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RDC Development for Neuroendocrine Tumors

As a novel cancer treatment drug, RDC (Radionuclide Drug Conjugate) can be used to treat neuroendocrine tumors through the guidance of targeted molecules.

Introduction into Neuroendocrine Tumors

The neuroendocrine (NE) system distributes in the whole body, including the central nervous system, the larynx, gastrointestinal (Gl) tract, thyroid, skin, breast, and urogenital system. The gastrointestinal tract and lungs are the most common primary tumor sites, as well as digestive and respiratory tracts, known as the diffuse endocrine system. Cancer in this area is called neuroendocrine tumors (NETs), a heterogeneous group of malignancies.

Epidemiology of Neuroendocrine Tumors

Neuroendocrine tumors account for about 0.5% of all newly diagnosed malignancies with an increased incidence of 5.86 per 100 thousand a year with a female preponderance of around 2.5:1, 12% to 22% of which are metastatic at presentation. Among the wide distribution area of neuroendocrine, the most frequent primary sites of neuroendocrine tumors are the gastrointestinal tract (62%-67%) and the lung (22%-27%).

Types and Symptoms

  • Carcinoid Tumors in the Luminal Gastrointestinal Tract

Appendiceal neuroendocrine neoplasms (NENs) are usually diagnosed postoperatively in the specimens of appendectomies with a large female preponderance.
Gastric neuroendocrine neoplasms can be divided into three types. The first one is associated with chronic atrophic gastritis type. The Second one is associated with Zollinger-Ellison syndrome and MEN-1 syndrome. The last one is the sporadic, large, solitary, and invasive tumor, occasionally with an atypical carcinoid syndrome mediated by histamine and serotonin.
Colorectal neuroendocrine neoplasms are associated with a more aggressive clinical course and a poorer prognosis than adenocarcinomas, which can be divided into two subtypes, including small-cell carcinomas and moderately differentiated neuroendocrine carcinomas.

  • Pancreatic Neuroendocrine Tumors

Insulinomas, the most common gastrointestinal neuroendocrine tumor, may appear with symptoms such as excessive insulin secretion, leading to symptoms of hypoglycemia and hypokalemia.
Gastrinomas are usually located in the pancreas and duodenum in older males, which may appear as symptoms as stomach acid hypersecretion.
Palomas (Pancreatic Polypeptide-Secreting Tumors) present with weight loss, jaundice, and abdominal pain.
VIPomas (Vasoactive Intestinal Peptide–Secreting Tumors) can lead to a syndrome initially, arising from the pancreas in 90% of adult cases.
Glucagonomas are extremely rare pancreatic tumors with overproduction of the counterregulatory hormone glucagon.
Somatostatinomas are primarily located in the pancreas and duodenum.

NETs may be divided by site of origin: foregut, midgut, and hindgut.Figure 1. Neuroendocrine tumors may be divided by site of origin: foregut, midgut, and hindgut.
(Oronsky, B., et al., 2017, Neoplasia)

Traditional Therapy for Neuroendocrine Tumors

Since most neuroendocrine tumors are diagnosed after metastases, surgery is not possible, leading to the requirement of a chronic medical strategy to relieve symptoms and suppress tumor growth and spread. However, traditional surgery may still be indicated for palliative debulking to decrease tumor burden and help control hormone production. Another option is hepatic-directed procedures, including ablative therapy, transarterial embolization, transarterial chemoembolization, and selective internal radiation therapy with 90-Y microspheres.

Fortunately, novel systemic options approved include somatostatin analogs, peptide receptor radionuclide therapy (PRRT), low-dose interferon, everolimus, sunitinib, bevacizumab, and cytotoxic regimens to be applied in neuroendocrine tumors treatment.

Neuroendocrine Tumors Treatment with RDC

Well-differentiated neuroendocrine tumors show subtle responses to conventional chemotherapy as a result of their slow proliferation rate. Notably, the expression of SSR2 (somatostatin receptor subtype-2) is a popular targeted molecule in NET. The alpha emitters 225Ac and 213Bi used to label the somatostatin analog DOTATOC have demonstrated promising antitumor effects in animal studies, which supports the 213Bi-DOTATOC, as a newly discovered RDC (Radionuclide Drug Conjugate), offers effective therapy to neuroendocrine tumor patients by directly delivering to metastases via intraarterial administration might.

Illustration of radionuclide-labeled octreotide analog DOTATOC binding to the SSR2.Fig.2 Illustration of radionuclide-labeled octreotide analog DOTATOC binding to the SSR2.
(Kratochwil, C., et al., 2014, Eur J Nucl Med Mol Imaging)

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  1. Oronsky, B., Ma, P. C., Morgensztern, D., & Carter, C. A. (2017). Nothing but NET: a review of neuroendocrine tumors and carcinomas. Neoplasia, 19(12), 991-1002.
  2. Kratochwil, C., Giesel, F. L., Bruchertseifer, F., Mier, W., Apostolidis, C., Boll, R., ... & Morgenstern, A. (2014). 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience. Eur J Nucl Med Mol Imaging, 41(11), 2106-2119.
For research use only. Not intended for any clinical use.

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