The theranostic revolution began over three decades ago, following the medical conception of somatostatin receptors (SSTRs) and their analogs (SSA). The identification of specific tumor targets for diagnosis and therapy of advanced diseases has been a continuing trend in oncology since its innovation. Neuroendocrine tumors (NETs) with the overexpression of SSTRs are ideal cancer models for discovering the dual ability of diagnosis and treatment using SSAs.

Two decades after the identification of somatostatin (SST) as the central regulator of neuroendocrine cell physiology in the early seventies, five SSTR subtypes were discovered (1–4). The discovery of SSTRs led to the successful introduction of somatostatin analogs (SSAs), initially as antisecretory agents, and recently as antiproliferative agents based on the results of two large phase III trials (5–7).

Through recognition of the SST molecular pathway, we can extrapolate how SSAs exert these physiologic functions. SST inhibits the secretion of neuroendocrine hormones by activating seven-transmembrane somatostatin receptors, a type of G-protein coupled receptor (GPCR). Activation of GPCR initiates a cascade of inhibiting adenyl cyclase, lowering intracellular cAMP, decreasing protein kinase A (PKA) activity, and inhibiting/activating Ca² and K⁺ channels, respectively. This sequence leads to a decrease in exocytosis of peptides, effectors, or ligands resulting in a reduction of hormone secretion (8–17). SST antiproliferative effect has been much more difficult to elucidate, involving various pathways that result in a global imbalance toward increased apoptosis, cell growth modulation, and decreased angiogenesis. Besides the reduction in growth factors (GF) release, SST exerts the effect through SSTR₂ triggering and subsequent activation of phosphotyrosine phosphatases (PTPs). This causes a downregulation of the mitogen-activated protein kinase (MAPK) pathway and of tyrosine kinase receptor (TKR) phosphorylation, inducing cell cycle arrest and decreased cell proliferation (18–27).

Moreover, clinical imaging using radiolabeled SSAs to target SSTRs, known as somatostatin receptor imaging (SRI), became a prominent method in the diagnosis and management of NETs. The earliest success of SRI was pivotal in gastroenteropancreatic (GEP)-NETs and glomus paraganglioma (PGL) localization using ¹¹¹In-pentetreotide (Octreoscan^®) (28, 29). The progression of SRI in NETs increased with the introduction of radiolabeled isotope ⁶⁸Ga-SSAs for positron emission tomography (PET) imaging. Then, Lutetium-177 (¹⁷⁷Lu)-SSA was developed for peptide receptor radionuclide therapy (PRRT). A particular SST-based PRRT, ¹⁷⁷Lu-DOTA0-Tyr³-Octreotate (¹⁷⁷Lu-DOTATATE), was shown to be superior to other modalities in terms of progression-free survival (PFS) in a subset of GEPNETs (30). In 2018, based on the results of the NETTER-1 trial, ¹⁷⁷Lu-DOTATATE (Lutathera^®) was approved by the FDA for foregut, midgut, and hindgut GEPNET treatment. Current management algorithms for GEPNET patients use radiolabeled, and “cold” or unlabeled SSAs for their antiproliferative and cytotoxic abilities.

The discovery of SSTR overexpression in pheochromocytomas and paragangliomas (PPGLs) occurred in the 1990s (31), predicting a limitless therapeutic potential of SSA; however, its role in PPGL management was not developed in parallel with GEPNETs. Initial efficacy testing of SSAs, both cold and radiolabeled, was futile, mostly due to small clinical trials without any clear accrual of therapeutic benefits (32–34) in PPGLs. Despite the therapeutic responses of SSAs in GEPNETs showing significant success (35–39), the application of cold and radiolabeled SSA in PPGL was prematurely abandoned. In the last decade, there was a rise in the use of octreotide and radiolabeled SSA for recommended therapies approved by the FDA for both functioning and nonfunctioning GEPNETs, without enough studies confirming the clinical benefits of these compounds in PPGLs for federal approval. Figure 1 is a timeline comparing important findings and trials in SSTRs and 121 SSAs between NETs and PPGLs.

The primary therapy of choice for PPGL is surgical resection, but not in the case of unresectable advanced and metastatic tumors. A significant proportion of patients with PPGL is due to an inheritable genetic component, where the incidence of metastatic PPGL (mPPGL) occurs due to succinate dehydrogenase subunit B (SDHB) germline mutation patterns (49). Interestingly, SDHB-related PPGLs overexpress SSTRs, mainly SSTR₂ (48). To advance and expand the clinical utilization of SSAs in this PPGL, it is imperative to view the SDHB subgroup as a prime example of clinical benefits that these analogs could provide.

