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Ronny Allan
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!
Somatostatin
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 but not limited to, 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 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, e.g. MyCapssa). 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
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 most somatostatin receptor PETs (SSTR PETs) e.g. 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) and more recently 161Tb DOTA-LM3 which appears to be promising for PRRT as it offers advanced beta PRRT (“beta plus”) with the advantages of the antagonist approach over an agonist one.
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.
And this trial in 2022 uses a novel approach of re-energising the receptors, therefore, increasing the availability or efficacy. 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 / Cu64 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.
Measuring and Assessing Uptake: Krenning Score and Standarised Uptake Value (SUV)
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 standardised 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 The Krenning Score and Standarised Uptake Value (SUV).
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
Standardized Uptake Value
Quantify the expression of the somatostatin receptors (SSTR2) using the maximum Standardised 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 some NET specialists suggest the Krenning Score remains useful in SSTR PETs. Many studies have concluded that the SUVmax threshold of >16 to 17 is a guideline. Some study authors also point out this figure could even vary between different machines (including an effect of a calibration defect). Further research is required.
In general, this is something not easily understood by most patients and is far from being an exact science.
Please be careful when googling his issue as the SUVmax thresholds for regular FDG PETs appear to be smaller. Moreover, higher figures found in FDG PET guidance can potentially mean something different in SSTR-positive NETs.
If you wanted to gain an understanding of how to interpret SSTR PET scans which include the use of SUV figures, try this article below:
Summary
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.
General Clinical Trials Disclaimer
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The inclusion of any trial within this blog should not be taken as a recommendation by Ronny Allan.
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Good morning Ronny
I have gastric NET.
At the beginning of this journey, the doctors used Ga68 (in PET CT).
Since last year are using 18F instead Ga68.
What is the difference between both?, please.
What is your grade, differentation and Ki-67?
Hi Ronny,
I have NET cancer since at least 2008, where a doctor saw my primary tumor by CT scan and told me it was benign and not worry about it. I was crazy enough to believe him and not reach for a second advice. It was finally diagnosed properly in 2016, but then metastatized in the liver and bones at early grade 2. I got PRRT in 2017 and the cancer is stable since then. I am also on Sandostatin LAR. I have a biochemistry degree and worked in peptide synthesis all my career, especially on Somatocrinin, also known as GRF (Growth hormone releasing factor), the peptide hormone doing the opposite job of Somatostatin. An analog of this peptide is approved in the US and Canada as Egrifta. This is quite ironic.
I know you are following all the new approches to treat NETs. Maybe you are aware of it, but just in case I am bringing up to you two new ways that the centre where I got my PRRT treatments are working on. The first one is to give the PRRT patient an enzyme inhibitor to enhance the efficacy of PRRT. The idea is to inhibit the enzyme involved in reparing the DNA damaged by the radiations of Lu177. Inhibiting the DNA repairs would lead to more cancerous cells to die. You can read the early work about this on the following link
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=25266
Another team is working on a similar enzyme inhibitor approach. It seems very promising.
https://erc.bioscientifica.com/view/journals/erc/26/4/ERC-18-0509.xml
The other therapeutic approach they are working on is to give the PRRT patient some chemotherapy drug that would lead to further expression of the somatostation receptors on cancerous cells, wich would lead to more Lu177-peptide to be absorbed by tumor cells. Both are still at the research stage, but to me it is clear that improvments will be made to PRRT in the future, not to make it a cure, but to enhance its effect and its ability to contain NETs ans make it even more a chronic disease. Thanks again for your great work.
https://app.dimensions.ai/details/grant/grant.7619916
thanks, will read up on it. Hope you’re doing OK!
Helpful. Thanks Ronny.
A bit over my head but you’re doing an amazing job with your research!
Ronny, your dedication in posting a continuous stream of helpful and current information is truly much appreciated. I was misdiagnosed for 5 years and then found out it was stage IV NET. Had extensive surgery in July 2014. Your blog has been the main source of info for me. I’m now on Lanreotide monthly indefinitely, and find it much better than the Somatostatin depot I originally got in 2014. My best wishes for your continuing strength and health to keep up this work. And best wishes for your personal happiness and success as well. I also get your email notices and am very happy. They always seem to arrive on a “down day”. That helps a lot.
Thank you for your nice commemt Ruth.
You are wonderful Ronny. The only source I’ve found that really helps with understanding nets. Thank goodness for you!
thank you
Hi Ronny,The info is great, I was diagnosed last year with a midgut tumor .initially went for cyst on ovary a month later called in and told you have carcinoid in 1 ovary but its not a primary and we think we have spread it, that was june,2016 3 scans later, 29th sep Right Hemi colectomy, when I woke was told you have a few nodules under diaphragm,0ne 3mm on left liver lobe, and fewmore nudules in pelvic area, surgeon said you may go to net centre Manchester, next appointment no mention of anything just come once a month for lanreotide, I don’t understand any of it, does it mean no more surgery is ever possible, do I need a second opinion, can anyone shed any light for me, Pat.
I suspect they have ‘debulked’ what they can and consider you ‘stable’ (assumption on my part – you need to ask). I think it’s too early to say no more surgery but please note many people live with remnant tumours (check my background). What you need to (persistently) ask is:
1. What is the grade of my tumour(s)
2. What is the stage of my cancer and can I have my TNM status
3. Will I be discussed at a NET multidisciplinary team (MDT) (Christies is excellent and personally I would push to be moved to them for future monitoring).
.
thank you for sharing information without us
Ronny,
Are you hooked into netcancerawareness ???
Their recent meeting in Colorado with Dr Liu was amazing! Their lectures with Dr Oberg and many other world renown experts are posted on facebook. Just wanted to be sure you were aware because receptors were discussed. Take care and thanks for all you do
NET Cancer awareness group. Support systems, cancer education, and key resources to help. Maryann Wahmann and Robert Wahmann. Numerous doctors and health professionals
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I don’t follow this ogranisation Jean, I was very badly treated by them when I was establishing my blog. Still waiting on an apology.
Some of this is a bit technical, but overall very useful information! My doctors did a pretty good job of explaining a lot of this at the time of diagnosis, but there was so much to take in at that point and I definitely didn’t absorb it all.
My husband has had NET (carcinoid cancer) for the past 15 years and has had numerous surgeries. This past surgery they took out a large part of his pancreas. He has been having ongoing pain and digestive problems. He takes pancreatic enzymes and PPI pills. He had the surgery 4 months ago and is recovering very, very slowly. The reason that I am posting this is to see if anyone else on this blog has had an experience with this type of surgery or Is there a site you could suggest we go to to find more pancreatic information? Thanks so much.
Where are you please Mary?
Not the easiest of things to explain, but nice job👍
My head hurts 😀
I’m not surprised!!