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. 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’.
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 causing the clinical syndromes described above. ……. 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 over secretion (i.e. the syndrome). Examples of Somatostatin Analogue include Octreotide (Sandostatin), Lanreotide (Somatuline), and the not-so-well-known Pasireotide (Signifor).
How do Somatostatin Analogues actually work?
For the inhibition to work effectively, there needs to be a route into the oversecreting tumours, normally initiated by short or long-acting injections or even intravenously (other trials are looking at oral methods). On the tumour cells, there are currently 5 known subtypes 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 a 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.
Somatostatin receptors are found in high numbers on the surface of NET’s. Most receptors are in an inactive state (based on something called phosphorylation status).
According to Dr Kjell Oberg (Swedish NET guru), a unique feature of neuroendocrine tumours is that they express peptide hormone receptors. All five subtypes of somatostatin receptors are expressed in neuroendocrine tumours with dominance for receptor type 2 (SST2). Stimulation of SST2 can not only inhibit hormone release from the tumour, but also tumour cell growth. Midgut and Pancreatic NETs express about 80% of the tumors SST2 (with the exception for some insulinomas that have a lower expression (50%). The use of somatostatin analogues, Octreotide and Lanreotide, has been a real breakthrough in the management of many NETs.
Octreotide and Lanreotide mainly 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 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 radiolabelled 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 Ga68 PET or Cu64 PET scans which are more advanced and more sensitive than SRS. However, due to a phenomenon called “physiological uptake” whereby normal metabolic activity will show as radiotracer uptake potentially leading to interpretative pitfalls.
This explains why somatostatin receptor-based imaging has been successful in supporting the diagnosis and staging of many NETs. 111Indium-DTPA-octreotide (Octreoscan®) and SSTR PETs such as Ga68 and Cu64 can be applied for localisation and staging of NETs.
Additionally, for somatostatin receptor-positive NETs 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. Lutetium 177 (Lu-177). It binds with the SSTRs on the tumour cells and the radioactive payload attacks the tumour having been brought there by the somatostatin analogue 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 patients may not be able to respond correctly to SSA treatment or get the right results from Octreoscans/SSTR PETs e.g. Ga 68 PET / Cu64 PET and/or PRRT. However, that needs to be taken into context as well-differentiated NETs express SSTRs at an increased frequency and higher levels compared with poorly differentiated tumours. But some well-differentiated types will have issues and it’s not sure why. In insulinomas, it is thought likely because of low expression of SSTR2 by these tumours.
Scientists are looking at ways to bind to inactive receptors to increase therapy success. These types tend to be called antagonists rather than agonists you find now (for example see clinical trial OPS 201).
In another example of antagonist research, I recently wrote about the SSTR antagonist 177Lu-DOTA-LM3 which appears to be promising for PRRT although it is not yet in the clinical trials pipeline. It provides a favorable biodistribution and higher tumor radiation doses than SSTR agonists and was effective in treating advanced metastatic NENs, especially in patients with low or no SSTR agonist binding, even achieving complete remission in some patients. Read more here.
I was also pleased to see a piece of research ongoing to look at the issues with the lack of somatostatin receptors. The research is looking at novel imaging agents for NETs that do not have working receptors. Read more here.
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 first 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 by comparing stuff lighting up on the nuclear scan to stuff picked up on conventional imaging (e.g. CT/MRI). I also suspect that if your syndrome symptoms are abated somewhat by SSA injections, then 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 as one potential reason.
Immunohistochemical detection of SSTR2 is one way to work out if someone expressed these receptors (at least in SSTR2, the key receptor). It’s said to be a quick, reliable and effective tool that can provide useful information to specialists to support a therapeutic decision. Because the incidence of neuroendocrine tumours is still relatively low, specialised pathological units may be needed to perform such techniques. 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). This is still fairly crude though as the science is not exact. 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:
a. The Krenning score. This is used to grade the uptake intensity of neuroendocrine tumors on somatostatin receptor imaging. Although this dates back to the days of Octreotide scans, some radiologists suggest some utility in SSTR PETs (e.g. Ga68,Cu64). PRRT is normally considered when the Krenning score is greater than 2.
Relative uptake score
- 0: none
- 1: much lower than liver
- 2: slightly less than or equal to liver
- 3: greater than liver
- 4: greater than spleen
b. Quantify the expression of the somatostatin receptors (SSTR2) using the maximum Standardized Uptake Value (SUVmax) of SSTR PET scans (e.g. Ga68, Cu64) 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 is a guideline. The study authors also point out this could even vary between different machines (including an effect of a calibration defect). Further research is required.
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.
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