Advances in Molecular Imaging for Renal Tumors

You have accessJournal of UrologyJU Forum3 May 2024Advances in Molecular Imaging for Renal Tumors Zhuo Tony Su, Nirmish Singla, and Mohammad E. Allaf Zhuo Tony SuZhuo Tony Su Corresponding Author: Zhuo Tony Su, MD, Department of Urology, Johns Hopkins University School of Medicine, 600 N Wolfe St, Marburg 134, Baltimore, MD 21287 ([email protected]) , Nirmish SinglaNirmish Singla , and Mohammad E. AllafMohammad E. Allaf View All Author Informationhttps://doi.org/10.1097/JU.0000000000003904AboutPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Contemporary evaluation of renal tumors remains reliant on conventional imaging modalities including CT, ultrasound, and MRI. CT and MRI provide high-resolution structural information of renal tumors, but these imaging modalities cannot characterize tumor biological processes and have a poor ability to differentiate among benign, indolent, and aggressive renal masses. This poor differentiation can lead to unnecessary treatment for benign masses and overtreatment for indolent tumors, while failure to timely intervene on aggressive renal cell carcinoma (RCC) risks metastatic progression. Furthermore, conventional CT does not offer sufficient sensitivity for detecting small foci of recurrent or metastatic RCC.1,2 CT and MRI also have limited utility for assessing RCC response to treatment, as these modalities can only characterize late treatment responses such as changes in tumor size and perfusion.1 Therefore, there is a clear need for improved diagnostic, staging, and surveillance imaging for patients with renal tumors. Recently, advances have been made in molecular imaging to address these limitations. Positron emission tomography (PET) and single-photon emission CT (SPECT) utilize radionuclide-labeled molecular tracers to target specific biological processes of renal tumors. When coadministered with conventional imaging, PET/CT, PET/MRI, and SPECT/CT combine the sensitivity and specificity of radiotracers with the high resolution of structural imaging.1 Because several common genetic mutations in RCCs are involved in various metabolic pathways and cause upregulation of tumor-specific cellular membrane proteins,1 radiotracers have been employed to target metabolites that preferentially accumulate in renal tumor cells and receptors that are selectively expressed on RCC cells (Table).1 Here we review several of these radiotracers as illustrative examples and highlight opportunities for further development. Table. Representative Radiotracers Targeting Membranous Receptors and Metabolic Pathways of Renal Tumors Radiotracer Receptor/metabolic pathway targeted Indications1,9 Tracers targeting membranous biomarkers cG250 (girentuximab) mAb ligand for CA-IX Diagnosis of primary RCC, detection of metastatic RCC, and assessment of response to TKI VM4-037 Small-molecule ligand for CA-IX Preclinical data suggest utility for detection of metastatic RCC XYIMSR-06 Small-molecule ligand for CA-IX Improved pharmacokinetics than other radiotracers targeting CA-IX; preclinical data suggest utility for diagnosis of primary RCC and detection of metastatic RCC; compatible with SPECT/CT 68Ga-PSMA-11 Small-molecule ligand for PSMA Detection of metastatic RCC 18F-PSMA-1007 Small-molecule ligand for PSMA Potential utility for diagnosis of primary RCC, detection of metastatic RCC, and assessment of response to TKI and ICI 18F-DCFPyL Small-molecule ligand for PSMA Detection of metastatic RCC 89Zr-bevacizumab mAb ligand for VEGFA Assessment of response to antiangiogenic treatment 89Zr-atezolizumab mAb ligand for PD-L1 Assessment of response to ICI Tracers targeting metabolic pathways 18F-FDG Glucose uptake and phosphorylation Surveillance for recurrent and metastatic RCC, and assessment of response to TKI and ICI 99mTc-sestamibi Uptake in cells with high mitochondrial content and low MDR pump expression Differentiation of renal oncocytomas and HOCTs from other renal masses 11C-acetate Lipid synthesis Diagnosis of primary RCC 11C-choline Cellular membrane synthesis Diagnosis of primary RCC 11C-methionine Amino acid metabolism RCC staging and prognosis prediction 18F-(2S,4R)-4-fluoroglutamine Amino acid metabolism Detection of glutamine-dependent RCC Abbreviations: CA-IX, carbonic anhydrase IX; FDG: fluoro-2-deoxy-d-glucose; HOCT, hybrid oncocytic/chromophobe tumor; ICI, immune checkpoint inhibitor; mAb, monoclonal antibody; MDR, multidrug resistance; PD-L1, programmed cell death ligand-1; PSMA, prostate-specific membrane antigen; RCC, renal cell carcinoma; SPECT/CT, single-photon emission CT/CT; TKI, tyrosine kinase inhibitor; VEGFA, vascular endothelial-derived growth factor A. METABOLIC RADIOTRACERS Among radiotracers targeting renal tumor metabolic pathways, 18F-fluorodeoxy-glucose (FDG) has been the most extensively studied. 