Somatostatin analogs in pheochromocytoma research:

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Pheochromocytomas and extra-adrenal paragangliomas
Pheochromocytoma (PHEO) is a rare type of tumor that develops from neural crest tissue in the central medulla of the adrenal gland. They affect only about 4 in every 106 people each year, but until relatively recently they remained largely undiagnosed1.

PHEOs secrete adrenaline and noradrenaline, the hormones that control the body’s stress response. Consequently, symptoms of PHEOs are related to the excess of these hormones: hypertension, tachycardia, headache, sweating, irritability and anxiety.

PHEOs can develop at any age but they are most common in early to middle adulthood. There are no known risk factors for developing PHEOs; it is believed that many have a genetic basis and a predisposition for PHEO is inherited.

Paragangliomas (PGLs) are essentially PHEOs that occur outside the adrenal gland. They are most commonly found in the abdominal region, close to the adrenal glands, but can occur in other locations, such as the head and neck.

Diagnosis of PHEOs and PGLs is complicated and relies heavily on measurement of plasma levels of adrenaline and noradrenaline. A suspected diagnosis can be confirmed using a variety of imaging techniques, such as computed tomography and magnetic resonance imaging2.

The treatment for PHEO and PGL commonly involves surgical removal, but this can be difficult for PHEOs since the adrenal gland performs essential functions and so damage to this gland must be avoided during excision of the tumor.

PHEOs and PGLs are usually benign but can, particularly in the case of PGLs, be malignant. PHEO and PGL metastases do not respond well to treatment. Palliative treatment is achieved using a variety of chemotherapy and radiotherapy combinations, but complete remission is rare.

Somatostatin analogs
Somatostatin is a hormone produced by the body to control the production of hormones released by the gut, pancreas and pituitary gland. In turn it slows down the emptying of the stomach and bowel, increases blood sugar levels and impedes cell growth3. It exerts its effect by binding to receptors on the surface of target cells.

Somatostatin receptors are commonly over-expressed on the surface of tumor cells3. Due to the inhibitory effects of somatostatin, stimulation of these receptors can slow down the growth of tumors. Consequently, somatostatin analogs that persist in the body longer than somatostatin itself were developed as cancer therapies. Somatostatin analogs can also be conjugated to a radionuclide for imaging tumors or to a cytotoxin to destroy tumors.

Novel somatostatin analogs are continually being developed in order to increase their efficacy as imaging and chemotoxic agents for use in the diagnosis and treatment of a range of cancers.

Somatostatin analogs in the management of PHEO and PGL
PHEOs and PGLs express an abundance of somatostatin receptors on the surface of their cells. Somatostatin analogs, e.g. AN-238, have shown efficacy in imaging and inhibiting neuroendocrine tumors4,5. However, due to the rarity of PHEOs and PGLs, further investigation is still needed to confirm that they can inhibit the growth of these tumors.

To expedite such research, the mouse pheochromocytoma mCherry tumor allograft model was developed. This is functionally similar to human PHEOs and PGLs and so can provide a good indication of whether a treatment is likely to be effective.

Latest research
The pheochromocytoma mCherry model has recently been used to investigate the somatostatin receptor analog DOTA-(Tyr3)octreotate (DOTATATE) in the treatment of metastatic PHEOs and PGLs6.

The research was conducted in mice with continually growing tumors with a diameter of approximately 5 mm. Groups of the mice with a similar average tumor volume were administered one of six treatments: vehicle only; doxorubicin; DOTATATE; DOTATATE+ doxorubicin; AN-238; DOTATATE+AN-238.

In vivo imaging and x-raying of the mice using the In-Vivo Xtreme system (Bruker, Billerica, MA, USA) revealed that tumors of the pheochromocytoma mCherry allograft model had high densities of somatostatin-2 receptor to which [64Cu]Cu-DOTATATE bound readily.
Determination of the change in tumor size after 15–30 days of treatment revealed that [177Lu]Lu-DOTATATE reduced tumor growth. This was reflected in reduced tumor-related renal monoamine excretion. The tumoristatic action of [177Lu]Lu- was shown to be greater than that observed with either AN-238 or doxorubicin.

Importantly, none of the somatostatin analogs assessed caused down-regulation of the somatostatin-2 receptor. DOTATATE can therefore be safely used for repeated treatment cycles, as is usually required for anti-tumor chemotherapy. In addition, it allows for administration of both radiolabeled and cytotoxic analogs so that imaging and tumor inhibition can be executed concomitantly.

There is an unmet treatment need for rare metastatic pheochromocytomas and paragangliomas. Since these tumors abundantly express somatostatin receptors, somatostatin analogs (powerful tools for the visualization and control of a range of tumors) represent obvious candidates. Available data suggest that they may be valuable in the management of pheochromocytomas and paragangliomas, but the rarity of these tumors make it difficult to conduct robust investigations in patients in an acceptable time frame.

The mouse pheochromocytoma mCherry tumor allograft model enables the evaluation of therapeutic or diagnostic agents that specifically target the somatostatin-2 receptor.

References
Kiernan CM, Solórzano CC. Pheochromocytoma and Paraganglioma: Diagnosis, Genetics, and Treatment. Surg Oncol Clin N Am. 2016 Jan;25(1):119-38.
Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-42.
Wolin EM. The Expanding Role of Somatostatin Analogs in the Management of Neuroendocrine Tumors. Gastrointest Cancer Res. 2012 Sep-Oct; 5(5): 161–168.
Oberg K, Kvols L, Caplin M, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun; 15(6):966-73.
Cirillo F. Treatment of neuroendocrine gastroenteropancreatic tumours with somatostatin analogues: a personal series and review of the literature. Eur J Oncol. 2006;11:57–64.
Ullrich M, Bergmann R, Peitzsch M, et al. Multimodal Somatostatin Receptor Theranostics Using [64Cu]Cu-/[177Lu]Lu-DOTA-(Tyr3)octreotate and AN-238 in a Mouse Pheochromocytoma Model. Theranostics 2016; 6(5): 650–665.
About Bruker
Bruker is market leader in analytical magnetic resonance instruments including NMR, EPR and preclinical magnetic resonance imaging (MRI). Bruker’s product portfolio in the field of magnetic resonance includes NMR, preclinical MRI ,EPR and Time-Domain (TD) NMR. In addition.

Bruker delivers the world’s most comprehensive range of research tools enabling life science, materials science, analytical chemistry, process control and clinical research. Bruker is also the leading superconductor magnet and ultra high field magnet manufacturer for NMR and MRI solutions.

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