Call us
301-363-4651 (Available 9 a.m. to 5 p.m. CST from Monday to Friday)
The 19th Annual Meeting of the European Neuroendocrine Tumor Society (ENETS) was held in Barcelona from Mar 10-11, 2022. ENETS is the highest level academic meeting in the field of neuroendocrine tumors (NET) diagnosis and treatment. NET is today a well-established highly heterogeneous and rare tumor. Hence, it is a huge challenge for precise tumor therapy for NET. In recent years, SSTR family targets are considered to be the most important targets in neuroendocrine tumors (NET) treatment.
Notably, among the SSTR family, the most researched candidate is the Somatostatin Receptor 2 (SSTR2). Ample research confirms that SSTR2 is widely specifically expressed in neuroendocrine tumors and becomes a very attractive target for NET therapy. In fact, SSTR2-based drugs have been widely used in the diagnosis and treatment of various endocrine diseases, such as acromegaly and the rare disease Cushing's syndrome. Now, there is a hope that SSTR2 may offer a more precise therapy in NET, providing a wider strategy for NET patients. Without further ado, here is the introduction of SSTR2.
1. How was the SSTR Family Discovered?
3. What's the Mechanism of Anti-Tumor Effects of SSTR2 Binding to SST?
How was the SSTR family discovered? Initially, somatostatin (SST) was first identified in 1973 by Brazeau et al. in hypothalamic extracted from sheep [1], which has an efficient antisecretory function and is an important inhibitor of hormone secretion. After the 1990s, the Somatostatin Receptor (SSTR) was discovered using ligand binding studies. To date, researchers have cloned and identified five SSTR subtypes, named SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5 [2-3]. Various SSTR can be expressed by various tissues in the organism. SSTR2 among is the most abundantly expressed.
SSTR subtypes belong to the G protein-coupled receptor (GPCR) family. SST exerts its effects by binding to a SSTR. All five isoforms are coupled to Gi proteins and transmit exogenous signals into the cell by regulating the activity of Adenylate Cyclase (AC), which in turn affects the intracellular cAMP concentration. Therefore, SSTR is the key mediator in the biological activity. Findings suggested that SSTR is related to hormonal secretion, influencing the tumor growth and proliferation (Figure 1) [4]. The effect of SSTR on various types of cells depends on the SSTR members expressed on the cell surface. SSTR2 among is the most widely reported.
Figure 1. SSTR family regulates important biological activities [4]
*The Figure was derived from Nature Reviews Endocrinology publication [4]
Somatostatin Receptor 2 (SSTR2) is a class of G protein-coupled receptors (GPCRs) superfamily. Its natural ligand is somatostatin (SST) [5]. SSTR2 is a stable hydrophilic protein with no signal peptide. Structurally they possess seven transmembrane (7tm) (Figure 2) [1]. The secondary structure is mainly α-helical and belongs to the 7tm superfamily of GPCRs. SSTR2 gene and its encoded protein are evolutionarily highly conserved. SSTR2 proteins are involved in the regulation of the GPCR signaling pathway. SSTR2 is the only SSTR receptors protein with two isoforms, SSTR2a and SSTR2b [6]. By STRING protein network interactions analysis, SSTR2-interacting proteins include CORT, SST, NPY, GHRL, GNAI1, GNAI2, GNAI3, SHANK1, and HIVEP2 [7]. Numerous studies have confirmed that SSTR2 proteins are mainly involved in biological processes such as the G protein-coupled receptor pathway; they are involved in the regulation of molecular functions, such as the binding of GTPase-activating protein (GAP) and the activity of the multiple hormone, which are closely linked to different diseases [8].