This review summarizes the studies on the role of SSTRs focusing on PPGLs. We detail the discovery of PPGL receptors and the creation of diagnostic and therapeutic radionuclide-bound moieties to target these receptors. We also explore future perspectives for SSTRs and SSAs in driving precision-based care of PPGL patients.

PPGLs are rare NETs arising from neural crest cells, specifically chromaffin cells. Differentiated based on anatomic locations, tumors from the adrenal medulla are defined as pheochromocytoma (PCC), whereas tumors from the sympathetic and parasympathetic ganglia are known as paraganglioma (PGL). While both these tumors present with similar molecular findings on pathology, they vary in manifested symptoms based on their biochemical profile (50).

More than 20 susceptibility genes (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, EPAS1, CSDE1, MAML3, RET, NF1, MAX, HRAS, TMEM127, HIF2A, PHD1/2) indicate predisposition to PPGLs (50). SDHB-related PPGLs are considered aggressive, causing more than 40% of all the metastatic cases (47). The risk of metastatic progression necessitates early diagnosis and intervention for obtaining good outcome in patients. It is important to identify symptoms and perform laboratory tests using plasma or urine metanephrines to confirm the diagnosis, followed by tumor localization through imaging.

Imaging allows personalized therapy by assisting clinicians in deciding whether surgical interventions can render the patient disease-free. PPGLs occur in a wide range of anatomical locations, from the base of the skull to the bladder, making computed tomography (CT) with intravenous contrast the initial choice of imaging modality. However, magnetic resonance imaging (MRI) with or without gadolinium is recommended if there are contraindications to CT imaging, for example contrast allergy, pregnancy, young age, and surgical clip artifacts (51).

Several predictors increase the risk of metastases: PPGL tumor > 5 cm, noradrenergic phenotype, dopaminergic phenotype, familial PPGLs (especially SDHB and SDHA), young age at initial diagnosis, multiple tumors, and recurrent disease (52, 53). PPGLs are more likely to metastasize to the lungs, liver, bones, and lymph nodes (54). While MRI has high sensitivity and specificity for PPGLs, functional imaging has shown to surpass it (55, 56). The advent of functional imaging utilizing SSTRs dramatically improved PPGL localization and identification, enabling clinicians to guide precision medicine.

Success in nuclear imaging of PPGLs was achieved in 1990, when Lamberts et al. conducted a study on three NETs, including one PGL, by labeling Tyr³-octreotide with radioisotope ¹²³Iodine (¹²³I-Tyr³-octreotide) to target SSTRs and capturing them using gamma cameras to produce single photon emission computed tomography (SPECT) and planar images. Results showed that 29 of the 31 possible PGLs were identified, and the two missed lesions were less than 5 mm in size (40). Although it was a relatively small study in terms of patient number, these findings on SRI-related PGLs could not be ignored. Subsequent studies improved the radiolabeled nucleotide by substituting ¹²³Iodide with ¹¹¹Indium in octreotide (¹¹¹In-pentetreotide), chelated by a diethylene triamine penta-acetic acid (DTPA) group, thus solving the problems of short half-life half-life: 13 hours for ¹²³Iodide versus 24-48 hours for ¹¹¹Indium and obscured pathology identification due to biliary excretion with subsequent accumulation in the intestines (57). A study detected 94% of PGLs in 25 patients, and an additional 36% of tumors that were not recognized with conventional imaging [CT, ultrasound, ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG), MRI, and bone scanning] were detected using ¹¹¹In-pentetreotide. The study showed that using ¹¹¹In-pentetreotide could identify the PGLs identified by conventional imaging and others that were not initially visualized (58). In PCCs, ¹²³I-MIBG significantly outperformed ¹¹¹In-pentetreotide in detection (57). ¹¹¹In-pentetreotide had higher sensitivity than ¹²³I-MIBG in detecting head and neck PGLs (HNPGLs) (59–61) and mPPGL (62, 63). The ability of ¹¹¹In-pentetreotide to bind with SSTRs, especially SSTR₂, provided an additional diagnostic tool for clinicians to identify PPGL; however, their sole gamma-emitting capability allows the application of only SPECT to visualize them. SPECT images do not provide spatial resolution to pinpoint the precise anatomical location of PPGL.

