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 simplistic!
It’s important to understand this hormone and why your ‘butt dart’ is 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 hormones and peptides that can be over secreted by NETs. 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.
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.
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 intravenously (IV). On the tumour cells, there are currently 5 known ‘Somatostatin Receptors’ which are ‘expressed’ by most NETs. These are known as SSTR1 – SSTR5. The SSA will attempt to bind with these receptors to inhibit certain hormones and peptides.
Without going into too much technical detail, let’s just say the SSA binds to these receptors (or at least tries to). 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. Interesting to note that non-functional NETs do have SSTRs and SSAs will bind to them albeit less efficiently.
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|
|Carcinoid tumour of the gut||76||80||43||68||77|
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)|
Octreotide and Lanreotide seem to have high affinity for SSTR2 and 5 but Pasireotide (Signifor or SOM-230) is interesting as it appears to have affinity for SSTRs 1-3 and 5, probably why it has been approved for Acromegaly and Cushing’s Disease. 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 associated with hyperglycemia. You may find this video interesting as the doctor is suggesting it could be used by NET patients in certain scenarios.
What about SSA labelled diagnostics and therapies?
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 version of Octreotide (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 also apply to Ga 68 PET scans which are more advanced and more sensitive than SRS.
With (say) Peptide Receptor Radiotherapy (PRRT), there is a similar binding mechanism going on. In PRRT, Octreotide is combined with a therapeutic dose of the radionuclides, e.g. Yttrium 90 (Y-90) and Lutetium 177 (Lu-177). It binds with the SSRTs on the tumour cells and the therapeutic dose attacks the tumour having been brought there by the binding effect.
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 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 Ga 68 PET, could have a receptor issue. I suspect there is a more scientific method but I’m still looking for it!
I hope this gives you a very basic outline of why Somatostatin Receptors are important to support the diagnosis and treatment of NETs. Having just researched that, I can see that the researchers and the pharma industry will be working to produce more effective ‘binding agents’ to enhance diagnostics and treatment. I’ll maintain this blog as a ‘live’ feature making updates and improvements where necessary.
Thanks for reading
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