SSTR2: A Prominent Target in SSTR Family, Offers a More Precise Therapy in Neuroendocrine Tumors (NET)

1. How was the SSTR Family Discovered?

How was the SSTR family discovered? Initially, somatostatin (SST) was first identified in 1973 by Brazeau et al. in hypothalamic extracted from sheep ^[3], 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 ^[4-5]. 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) ^[6]. 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 ^[6]

*The Figure was derived from Nature Reviews Endocrinology publication ^[6]

2. What is SSTR2?

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) ^[3]. 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 ^[8]. By STRING protein network interactions analysis, SSTR2-interacting proteins include CORT, SST, NPY, GHRL, GNAI1, GNAI2, GNAI3, SHANK1, and HIVEP2 ^[9]. 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 ^[10].

Figure 2. Schematic diagram of SSTR2a structure ^[3]

*The Figure was derived from Cellular peptide hormone synthesis and secretory pathways publication ^[3]

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 ^[11]. Further studies have shown that SSTR2 is often highly expressed in several types of solid tumors, including neuroendocrine tumors and small cell lung cancer ^[12-13]. 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.

3. What's the Mechanism of Anti-Tumor Effects of SSTR2 Binding to SST?

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 ^[14-16] (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 ^[16]

*The Figure was derived from of Molecules Publications ^[16]

4. The Roles of SSTR2 in Tumors and Other Diseases

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.

4.1 SSTR2 and 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 ^[17-18]. 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 ^[19], pituitary adenoma ^[20], melanoma ^[21], thyroid cancer ^[22], meningioma ^[23], breast cancer ^[24], gastric cancer ^[25], lung cancer ^[26], etc. Therefore, SSTR2 is becoming an attractive target in tumor therapy, especially in NET.

4.2 SSTR2 and Other Diseases

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 ^[27-28]. 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.

5. SSTR2 Clinical Research Prospects

SSTR2-targeted therapies show significant clinical promise, with 66 medications in development across a variety of indications, as recorded in the Pharmsnap Database. These are being explored by 53 research entities in 297 clinical studies. The therapeutic drugs are diverse, including peptide-nucleotide conjugates, radiopharmaceuticals, synthetic peptides, small molecules, and antibodies. SSTR2, which is highly expressed in several solid tumors, particularly neuroendocrine and thyroid cancers, is targeted for its role in inhibiting cancer cell growth and proliferation. Existing SSTR2 drugs on the market address conditions like neuroendocrine tumors with Lutetium Dotatate LU-177 and acromegaly with Pasireotide Diaspartat. Additionally, the bispecific antibody CS-2012 from Cornerstone Pharmaceuticals is in preclinical stages, investigating its efficacy in treating solid tumors. These developments underscore the growing interest in SSTR2 as a therapeutic target, with implications for cancer, autoimmune, and neurological disease treatments (Table 1).

Table 1. Part SSTR2 clinical 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)

High Specificity Validated by Western Blot

The Specificity was validated by Western Blot. CSB-MP022725HU is detected by Mouse anti-6*His monoclonal antibody.

Excellent Bioactivity Validated by Functional ELISA

Immobilized Human SSTR2 at 10 μg/ml can bind Anti-SSTR2 recombinant antibody (CSB-RA022725MA01HU), the EC₅₀ is 58.13-81.28 ng/mL.

TEM

The presence of VLP-like structures was confirmed by TEM

FACS Blocking

Blocking experiment on Anti-SSTR2 antibody (CSB-RA022725MA01HU) between Human SSTR2-VLPs protein and CT26/Human SSTR2 Stable Cells (CSB-SC022725HU) by Flow cytometry.