Figure 2. Schematic diagram of SSTR2a structure [1]
*The Figure was derived from Cellular peptide hormone synthesis and secretory pathways publication [4]
SSTR2 is widely distributed in normal tissues, such as pituitary, islet, adrenal, thymus, gastrointestinal tract and immune system. The expression profile varies in tissues with different receptors. Studies have shown that SSTR2 is closely related to gastric acid secretion, histamine release [9]. Further studies have shown that SSTR2 is often highly expressed in several types of solid tumors, including neuroendocrine tumors and small cell lung cancer [10-11]. Currently, SSTR2 is widely used in the treatment of acromegaly, Cushing's disease, gastrointestinal bleeding and pituitary tumors, neuroendocrine tumors, and neuroblastoma. Therefore, SSTR2 has been developed as a potential drug candidate for the treatment of many diseases.
When SSTR2 or other SSTR subtypes bind to SST, they may exert anti-tumor effects by inhibiting DNA synthesis via cAMP, MAPK, PI3K and other pathways [12-14] (Figure 3). It has been found that the anti-tumor mechanism of SSTR2 or other SSTR subtypes upon binding to SST mainly involves the following signaling pathways:
1) Adenylate cyclase pathway: SSTR binds to adenylated cyclase and reduces intracellular levels of cyclic adenosine monophos-phate (cAMP). The reduced concentration of cAMP results in the inhibition of protein kinase activity, which in turn prevents the activation of oncogenes and suppresses tumor development and progression.
2) Protein tyrosine phosphate pathway: SSTR binds to SST, leading to upregulation of protein tyrosine phosphatase (PTP), which dephosphorylates and inactivates tyrosine kinase. A variety of protein kinases can be restrained, such as mitogen-activated protein kinase (MAPK), thereby inhibiting DNA and protein synthesis.
3) Phospholipid inositol 3 kinase (PI3K) pathway: SSTR upregulates the expression of p21 and p27 via PI3K, which then curb phosphorylation of PRb and the cyclin E-cyclin-dependent kinase 2 complex.
4) Calcium signaling pathway: SSTR causes ion exchange between Ca2+ and H+, decreasing the concentration of intracellular Ca2+, increasing the acidification level of the intracellular environment, and causing inhibition of cell proliferation.
Figure 3. The mechanism of anti-tumor effects of SSTR2 binding to SST [14]
*The Figure was derived from of Molecules Publications [14]
In recent years, SSTR2 has been found to play roles in acromegaly, Cushing's disease and gastrointestinal bleeding. In addition, numerous studies have confirmed that SSTR2 is frequently highly expressed in a variety of tumor cells, especially in neuroendocrine tumors (NET). With these properties, SSTR2 has become an important target for the treatment of acromegaly, as well as neuroendocrine tumors and other tumors.
In addition to being more widely distributed in normal tissues, SSTR2 is often overexpressed in many types of solid tumors, such as the popular neuroendocrine tumors. It has been found that 80-90% of pulmonary neuroendocrine tumors express SSTR, and mainly SSTR2. Research further observed that the higher expression levels and the higher density of SSTR2 in well-differentiated pulmonary neuroendocrine tumors compared to undifferentiated SSTR2 [15-16]. Neuroendocrine tumors (NET) include a variety of hormone-secreting tumors from the endocrine and nervous systems. NET cells often have inherited or sporadic genetic mutations. In addition to NET, SSTR2 is also widely expressed in other tumors, including neuroblastoma [17], pituitary adenoma [18], melanoma [19], thyroid cancer [20], meningioma [21], breast cancer [22], gastric cancer [23], lung cancer [24], etc. Therefore, SSTR2 is becoming an attractive target in tumor therapy, especially in NET.
SSTR2 not only exhibited essential roles in tumors, its expression is also associated with endocrine and metabolic disorders such as Cushing's syndrome, acromegaly, and pituitary ACTH hypersecretion [25-26]. Acromegaly is a chronic progressive endocrine disorder due to excessive growth hormone secretion by pituitary adenomas. Cushing's disease is a rare disorder, which is a clinical syndrome resulting from chronic overproduction of glucocorticoids. Several drugs based on SSTR2 target are currently available for the treatment of these diseases.
