Don’t understand Somatostatin Receptors? Join the club! I got my head around the term ‘Somatostatin’ and ‘Somatostatin Analogues’ some time ago but the term ‘Somatostatin Receptor’ (SSTR) is still a bit of a mystery and it’s come to the top of my list of things to study. SSTRs do come up in conversation quite often and I’m fed up of nodding sagely hoping it will eventually become clear! On analysis it looks like a technical subject – and therefore a challenge 🙂
I’ve taken a logical approach working from ‘Somatostatin’ to ‘Somatostatin Analogue’ before commencing on the ‘receptor’ bit. It is intentionally brief and (hopefully) simplistic!
It’s important to understand this hormone and then why your ‘butt dart’ is generically called a ‘Somatostatin Analogue’.
Some Neuroendocrine Tumours secrete hormones and peptides that cause distinct clinical syndromes, including amongst others, carcinoid syndrome. Somatostatin is a naturally occurring hormone and a known inhibitor of some of these NET related hormones and peptides that can be over secreted and cause syndromes. For example, somatostatin from the hypothalamus inhibits the pituitary gland’s secretion of growth hormone (GH) and Thyroid Stimulating Hormone (TSH). In addition, somatostatin is produced in the pancreas and inhibits the secretion of other pancreatic hormones such as insulin and glucagon. However, the naturally produced Somatostatin does not have the lifespan to have any effect on Neuroendocrine Tumours which are over secreting these hormones and peptides. ……. cue manufactured versions that can!
Somatostatin Analogue (SSA)
These are manufactured versions of Somatostatin known as Somatostatin Analogues. These are designed to have a lasting effect to inhibit for much longer and therefore reduce the symptoms caused by the over secretion (i.e. the syndrome). Examples of Somatostatin Analogue include Octreotide (Sandostatin), Lanreotide (Somatuline) and Pasireotide (Signifor).
So how do Somatostatin Analogues actually work?
For the inhibition to work effectively, there needs to be a route into the over secreting tumours, normally via short or long acting injections or even intravenously. On the tumour cells, there are currently 5 known sub-types of ‘Somatostatin Receptors’ (SSTR) which are ‘expressed’ by most NETs. These are known as SSTR1 through to SSTR5. The naturally occurring hormone Somatostatin attempts to bind with all 5 but as above, it lacks the lifespan to make any impact to inhibit sufficiently in cases of overecretion. However, SSAs can overcome this with the longer lifespan. They can successfully in most cases bind with these receptors to inhibit the hormones and peptides causing the problems, particularly SSTR2 with modest affinity to SSTR5. Clearly it’s therefore advantageous to target SSTR2.
The subtypes expressed by NETs are variable and the efficiency of different SSAs in binding to each SSTR subtype also varies. For example the table below lists the variability of Somatostatin Receptor efficiency in different types of NET. This does not have any effect on the anti-tumour function.
Somatostatin receptors are found in high numbers on the surface of NET’s. Most receptors are in the inactive state (based on something called the phosphorylation status). Traditionally, agents such as dotatate have only bound to activated receptors on the surface. Scientists are looking at ways to bind to inactive receptors to increase therapy success (for example see clinical trial OPS 201)
Table 1 – Somatostatin receptor subtypes in neuroendocrine tumours (mRNA) (See Copyright)
|Tumour||SSTR1 (%)||SSTR2 (%)||SSTR3 (%)||SSTR4 (%)||SSTR5 (%)|
|Non-functioning pancreatic tumour||58||88||42||48||50|
This table above clearly shows the variability of SSTRs when binding with different types of NETs. It follows that manufacturers of SSAs will be using this data in the formulation of their drugs. If you now look at the table below, you can see how efficiently the 3 well-known SSAs inhibit NETs on each SSTR.
Table 2 – Somatostatin receptor subtype-binding affinity of somatostatin analogues (See Copyright)
|RECEPTOR SUBTYPE AFFINITY (IC50, nM)|
You can see from the data why Octreotide and Lanreotide target SSTR2 and to a lesser extent SSTR5 but Pasireotide (Signifor or SOM-230) is interesting as it appears to have affinity for SSTRs 1-3 and 5, possibly connected to its Cushing’s Disease (ATCH producing) approval. However, to date, there has not been enough evidence showing that Pasireotide has a progression-free survival benefit over the other 2 therapies. It is also heavily associated with hyperglycemia. You may find this video interesting as the doctor (Strosberg) is suggesting it could be used by NET patients but only in certain scenarios.
