Now, neuroendocrine tumors come from neuroendocrine cells and exist normally. They all seem-at least probably 90%-seem to have receptor subtype 2 on them, and they're under strict regulatory control by native somatostatin. These tumors are under control as well by the congener of native somatostatin, which is, in this case, octreotide acetate. It has a predominant action via SST2, or somatostatin receptor subtype 2, to regulate the release of the peptide hormone in the normal neuroendocrine cell, for example gastrin, or insulin from the insulin neuroendocrine cell. And it has the same regulatory action in the neuroendocrine cell gone awry; enterochromaffin cells causing serotonin release, or a gastrin tumor causing excess gastrin release. It regulates it. It decreases it, inhibits the release of that hormone from its tumor. It also is antiproliferative, and that's very remarkable. But for the most part it stabilizes the tumor. It's really tumor static, and it's by way of the SST2. I'm not saying much about SST1 and SST5. We don't know that much. It may well be that the partner for SST2 action may be the receptor subtype 5.

We're learning from Patel and his group in Canada that 5 may be a very important facilitator in for the action of SST2 to receive the peptide or the congener, and then to move it inside the cell. Maybe SST1 might be a decoy receptor-we don't know.

It's very interesting, though. Native somatostatin doesn't have the same affinity for each of its receptor subtypes. One of its highest affinities is for receptor subtype 2, and the lowest probably for receptor subtype 5. That just doesn't seem to be a high affinity for receptor subtype 5, and that makes a bit of sense, because the beta cell seems to have more receptor subtype 5.

If you look at native somatostatin and you look at the congener, it does everything it can not to mess with insulin.

Of all the neuroendocrine tumors that we talk about, insulinoma is the least responsive to somatostatin therapy. In fact, it can be dangerous if you use congener therapy initially without checking first, because if they don't have receptors for SST2, then you may have inhibition of glucagon, insulin being unantagonized, and it will cause profound hypoglycemia.
It appears that, to the best of my knowledge, once a neuroendocrine tumor metastasizes, they all assume the mantle of SST2 upregulation, so that all the malignant insulinomas that have metastasized have SST2 and will respond to somatostatin congener therapy. That's remarkable.
Medullary thyroid cancer is another that upregulates receptor subtype 2 when it metastasizes. To me that's very interesting: it offers you a biotherapeutic that you might not have in some of these tumors.

Thomas O'Dorisio MD