Based on the Umabs DB antibody drug database (https://www.umabs.com/) and the ParmSnap database, it suggested that SSTR2 therapeutic antibodies is in an early-drug development stage, with only one drug, Tidutamab from Xencor, Inc., in the clinical phase for the indications of neuroendocrine tumors, cutaneous malignancies, and small cell lung cancer. Tidutamab is a bispecific antibody, targeting SSTR2 x CD3 that limits SSTR2-expressing tumor cells by relying on CD3-activated T cells. Over the past years, much progress has been made in the development of SSTR2 based drugs, including synthetic peptides, small molecule chemotherapeutics, fusion proteins, and antibody drugs (Table 1).
Presently, antibody drugs constitute a promising class of targeted anticancer agents due to less side effects on normal cells and greater enhanced efficacy in patients. With more extensive researches of SSTR2, it is pointed out that SSTR2 carries a great potential in targeted tumor therapy, especially in neuroendocrine tumors (NET). Given the competitive advantages, SSTR2 therapeutic antibodies are being favored by pharmaceutical companies. It is believed that SSTR2 will provide a wider treatment approach for diseases, notably in neuroendocrine tumors!
| Drugs | Target | Indications | Drug Type | Institutes | R&D Status |
|---|---|---|---|---|---|
| Lutetium Dotatate LU-177 (177 Lutetium) Lutetium Oxy-Octreotide |
SSTR2 | Neuroendocrine tumor; pancreatic neuroendocrine tumor; gastric cancer | Synthetic peptides | Beijing Centron International Pharmaceutical Technology Co., Ltd; Advanced Catalyst Application Products Co. | Approval |
| PASIREOTIDE DIASPARTATE Mentholatine pareotide |
SSTR1; SSTR2; SSTR3 | Cushing's syndrome; acromegaly; pituitary ACTH hypersecretion | Synthetic peptides | Novartis Europharm Ltd.; Novartis Pharma AG; Beijing Novartis Pharmaceutical Co. | Approval |
| Vapreotide Acetate Vapreotide Acetate |
SSTR2; SSTR5 | Diarrhea; esophagogastric varices; neuroendocrine tumors | Synthetic peptides | Debiopharm Group; Debaiovision | Approval |
| Somatostatin Acetate Growth inhibitor acetate |
SSTR1; SSTR2; SSTR3 | Gastrointestinal bleeding; pancreatitis | Synthetic peptides | Leyland Pharmaceuticals, Germany | Approval |
| Somatostatin(BCN Peptides SA) Growth inhibitor (BCN Peptides SA) |
SSTR1; SSTR2; SSTR3 | Diabetic retinopathy | Synthetic peptides | BCN Peptides Co. | Clinical Phase 3 |
| Paltusotine | SSTR2 | Acromegaly; malignant carcinoid syndrome; neuroendocrine tumors | Small Molecule Chemicals | Clinticus Pharmaceuticals Co. | Clinical Phase 3 |
| ITF-2984 | SSTR5; SSTR4; SSTR3 | Acromegaly | Small Molecule Chemicals | Italfarmaco SA | Clinical Phase 2 |
| Tidutamab (Xencor, Inc.) | SSTR2; CD3 | Merkel cell carcinoma; small cell lung cancer; neuroendocrine tumors | Bispecific antibodies | Xencor, Inc. | Clinical Phase 2 |
| Gallium-68 satoreotide | SSTR2 | Neuroendocrine tumor; pancreatic neuroendocrine tumor; gastric cancer | Synthetic peptides | Ipsen | Clinical Phase 2 |
| DG-3173 | SSTR2; SSTR5; SSTR4 | Acromegaly | Synthetic peptides | Strongbridge Biopharma Plc; Aspire Pharma Ltd. | Clinical Phase 2 |
| Dopastatin | SSTR2; DRD2; SSTR5 | Pituitary tumors | Synthetic peptides | Tiburio Therapeutics, Inc. | Clinical Phase 2 |