18F-FDG is structurally similar to glucose and can be used to measure glucose uptake by tumor cells. 18F-FDG has limited utility for diagnosing primary RCC due to high renal uptake of the radiotracer. Instead, 18F-FDG may be suitable for detecting recurrent and metastatic RCC. In a retrospective study, 18F-FDG PET/CT demonstrated a sensitivity of 96% and specificity of 100% for RCC local recurrence after surgical resection, vs 100% and 98.6% for CT, and a sensitivity of 92.5% and specificity of 99.6% for distant metastases, compared to 93.3% and 94.0% for CT. While CT detected pulmonary metastases better, 18F-FDG PET/CT was more sensitive for nodal, bone, and soft tissue metastases.3 Moreover, 18F-FDG may be used to monitor RCC response to tyrosine kinase inhibitors and immune checkpoint inhibitors. For example, in a small prospective study of patients treated with nivolumab for metastatic RCC, elevated maximum standardized uptake value assessed by 18F-FDG PET/CT 1 month after treatment was an independent predictor of disease response.4 Larger, prospective, multi-institutional studies are needed to validate the clinical value of 18F-FDG PET/CT and other metabolic radiotracers before they can be adopted for routine use. MEMBRANE RECEPTOR LIGANDS An active area of research focuses on identifying and validating radiotracers targeting RCC-specific membranous receptors, with monoclonal antibody (mAb) ligands for carbonic anhydrase IX (CA-IX) among the most promising. CA-IX is a transmembrane protein that has very limited expression under normal physiological conditions but is highly expressed in over 95% of clear cell (cc) RCCs.1 The phase III multicenter REDECT trial demonstrated the utility of 124I-labeled chimeric G250 (cG250; girentuximab), a mAb targeting CA-IX, for diagnosing primary ccRCC. The study compared 124I-cG250 PET/CT and CT for detecting ccRCC in 195 patients undergoing surgery for resectable renal masses. 124I-cG250 PET/CT exhibited a sensitivity of 86.2% and specificity of 85.9% for detecting primary ccRCC lesions, superior to 75.5% and 46.8% for CT.5 Since 124I-labeled radiotracers tend to accumulate in the thyroid, 89Zr-labeled cG250 has been developed. Recently, a prospective, multicenter, phase 3 study (ZIRCON) evaluated the utility of 89Zr-cG250 for diagnosing primary ccRCC. In 284 patients, 89Zr-cG250 achieved a sensitivity of 85.5% and specificity of 87.0% for identifying primary ccRCC lesions, exceeding the study's predetermined sensitivity and specificity targets.6 Furthermore, 89Zr-cG250 has shown utility for detecting metastatic RCC. In a prospective study of 42 patients with metastatic ccRCC, 89Zr-cG250 PET/CT combined with CT detected 91% of metastatic lesions, significantly higher than 56% by CT alone and 84% by combined 18F-FDG PET/CT and CT.2 Currently, efforts are underway to develop and validate radiotracers of lower molecular weights than mAb ligands, in order to achieve better penetration to solid tumors, shorter circulation time, and therefore more rapid attainment of a high tumor-to-blood ratio convenient for real-world use. VM4-037 and XYIMSR-06 are 2 such small-molecule ligands for CA-IX. In a phase II study evaluating 18F-VM4-037 PET/CT in 11 patients, 18F-VM4-037 reached a tumor mean standardized uptake value of 2.55 at 1 hour after injection. However, high uptake of the tracer in the renal parenchyma limited visualization of primary renal lesions. In contrast, the tracer led to excellent visualization of CA-IX‒positive metastatic lesions, suggesting its potential utility for detecting metastatic RCC.764Cu-XYIMSR-06, a dual-motif small-molecule ligand for CA-IX, is particularly promising. In RCC xenograft models, 64Cu-XYIMSR-06 PET/CT demonstrated superior pharmacokinetics compared to existing radiotracers targeting CA-IX and most notably achieved an average tumor-to-kidney ratio of 7.1 at 24 hours post injection.8 Therefore, 64Cu-XYIMSR-06 may be the first small-molecule ligand for CA-IX appropriate for diagnosing primary RCC. Clinical evaluation of 64Cu-XYIMSR-06 is ongoing. SPECT/CT RADIOTRACERS All radiotracers discussed thus far have been applied in PET/CT imaging. Another opportunity in molecular imaging of renal tumors is to develop radiotracers for use with SPECT/CT. Currently, PET/CT remains expensive and not widely available, whereas SPECT/CT requires low costs and can be performed in most hospitals. A successful example of a SPECT/CT radiotracer employed for renal tumor imaging is 99Tc-sestamibi, a widely used radiotracer approved for imaging of multiple organs. Because of preferential 99Tc-sestamibi uptake in cells with high mitochondrial content and low multidrug resistance pump expression, characteristic of renal oncocytomas and hybrid oncocytic/chromophobe tumors, 99Tc-sestamibi SPECT/CT has been utilized to distinguish these 2 types of renal masses from malignant tumors. 