Hormone-Mimicking Drugs Are Used To Treat Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)


Neuroendocrine tumors (NETs) can arise wherever neuroendocrine (hormone-producing) cells are found—which is in most organs. Most NETs (65%-70%) are gastroenteropancreatic, or GEP, arising in different gastrointestinal organs. GEP-NETs are most commonly found in the small bowel (including the appendix), stomach, and rectum. Still, NETs in general are rare, which complicates the development of new treatments and identification of the genetic drivers of these cancers. Treatment of GEP-NETs is clearly an unmet medical need, and is now even more urgent because their incidence has been on the rise in the last 20 years.

Most GEP-NETs are not malignant and grow very slowly. Collectively, these are known as carcinoids (with the exception of pancreatic NETs). Surgical resection is the usual treatment for carcinoids, but most are never even detected and do not require treatment. However, about 9% of GEP-NETs are aggressive tumors with poor prognoses and a relative lack of effective treatment options. Treatment options for malignant GEP-NET are described below.

Because of their neuroendocrine origin, GEP-NETs may secrete excessive amounts of various hormones. Thus, patients may suffer from a variety of hormonal symptoms—from abdominal cramping and diarrhea to flushing and heart problems—which are collectively known as ‘carcinoid syndrome.’ For example, gastrointestinal NETs produce hormones like serotonin and substance P, while pancreatic NETs secrete insulin, glucagon, and gastrin.

Gastrointestinal NETs express somatostatin receptors, which guides most of the existing diagnostic and treatment strategies for these cancers. Somatostatin is an inhibitory hormone with many functions, including regulation of the digestive system and cell proliferation. Three homologues (similar synthetic molecules) of somatostatin have been developed—octreotide, lanreotide, and pasireotide. Of these, octreotide has been approved by the U.S. Food and Drug Administration (FDA) for controlling NET-related carcinoid syndrome. Octreotide is similar to somatostatin, but lingers longer in the body. It is also more potent in reducing the secretion of other hormones by GEP-NETs, thereby alleviating carcinoid syndrome. Octreotide is (or should be) used in practically all patients who develop carcinoid syndrome.

Increasingly, somatostatin homologues are used to treat NETs, rather than only to alleviate symptoms. The PROMID clinical trial showed that octreotide significantly extends progression-free survival (time without cancer worsening) in patients with NETs in the midgut, thereby clearing it for use as an anticancer drug. In December 2014, lanreotide was approved for treatment of metastatic GEP-NETs. In the phase III, randomized CLARINET trial, 65% of GEP-NET patients treated with lanreotide were still alive after 1 year, versus 33% in the placebo group.

More recently, clinical researchers have been exploring peptide-receptor radionuclide therapy (PRRT) for treatment of all NETs. In PRRT, lanreotide is attached to a radioactive metal, which is then selectively absorbed by tumors that express somatostatin receptors. PRRT drugs differ according to the type of radioactive isotope attached to lanreotide. For example, (177)Lu-DOTATATE contains radioactive lutetium, and (90)Y-DOTATOC contains Yttrium; the former is now generally thought to provide higher treatment efficacy and less toxicity. Several trials have tested PRRT in people with advanced NETs. It has been shown to induce complete or partial response in 20% of patients and minor response or tumor stabilization in 60% of patients, with responses lasting up to 3 years.

Pancreatic NETs are often considered to be a separate subgroup within the GEP-NET category, but treatment of pancreatic NETs could involve somatostatin homologues as well. In addition, the FDA has approved two other drugs—Sutent and Afinitor—for advanced pancreatic NETs, even though response rates are modest at best. Other potential treatments for NETs are being tested, including a very new type of drug, DCR-MYC. DCR-MYC targets a protein called MYC, which is expressed at high levels in neuroendocrine cancers and is implicated in their growth. Based on preliminary results, a phase I trial testing DCR-MYC in GEP-NETs has now been expanded specifically for patients with pancreatic NETs.