PET, which captures emitted positrons from radiotracers and combines them with low dose CT (PET-CT) for targeted receptor localization, was developed in the late nineties (64). Not only does PET have better spatial resolution than SPECT, it can also quantify radiotracer uptake in the form of a standardized uptake value (SUV) (65). To utilize PET-CT hybridized imaging, radiotracers -emitting positrons and targeting SSTRs were created. The first discovered radiotracer was a somatostatin analog 1-Nal3-octreotide (NOC) combined with ⁶⁸Gallium (⁶⁸Ga)-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), better known as ⁶⁸Ga-DOTANOC. ⁶⁸Ga-DOTANOC targets SSTR_{2,3, and 5} (66, 67) subtypes, while another moiety, ⁶⁸Ga-labeled DOTA-Tyr³-octreotide (⁶⁸Ga-DOTATOC), showed affinity for SSTR₅, which is not specific to PPGLs. The last moiety of the three ⁶⁸Ga-labeled DOTA peptides is ⁶⁸Ga-DOTA-Tyr³-octreotate (⁶⁸Ga-DOTATATE), which showed a strong tendency to bind with SSTR₂ and is ideally suited for PPGLs because of the preferential expression of these SSTR subtypes (68). These three radiolabeled somatostatin analogs were compared with previous somatostatin-targeting ¹¹¹In-pentetreotide. The overall sensitivities for NET detection, including metastatic lesions, were much higher with ⁶⁸Ga-labeled DOTA-peptides by PET imaging than ¹¹¹In-pentetreotide by SPECT imaging (69–75). While these studies were not specific to PPGL tumors, one study found 16 and 12 additional PGLs on ⁶⁸Ga-DOTATATE compared to only two on ¹¹¹In-pentetreotide (71). The other study included two patients with PGLs, comparing ⁶⁸Ga-DOTATOC to ^99mTechnetium-labeled hydrazinonicotinyl-Tyr³-octreotide (^99mTc-HYNIC-TOC). While the study proved that ⁶⁸Ga-labeled DOTA-peptide was superior, individual details of these PGL patients cannot be inferred from the analysis because it was performed on a regional basis, and on other NETs (75). There were no studies comparing the efficiency of ⁶⁸Ga-DOTATATE to that of its predecessor, ¹¹¹In-pentetreotide, but it was widely shown to be effective in tumors that express SSTRs. In an individual case of metastatic PGL with SDHD germline mutation, ⁶⁸Ga-DOTATATE PET/CT produced higher resolution of tumors than Octreoscan^®, as seen in Figure 2 .

Among the three radiolabeled somatostatin analogs, ⁶⁸Ga-DOTATATE provided a brighter outlook for PPGL evaluation. SSTR expression by PPGLs, mainly extra-adrenal PGLs and mPPGLs, was found to be the subtype 2 variety (76). This subtype was the preferred target of ⁶⁸Ga-DOTATATE (68). ⁶⁸Ga-DOTATATE was shown to be superior to alternative PET radiotracers in imaging for genotypes, phenotypes, metastases, and PGL-predominant diseases. The two alternative PET radiotracers used to diagnose PPGLs, ¹⁸Flourine-fluorodeoxyglucose (¹⁸F-FDG) and ¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-FDOPA), were inferior to ⁶⁸Ga-DOTATATE in the following cohorts of patients with:

At a molecular level, the utility of ⁶⁸Ga-based SRI in these patient cohorts can be explained by the current knowledge that SDHx-based lesions and extra-adrenal PGLs have higher proportions of SSTR₂ than other PPGL types. Even though ⁶⁸Ga-DOTATATE has lower sensitivity in other types of PPGLs than ¹⁸F-FDOPA, it remains the secondary radiopharmaceutical of choice in the evaluation of PPGL genotypic and phenotypic subtypes that do not fit in the cohorts mentioned above.

In two recent meta-analyses, ⁶⁸Ga-DOTA-SSA had outperformed several radiotracers, including ¹⁸F-FDOPA and ¹⁸F-FDG. The pooled detection rate of unknown genetic mutational status in ⁶⁸Ga-DOTA-SSA was 93% ([95% CI, 91%-95%], P < 0.005), higher than 80% in ¹⁸F-FDOPA ([95% CI, 69%–88%], P < 0.005) or 74% in ¹⁸F-FDG PET ([95% CI, 46%–91%], P < 0.005). The analyses showed that while genetic mutations can help select the type of radiotracers to be used in staging and diagnosing PPGL, it was not always required prior to the selection of ⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTATOC, and ⁶⁸Ga-DOTANOC PET exams (83). A second meta-analysis pooled results of mPPGLs with germline mutational status, and the outcomes showed that ⁶⁸Ga-DOTA-SSA PET/CT (0.97 [95% CI: 0.94-0.98]) detected more lesions than ¹⁸F-FDG PET/CT (0.79 [95% CI: 0.69–0.87]) (84).