| TBR-065 | SSTR2; DRD2 | Acromegaly | Fusion proteins | Ipsen; Tiburio Therapeutics, Inc. | Clinical Phase 2 |
| 68Ga-NOTA-3PTATE-RGD | SSTR2; ITGAV & ITGB3 | Lung Cancer | Peptides | Peking Union Medical College Hospital, Chinese Academy of Medical Sciences | Clinical Phase 1 |
| ONO-5788 | GHRH; SSTR2 | Acromegaly | Small Molecule Chemicals | Ono Pharmaceutical Industries, Ltd. | Clinical Phase 1 |
| CRN-01941 | SSTR2 | Neuroendocrine tumors | Small Molecule Chemicals | Clinticus Pharmaceuticals Co. | Clinical Phase 1 |
| ZT 01 | SSTR2 | Hypoglycemia; type 2 diabetes | / | Zucara Therapeutics, Inc. | Clinical Phase 1 |
| Somatostatin Growth inhibitor |
SSTR5; SSTR4; SSTR3 | / | Chemical drugs | Shandong New Era Pharmaceutical Co. | Clinical Applications |
| ONO-ST-468 | SSTR2 | Acromegaly | Chemical drugs | Ono Pharmaceutical Industries, Ltd. | Preclinical |
Table 1. Recent advances in SSTR2 drug development
To fully serve the pharmaceutical companies in SSTR2 drug based research for neuroendocrine tumors (NET) or other diseases, CUSABIO offers the SSTR2 active protein product (Code: CSB-MP022725HU) to support your research on SSTR2 mechanism or its potential clinical value.
● Recombinant Human Somatostatin receptor type 2(SSTR2)-VLPs (Active)
The Specificity was validated by Western Blot. CSB-MP022725HU is detected by Mouse anti-6*His monoclonal antibody.
Immobilized Human SSTR2 at 10 μg/ml can bind Anti-SSTR2 recombinant antibody (CSB-RA022725MA01HU), the EC50 is 58.13-81.28 ng/mL.
The presence of VLP-like structures was confirmed by TEM
Blocking experiment on Anti-SSTR2 antibody (CSB-RA022725MA01HU) between Human SSTR2-VLPs protein and CT26/Human SSTR2 Stable Cells (CSB-SC022725HU) by Flow cytometry.
References
[1] Kumar, Ujendra, and Michael Grant. "Somatostatin and somatostatin receptors. "Cellular peptide hormone synthesis and secretory pathways (2009): 97- 120.
[2] Kumar, Ujendra, et al. "Subtype-selective expression of the five somatostatin receptors (hSSTR1-5) in human pancreatic islet cells: a quantitative double-label immunohistochemical analysis." diabetes 48.1 (1999): 77-85.
[3] Guillermet-Guibert, J., et al. "Physiology of somatostatin receptors." J Endocrinol Invest 28.11 (2005): 5-9.
[4] Gueorguiev, Maria, and Ashley B. Grossman. "A new therapeutic era for pituitary tumors." Nature Reviews Endocrinology 7.2 (2011): 71-73.
[5] Franko-Tobin, Laura G., et al. "Notch1-mediated tumor suppression in cervical cancer with the involvement of SST signaling and its application in enhanced SSTR-targeted therapeutics." the Oncologist 17.2 (2012): 220-232.
[6] Elliott, David E., et al. "SSTR2A is the dominant somatostatin receptor subtype expressed by inflammatory cells, is widely expressed and directly regulates T cell IFN-γ release." European journal of immunology 29.8 (1999): 2454-2463.
[7] Zhang Limeng., et al. "Physicochemical properties and bioinformatics analysis of Somatostatin Receptor 2." Guangxi Normal University Journal of Guangxi Normal University ( Natural Science Edition ): 2022.
[8] Ishida, Akiharu, et al. "Discovery and SAR Studies of Orally Active Somatostatin Receptor Subtype-2 (SSTR2) Agonists for the Treatment of Acromegaly." ACS chemical neuroscience 11.10 (2020): 1482-1494.
