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Paper Abstract

Exendin PET/CT imaging of paragangliomas: stacking the odds in the patient’s favor

Paragangliomas are neuroendocrine tumors that develop from cells outside the adrenal gland and are often recognized as extra-adrenal tumors. They are most frequently found in the head and neck region and rarely, paragangliomas have been located within the larynx, nasopharynx, thyroid gland, orbit, soft palate, mandible, face, and cheek.  The adrenal glands are located directly above the kidneys and produce epinephrine and norepinephrine, which are stress hormones. Paragangliomas are rare tumors that are frequently misdiagnosed, which is dangerous for patients. Thus, there is a need for an active multidisciplinary approach for the best possible patient care and diagnosis of such rare tumors.

The present state of affairs:

The recent advances in the knowledge regarding the pathophysiology and heterogeneous clinical presentation of paragangliomas improve the clinical management of patients with paragangliomas. It can be difficult for imaging paragangliomas and other neuroendocrine tumors since they are often multifocal and hereditary, and have variable biological and metabolic activity. Previously, surgery was the only technique to successfully detect and stage these tumors. This highlights the need for the introduction of molecular imaging with the conjunction of anatomic imaging (computed tomography (CT) or magnetic resonance imaging (MRI)) in the diagnostics of paragangliomas.

 

Molecular imaging has several uses in oncology since many tumors express or activate target molecules or pathways that are particular to those tumors. This relatively new imaging method improves tumor staging and localization, particularly when used with anatomic imaging such as computed tomography or MRI [1], [2].

 

Molecular imaging can be precisely utilized:

  • To localize the paraganglioma tumors

  • To stage paragangliomas

  • To assess treatment responses

  • To provide information important for radionuclide therapy selection in metastatic disease

Exendin PET/CT: what is it?

Functional imaging of paraganglioma is not completely conclusive. The hunt for novel molecular imaging targets is justified given that paragangliomas respond well but inconsistently to current functional imaging modalities. Thus, imaging of paragangliomas by using modern imaging modalities like exendin positron emission tomography/computed tomography (PET/CT) is a significant breakthrough for paraganglioma patients because of its high sensitivity and specificity. It also lowers the risk of postoperative complications. Exendin PET/CT can also be used to track the effectiveness of the treatment as well as keep an eye out for the recurrence of the disease.

 

In recent years, receptors targeting radiolabeled peptides have gained significant importance in nuclear medicine and oncology. The molecular basis for in vivo imaging and targeted radionuclide therapy using radiolabeled peptide-based probes is the overexpression of multiple peptide receptors in a variety of malignancies in contrast to their comparatively low density in normal organs. The clinical success of targeting the various receptors for the diagnostic purpose of neuroendocrine tumors has sparked a hunt for additional peptide receptors appropriate for related uses.

 

Over the past few years, numerous peptide families, including bombesin, cholecystokinin/gastrin, arginine-glycine-aspartic acid (RGD), and glucagon-like peptide-1 (GLP-1)/exendin have been investigated. The glucagon-like peptide 1 receptor (GLP-1R), a member of the G-protein-coupled receptor family is a potential candidate with rising clinical attention. The GLP-1R is being examined by researchers as a potential new target for paraganglioma molecular imaging. The 68Ga-NODAGA-exendin 4 tracers for positron emission tomography/computed tomography (PET/CT) imaging may also be used for this purpose. Currently, a prospective pilot trial is investigating the practicability of 68Ga-NODAGA-exendin-4 PET/CT in paraganglioma patients (who have undergone standard diagnostic procedures like CT, somatostatin receptor PET/CT and 18F-FDG PET/CT and are planned for surgery) for localization and functional characterization of paragangliomas (NCT05418907) [3], [4].

Exendin PET/CT: is it a step in the right direction?

With the development of novel tracers like GLP-1R agonists, significant progress can be achieved in the diagnosis of neuroendocrine tumors in the upcoming years. Additionally, there is a need for a wide spectrum and effective investigation of an efficient strategy to specifically target GLP-1R using 68Ga-NODAGA-exendin-4. When traditional morphological imaging fails, these strategies may be the imaging modality of choice.

 

In the coming years, major advancements in the diagnosis of neuroendocrine tumors are possible with the help of the introduction of novel tracers such as GLP-1R agonists. There is also a   need to thoroughly research the best way to use 68Ga-NODAGA-exendin-4 to specifically target the GLP-1R. These techniques will be the go-to imaging modality when conventional morphological imaging fails for the treatment of these rare diseases.

Paragangliomas.jpg

Outlook:

The clinical success of 68Ga-NODAGA-exendin-4 PET/CT to specifically target the GLP-1R may help to open new avenues in nuclear medicine and oncology. The development of novel peptide analogs with high affinity for these receptors was prompted by the simultaneous identification of new receptor targets that were overexpressed in human malignancies. Even though many of these probes displayed incredibly promising outcomes in preclinical testing, only a small portion of them have so far made it to the clinic. Nevertheless, the attained knowledge and continuous research ensure the development of new peptide-based radiopharmaceuticals.

References:

  1. E. P. Lin et al., “Head and Neck Paragangliomas: An Update on the Molecular Classification, State-of-the-Art Imaging, and Management Recommendations,” Radiol Imaging Cancer, vol. 4, no. 3, p. e210088, May 2022, doi: 10.1148/rycan.210088.

  2. J. A. Carrasquillo et al., “Imaging of Pheochromocytoma and Paraganglioma,” J Nucl Med, vol. 62, no. 8, pp. 1033–1042, Aug. 2021, DOI: 10.2967/jnumed.120.259689.

  3. K. Antwi et al., “68Ga-Exendin-4 PET/CT Detects Insulinomas in Patients With Endogenous Hyperinsulinemic Hypoglycemia in MEN-1,” The Journal of Clinical Endocrinology & Metabolism, vol. 104, no. 12, pp. 5843–5852, Dec. 2019, DOI: 10.1210/jc.2018-02754.

  4. Radboud University Medical Center, “Exendin PET/CT for Paragangliomas,” clinicaltrials.gov, Clinical trial registration NCT05418907, Jun. 2022. Accessed: Nov. 06, 2022. [https://clinicaltrials.gov/ct2/show/NCT05418907?cond=Paraganglioma&draw=1&rank=2]. Available: https://clinicaltrials.gov/ct2/show/NCT05418907

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