What about SSA labelled diagnostics?
The same principles apply. For example, an Octreotide Scan (actually known as ‘Somatostatin Receptor’ Scintigraphy (SRS)) works by taking pictures using a gamma camera which is designed to see radiation from a ‘tracer’. The tracer in question is a radio labelled with an Octreotide variant (such as pentetreotide) which will bind to somatostatin receptors on the surface of the tumour cells In the simplest of terms, this shows up where NETs are. The same principles apply to Ga 68 PET scans which are more advanced and more sensitive than SRS.
What about SSA labelled therapies?
With (say) Peptide Receptor Radiotherapy (PRRT), there is a similar binding mechanism going on. In PRRT, Octreotide or a variant, is combined with a therapeutic dose of the radionuclides, e.g. Yttrium 90 (Y-90) and Lutetium 177 (Lu-177). It binds with the SSTRs on the tumour cells and the therapeutic dose attacks the tumour having been brought there by the binding effect. Simple isn’t it?
Do Somatostatin Receptors work for everyone?
Unfortunately not. Some people have more sensitive receptors than others and the figure of 80% appears to be the most common statistic indicating one-fifth of all NET patients may not be able to respond correctly to SSA treatment or get the right results from Octreoscans/Ga 68 PET and/or PRRT. However, that needs to be taken into context and probably applies to midgut NETs measured against SSTR2 – the tables above tend to confirm this figure. During my research, I did read that higher than normal doses of SSAs may have some effect on those with less sensitive SSTRs. Also, SSAs seem to work much better with well-differentiated tumours.
How do I know if my Somatostatin Receptors work?
When I was completing my NET checks after diagnosis, my Oncologist declared I was “Octreotide avid” shortly after my Octreoscan was compared with my CT. I’m guessing that is a simple and crude test and how most people find out they have working receptors. I also suspect that if your syndrome symptoms are abated somewhat by SSA injections, then you there is a good chance your SSTRs are working normally. I also suspect those who show clear signs of tumour on CT but not on Octreoscan or Ga68 PET, might have a receptor issue.
Immunohistochemical detection of SSTR2 is one way to work out if someone expressed these receptors (at least in SSTR2, the key receptor. It’a said to be a quick, reliable and effective tool that can provide useful information to the specialists to support a therapeutic decision. Because the incidence of the neuroendocrine tumours is still relatively low, specialised pathological units may be needed to perform such technique. One study also noted there was no correlation between the expression of SSTR2 and the Chromogranin A levels, the grades or the hormonal activity/inactivity of the NETs.
The advent of modern PET scanning (e.g. Ga68) has meant more accurate methods of working out if someone has the right receptors for PRRT through analysis of something known as standardized uptake values (SUV).
A more modern approach is to use a ‘Theranostic Pair” where the same radiolabelled tracer is used with the advantage that the diagnostic element can predict suitability for the therapy component. The quantification of the uptake can help decide whether a patient is suitable for radionuclide therapy such as PRRT. This involves assessments using measurement standards such as:
- The Krenning score. This is used to grade the uptake intensity of neuroendocrine tumors on somatostatin receptor imaging. Typically, PRRT is considered when the Krenning score is greater than 2.
- Quantify the expression of the somatostatin receptors (SSTR2) using the maximum Standardized Uptake Value (SUVmax) of Ga68 PET scans to predict the response probability of PRRT in NETs. There is no set standard for this measurement but many studies have concluded that the SUVmax threshold of >16 to 17 as a guideline. The study authors also pointed out this could every vary between different machines and further research is required.
Somatostatin Receptor Research – Interest Point
I was pleased to see a piece of research ongoing to look at the issues with lack of somatostatin receptors. The research is looking at novel imaging agents for NETs which do not have working receptors. Read more here.
I hope this gives you a very basic outline of why Somatostatin Receptors are important to support the diagnosis and treatment of NETs.
My article “If you can see it, you can detect it” is almost 100% accurate but having working receptors really helps with nuclear scans.
Preclinical and clinical studies have indicated that somatostatin receptor (SSTR) expressing tumors demonstrate higher uptake of radiolabeled SSTR antagonists than of the currently approved SSTR agonist versions. See clinical trial OPS 201 for an example of the next generation of somatostatin receptor based theranostics where the use of somatostatin antagonists can potentially increase the numbers of available receptors.
thanks for reading