⁶⁸Ga-DOTATATE PET/CT proved to be more than a complementary imaging modality to traditional CT and MRI imaging modalities. ⁶⁸Ga-DOTATATE PET/CT has taken the place of ¹¹¹In-pentetreotide (Octreoscan^®) in becoming the SRI modality of choice in PPGLs, subject to the availability of a PET/CT scanner and radiotracer. It also outperformed ¹⁸F-FDOPA and ¹⁸F-FDG for detection of PGLs, mPGLs, HNPGLs, and SDHx PPGLs in adults and children. Figure 3 illustrates the superiority of ⁶⁸Ga-DOTATATE PET/CT compared to ¹⁸F-FDOPA and ¹⁸F-FDG of metastatic lesions in a PPGL patient with a SDHB mutation. While ⁶⁸Ga-DOTATATE PET/CT effectively localizes PPGL tumors, the benefit was ultimately attributed in conversion of the ⁶⁸Ga radiometal to a stronger beta-emitting one for therapeutic purposes.

An interchange of radiolabeling on a chelated SSA (e.g., DOTA-SSA) caused a functional switch of the molecular compound from diagnostic to therapeutic capabilities. ⁶⁸Ga-DOTA-SSA precisely located SSTRs on the surface of PPGL lesions through the capture of ⁶⁸Ga-beta emissions by PET/CT scanners. A change in radiometal to ¹⁷⁷Lutetium (¹⁷⁷Lu) or ⁹⁰Yttrium (⁹⁰Y) gave radiolabeled DOTA-SSA the ability to emit not only imageable radiations but also deliver beta radiations to the target lesions. Lutathera^® was approved by the FDA for GEPNET treatment; hopefully, it is only a matter of larger-model experiences and extensive reporting until its approval in surgically unamenable or metastatic PPGLs. More trials and research are needed to determine its actual applicability in PPGLs and to support the studies mentioned in this section.

The clinical side effects of SSA-based PRRT include nausea, vomiting, fatigue, and abdominal pain (106). Nausea and vomiting have been attributed to commercial amino acid infusion for renal protection prior to infusion of the selected PRRT. The occurrence of nausea and vomiting can be reduced by substituting the commercial amino acid infusion with an alternative containing _L-lysine and _L-arginine. More serious side effects include neutropenia, lymphopenia, thrombocytopenia, and nephrotoxicity. In a review of 45 PPGL patients treated with PRRT, 3% had grade 3/4 neutropenia, 9% had thrombocytopenia, 11% had lymphopenia, and 4% had nephrotoxicity. A long-term complication of myelodysplastic syndrome was also observed in an unreported number of PPGL patients receiving the therapy (105). In a case report by Wolf et al., a dangerous side effect of Lutathera^® in two mPGL patients was hyperprogression of mPGL disease after three cycles of ⁹⁰Y/¹⁷⁷Lu-DOTATOC (cycle one was ⁹⁰Y, and cycle two and three were ¹⁷⁷Lu) in patient A and two cycles of ¹⁷⁷Lu-DOTATATE in patient B (107). Future reporting of adverse effects of SSA-based PRRT is important in assessing the safety of this therapy in PPGL patients to determine whether the therapy can be effectuated in patients, without life-threatening side effects.

The following section will focus on ongoing studies that focus on the targeting of SSTRs by SSA based therapeutic compounds.

The “Old Players” in the title of this review shows that SSAs have a historic role in treating and managing NETs. The review hopes to restore clinical awareness of these analogs through successes achieved in PPGLs. The theranostic utility of SSAs in PPGLs can be realized once federal approval is achieved. However, research and innovation should not be halted once an approval of Lutathera^® for unresectable PPGLs is garnered. Research should be continued for targeting SSTRs with second-generation SSAs, SSTR-ANs, chimeric dual receptor-targeting peptides, chemotactic delivery through SSTRs, and other novel methods.

MP and IT share first co-authorship; they contributed to the conception of the idea, creation of the outline, writing, reviewing, and editing. AJ contributed to creating an outline, conceptualization, reviewing, and editing. DT contributed to reviewing. KP contributed to creating an outline, conceptualization, review, and edit of the manuscript. All authors contributed to the article and approved the submitted version.

This research was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The handling editor declared a past co-authorship with one of the authors KP.