Somatostatin Receptors and Analogs in Pheochromocytoma and Paraganglioma: Old Players in a New Precision Medicine World

Abstract

Neuroendocrine tumors overexpress somatostatin receptors, which serve as important and unique therapeutic targets for well-differentiated advanced disease. This overexpression is a well-established finding in gastroenteropancreatic neuroendocrine tumors which has guided new medical therapies in the administration of somatostatin analogs, both “cold”, particularly octreotide and lanreotide, and “hot” analogs, chelated to radiolabeled isotopes. The binding of these analogs to somatostatin receptors effectively suppresses excess hormone secretion and tumor cell proliferation, leading to stabilization, and in some cases, tumor shrinkage. Radioisotope-labeled somatostatin analogs are utilized for both tumor localization and peptide radionuclide therapy, with 68Ga-DOTATATE and 177Lu-DOTATATE respectively. Benign and malignant pheochromocytomas and paragangliomas also overexpress somatostatin receptors, irrespective of embryological origin. The pattern of somatostatin receptor overexpression is more prominent in succinate dehydrogenase subunit B gene mutation, which is more aggressive than other subgroups of this disease. While the Food and Drug Administration has approved the use of 68Ga-DOTATATE as a radiopharmaceutical for somatostatin receptor imaging, the use of its radiotherapeutic counterpart still needs approval beyond gastroenteropancreatic neuroendocrine tumors. Thus, patients with pheochromocytoma and paraganglioma, especially those with inoperable or metastatic diseases, depend on the clinical trials of somatostatin analogs. The review summarizes the advances in the utilization of somatostatin receptor for diagnostic and therapeutic approaches in the neuroendocrine tumor subset of pheochromocytoma and paraganglioma; we hope to provide a positive perspective in using these receptors as targets for treatment in this rare condition.

Pheochromocytomatosis Treated With Peptide Receptor Radionuclide Therapy

“…3 It is reasonable that targeted radionuclide therapy such as MIBG radiotherapy and PRRT intended for metastatic pheochromocytoma may also be used for pheochromocytomatosis recurrence after surgical debulking. [4][5][6][7][8] To our knowledge, this is the first case of pheochromocytomatosis treated with PRRT. Consistent with the results of PRRT for metastatic pheochromocytoma, which show that most patients exhibit stable disease after the treatment, [4][5][6][7] our patient also exhibits stable disease after PRRT.…”

Phase II Study of ONC201 in Neuroendocrine Tumors including Pheochromocytoma-Paraganglioma and Desmoplastic Small Round Cell Tumor

“…Patients with metastatic neuroendocrine tumors now have many systemic treatment options (1). These include not only FDA-approved chemotherapy options such as mTOR inhibitors such as everolimus and sunitinib (37)(38)(39), but also lanreotide (6,40), radiopharmaceuticals 131-MIBG, and 177-Lu-DOTATATE (3,41). Agents to possibly consider for future study could include checkpoint inhibitors (14) and ascorbic acid (42).…”

“…Ongoing efforts of Dr. Karel Pachak at NIH and others have increased genomic knowledge and therapeutic options for targeted treatment of neuroendocrine tumors, particularly pheochromocytoma-paraganglioma (PC-PG; refs. 1,2,[5][6][7][8][9][10][11][12][13][14].…”

Role of Peptides in Diagnostics

“…It is predominantly used for the assessment of neuroendocrine tumors and carcinoid tumors. Some other novel radiolabeled tracers for SSTRs also demonstrated decent affinity, including 68 Ga-DOTA-TOC (more selective to SSTR2 and SSTR5), 68 Ga-DOTA-TATE and 64 Cu-DOTA-TATE (affinity to SSTR2), 99m Tc-EDDA/HYNIC-TOC (affinity to 2 and 5 type receptors), and 68 Ga-DOTA-NOC (affinity to 2, 3 and 5 type receptors) [69,70]. A study was performed by Yamaga et al to compare the detection rate of 68 Ga-DOTATATE PET/CT with 111 In-octreotide SPECT/CT in medullary thyroid carcinoma patients (n = 15) with increased calcitonin levels but negative conventional imaging after thyroidectomy.…”