fuss CT, et al. Impact of the chemokine receptors CXCR4 and CXCR7 on clinical outcome in adrenocortical carcinoma. Front Endocrinol (Lausanne). 2020;11:597878.

3. Zhao H, Guo L, Zhao H, et al. CXCR4 over-expression and survival in cancer: a system review and meta-analysis. Oncotarget. 2015;6:5022-5040.

4. Bluemel C, Hahner S, Heinze B, et al. Investigating the chemokine receptor 4 as potential theranostic target in adrenocortical cancer patients. Clin Nucl Med. 2017;42:e29-e34.

5. Crowley MJ, Scognamiglio T, Liu YF, et al. Prostate-specific membrane antigen is a potential antiangiogenic target in adrenocortical carcinoma. J Clin Endocrinol Metab. 2016;101:981-987.

6. Buck AK, Grigoleit GU, Kraus S, et al. C-X-C motif chemokine receptor 4-targeted radioligand therapy in patients with advanced T-cell lymphoma. J Nucl Med. 2023;64:34-39.

7. Alyateem G, Nilubol N. Current status and future targeted therapy in adreno- cortical cancer. Front Endocrinol (Lausanne). 2021;12:613248.

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FIGURE 1. We report on an adrenocortical carcinoma (ACC) patient, which has exhausted previous treatment options and was scheduled for prostate-specific membrane antigen (PSMA)-directed 18F-PSMA1007 PET/CT and C-X-C motif chemokine receptor 4 (CXCR4)-targeted 68Ga-pentixafor imaging. We identified PSMA-avid pulmonary metastases exhibiting modest radiotracer accumulation (A), whereas chemokine receptor PET/CT provided intense uptake in the majority of those lung lesions (B, white arrows). Relevant CXCR4 expression has already been demonstrated in adrenocortical lesions1 and in ACC patients,2-4 whereas PSMA has also been described as a potential therapeutic target in an ex vivo setup in this tumor type.5 We herein provide for the first time an in vivo readout of both targets using respective theranostic PET agents. This dual-tracer molecular imaging approach revealed that chemokine receptor PET appears to be more suitable in patients with advanced ACC, indicating that CXCR4-directed radioligand therapy (RLT) may be considered in such patients experiencing end-stage disease. In a therapeutic setting, those findings may have implications on adequate treatment planning. Relevant antilymphoma efficacy has already been observed in hematological malignancies.6 CXCR4, however, is also part of the stem cell niche, and thus, RLT also exhibits myeloablation-a phenomenon that is desired in advanced blood cancers to prepare patients for stem cell transplantation.6 In ACC, such RLT-mediated bone marrow eradication would then require autologous stem cell transplantation, for example, by harvesting stem cells during previously scheduled chemotherapy. Nonetheless, given its dismal prognosis, chemokine receptor-directed theranostics may extend the therapeutic armamentarium as last-line option in advanced disease.ª

A

[18F]PSMA1007

B

[68Ga]Ga-PentixaFor

20

20

SUV

SUV

O

O