Free Somatostatin Receptor Fraction Predicts the Antiproliferative Effect of Octreotide in a Neuroendocrine Tumor Model: Implications for Dose Optimization

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-12, Vol.73 (23), p.6865-6873
• Main Authors: HEIDARI, Pedram, WEHRENBERG-KLEE, Eric, HABIBOLLAHI, Peiman, YOKELL, Daniel, KULKE, Matthew, MAHMOOD, Umar
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Hormonal - administration & dosage; Antineoplastic Agents, Hormonal - pharmacology; Biological and medical sciences; Biomarkers, Tumor - metabolism; Cell Proliferation - drug effects; Chemical Fractionation; Dose-Response Relationship, Drug; Gallium Radioisotopes; Humans; Intestinal Neoplasms - diagnostic imaging; Intestinal Neoplasms - drug therapy; Intestinal Neoplasms - metabolism; Medical sciences; Mice; Mice, Nude; Neuroendocrine Tumors - diagnostic imaging; Neuroendocrine Tumors - drug therapy; Neuroendocrine Tumors - metabolism; Octreotide - administration & dosage; Octreotide - analogs & derivatives; Octreotide - pharmacology; Pharmacology. Drug treatments; Prognosis; Radionuclide Imaging; Rats; Receptors, Somatostatin - agonists; Receptors, Somatostatin - metabolism; Solubility; Treatment Outcome; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-1199

Somatostatin receptors (SSTR) are highly expressed in well-differentiated neuroendocrine tumors (NET). Octreotide, an SSTR agonist, has been used to suppress the production of vasoactive hormones and relieve symptoms of hormone hypersecretion with functional NETs. In a clinical trial, an empiric dose of octreotide treatment prolonged time to tumor progression in patients with small bowel neuroendocrine (carcinoid) tumors, irrespective of symptom status. However, there has yet to be a dose optimization study across the patient population, and methods are currently lacking to optimize dosing of octreotide therapy on an individual basis. Multiple factors such as total tumor burden, receptor expression levels, and nontarget organ metabolism/excretion may contribute to a variation in SSTR octreotide occupancy with a given dose among different patients. In this study, we report the development of an imaging method to measure surface SSTR expression and occupancy level using the PET radiotracer (68)Ga-DOTATOC. In an animal model, SSTR occupancy by octreotide was assessed quantitatively with (68)Ga-DOTATOC PET, with the finding that increased occupancy resulted in decreased tumor proliferation rate. The results suggested that quantitative SSTR imaging during octreotide therapy has the potential to determine the fractional receptor occupancy in NETs, thereby allowing octreotide dosing to be optimized readily in individual patients. Clinical trials validating this approach are warranted.