[9] Piqueras, Laura, and Vicente Martínez. "Role of somatostatin receptors on gastric acid secretion in wild-type and somatostatin receptor type 2 knockout mice." Naunyn-Schmiedeberg's archives of pharmacology 370.6 (2004): 510-520.
[10] Si, Yingnan, et al. "Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy." Cancer gene therapy 28.7 (2021): 799-812.
[11] Lehman, Jonathan M., et al. "Somatostatin receptor 2 signaling promotes growth and tumor survival in small-cell lung cancer." International journal of cancer 144.5 (2019): 1104-1114.
[12] Cakir, Mehtap, Dorota Dworakowska, and Ashley Grossman. "Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1 -molecular pathways." journal of cellular and molecular medicine 14.11 (2010): 2570-2584.
[13] Ben-Shlomo, Anat, and Shlomo Melmed. "Pituitary somatostatin receptor signaling." Trends in Endocrinology & Metabolism 21.3 (2010): 123-133.
[14] Eychenne, Romain, et al. "Overview of radiolabeled somatostatin analogs for cancer imaging and therapy." Molecules 25.17 (2020): 4012.
[15] Gustafsson, Bjorn I., et al. "Bronchopulmonary neuroendocrine tumors." Cancer 113.1 (2008): 5-21.
[16] Righi, Luisella, et al. "Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 'clinically aggressive' cases." Annals of Oncology 21.3 (2010): 548-555.
[17] Cracolici, Vincent, et al. "SSTR2 expression in olfactory neuroblastoma: clinical and therapeutic implications." Head and neck pathology 15.4 (2021) : 1185-1191.
[18] Vieria Neto, Leonardo, et al. "ZAC1 and SSTR2 are downregulated in non-functioning pituitary adenomas but not in somatotropinomas." ploS one 8.10 (2013): e77406. ): e77406.
[19] Kouch-el Filali, Mariam, et al. "Expression of the SST receptor 2 in uveal melanoma is not a prognostic marker." Graefe's Archive for Clinical and Experimental Ophthalmology 246.11 (2008): 1585-1592.
[20] Woelfl, S., et al. "Expression of somatostatin receptor subtype 2 and subtype 5 in thyroid malignancies." Nuklearmedizin-NuclearMedicine 53.05 (2014 ): 179-185.
[21] De Oliveira Silva, Camila Batista, et al. "Expression of somatostatin receptors (SSTR1-SSTR5) in meningiomas and its clinicopathological significance." International Journal of Clinical and Experimental Pathology 8.10 (2015): 13185.
[22] Kharmate, Geetanjali, et al. "Inhibition of tumor promoting signals by activation of SSTR2 and opioid receptors in human breast cancer cells." Cancer Cell International 13.1 (2013): 1-13.
[23] WANG, Xiao-you, Nan-zheng ZHANG, and Xing-song JIANG. "The expression of SSTR subtypes 2 and 5 and their clinical significance in human gastric cancers." Acta Academiae Medicinae Xuzhou (2007).
[24] Dimitrakopoulou-Strauss, Antonia, et al. "Quantitative assessment of SSTR2 expression in patients with non-small cell lung cancer using68Ga- DOTATOC PET and comparison with18F-FDG PET." European journal of nuclear medicine and molecular imaging 33.7 (2006): 823-830.
[25] Yu, Benxia, et al. "Clinical importance of somatostatin receptor 2 (SSTR2) and somatostatin receptor 5 (SSTR5) expression in thyrotropin-producing pituitary adenoma (TSHoma)." Medical Science Monitor: International Medical Journal of Experimental and Clinical Research 23 (2017): 1947.
[26] Kasuki, Leandro, et al. "Ki-67 is a predictor of acromegaly control with octreotide LAR independent of SSTR2 status and relates to cytokeratin pattern." Eur J Endocrinol 169.2 (2013): 217-223.
Comments
Leave a Comment