99Tc-sestamibi SPECT/CT demonstrated a sensitivity of 87.5% and specificity of 95.2% for identifying renal oncocytomas and hybrid oncocytic/chromophobe tumors from other renal masses in prospective evaluation9 and has been adopted by centers across North America and Europe. Moreover, in health economic assessment, incorporation of 99Tc-sestamibi SPECT/CT to characterize indeterminate renal masses was noted to be cost-effective due to its low expense and avoidance of unnecessary treatment for benign renal masses.10 CONCLUSIONS Growing evidence suggests that molecular imaging can provide more sensitive and specific diagnosis of primary RCC, surveillance for recurrence, and detection of metastases than conventional imaging. Moreover, molecular imaging may be used to monitor RCC response to specific treatment and predict disease prognosis, thereby informing personalized treatment decisions for individual patients targeting their specific tumor biology. Small-molecule ligands for CA-IX, such as 64Cu-XYIMSR-06, which has exhibited improved pharmacokinetics than mAb radiotracers, have the potential to further enhance the diagnostic performance of molecular imaging. Additionally, development of radiotracers for use with SPECT/CT can reduce barriers to adoption of molecular imaging, thanks to the low cost and wide availability of SPECT/CT scans. Lastly, cost-effectiveness evaluations are needed to demonstrate the health economic value that molecular imaging may offer by improving clinical decision-making and treatment outcomes for patients with renal tumors. REFERENCES 1. . Molecular imaging of renal cell carcinoma in precision medicine. Mol Pharm.2022; 19(10):3457-3470. Crossref, Medline, Google Scholar 2. . Lesion detection by [89Zr]Zr-DFO-girentuximab and [18F]FDG-PET/CT in patients with newly diagnosed metastatic renal cell carcinoma. Eur J Nucl Med Mol Imaging. 2019; 46(9):1931-1939. Crossref, Medline, Google Scholar 3. . Diagnostic value of F-18 FDG PET/CT for local and distant disease relapse surveillance in surgically treated RCC patients: can it aid in establishing consensus follow up strategy?. Nucl Med Rev Cent East Eur. 2018; 21(2):85-91. Crossref, Medline, Google Scholar 4. . Early assessment with 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography to predict short-term outcome in clear cell renal carcinoma treated with nivolumab. BMC Cancer. 2019; 19(1):298. Crossref, Medline, Google Scholar 5. . Positron emission tomography/computed tomography identification of clear cell renal cell carcinoma: results from the REDECT trial. J Clin Oncol.2013; 31(2):187-194. Crossref, Medline, Google Scholar 6. . Results from phase 3 study of 89Zr-DFO-girentuximab for PET/CT imaging of clear cell renal cell carcinoma (ZIRCON). J Clin Oncol.2023; 41(6 suppl l):LBA602. Crossref, Google Scholar 7. . PET/CT imaging of renal cell carcinoma with 18F-VM4-037: a phase II pilot study. Abdom Radiol.2016; 41(1):109-118. Crossref, Medline, Google Scholar 8. . [64Cu]XYIMSR-06: a dual-motif CAIX ligand for PET imaging of clear cell renal cell carcinoma. Oncotarget. 2016; 7(35):56471-56479. Crossref, Medline, Google Scholar 9. . Prospective evaluation of 99mTc-sestamibi SPECT/CT for the diagnosis of renal oncocytomas and hybrid oncocytic/chromophobe tumors. Eur Urol.2016; 69(3):413-416. Crossref, Medline, Google Scholar 10. . Cost-effectiveness analysis of 99mTc-sestamibi SPECT/CT to guide management of small renal masses. Eur Urol Focus. 2021; 7(4):827-834. Crossref, Medline, Google Scholar Funding/Support: None. Conflict of Interest Disclosures: The Authors have no conflicts of interest to disclose. Ethics Statement: __. Author Contributions: Conception and design: Su, Singla, Allaf. Drafting the manuscript: Su, Singla. Critical revision of the manuscript for scientific and factual content: Su, Singla, Allaf. Supervision: Su, Singla, Allaf. © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Zhuo Tony Su Corresponding Author: Zhuo Tony Su, MD, Department of Urology, Johns Hopkins University School of Medicine, 600 N Wolfe St, Marburg 134, Baltimore, MD 21287 ([email protected]) More articles by this author Nirmish Singla More articles by this author Mohammad E. Allaf More articles by this author Expand All Funding/Support: None. Conflict of Interest Disclosures: The Authors have no conflicts of interest to disclose. Ethics Statement: __. Author Contributions: Conception and design: Su, Singla, Allaf. Drafting the manuscript: Su, Singla. Critical revision of the manuscript for scientific and factual content: Su, Singla, Allaf. Supervision: Su, Singla, Allaf. Advertisement Advertisement PDF downloadLoading ...