Neuroendocrine Cancer: Somatostatin Receptors

ct compare to g68 pet
CT and G68 PET fused showing somatostatin receptor pick up

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!

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 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 ‘Somatostatin Receptors’ which are ‘expressed’ by most NETs.   These are known as SSTR1 – 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 advantageous to target SSTR2.

Somatostatin Receptors

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 might not have efficient SSTRs but SSAs will still try to bind to them albeit it might not work or have a lesser effect.

Table 1 – Somatostatin receptor subtypes in neuroendocrine tumours (mRNA) (See Copyright)

Tumour SSTR1 (%) SSTR2 (%) SSTR3 (%) SSTR4 (%) SSTR5 (%)
Gastrinoma 79a 93 36 61 93
Insulinoma 76 81 38 58 57
Non-functioning pancreatic tumour 58 88 42 48 50
Gastro-intestinal NET 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.

Compound SSTR1 SSTR2 SSTR3 SSTR4 SSTR5
RECEPTOR SUBTYPE AFFINITY (IC50, nM)
Octreotide 1140 0.56 34 7030 7
Lanreotide 2330 0.75 107 2100 5.2
Pasireotide 9.3 1 1.5 >100 0.16

View it in a separate window

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, probably why it has been approved for Cushing’s Disease (ATCH producing).  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?

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 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.

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  – read more here

lutathera owl - Copy


Somatostatin Receptor Research – Interest Point

I was please 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.

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.

Thanks for reading

Ronny

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

Author: Ronny Allan

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13 thoughts on “Neuroendocrine Cancer: Somatostatin Receptors”

  1. 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.

  2. 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.

    1. 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).
      .

  3. 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

    ________________________________

  4. 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.

  5. 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.

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