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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Developed by Novartis, pasireotide (SigniforTM) (Figure 8.45) is the most recent somatostatin analog to be approved. Like octreotide and lanreotide, it is used to treat neuroendocrine (particularly carcinoid) and thyroid tumors, and acromegaly resulting from pituitary tumors. It has an advantage of a 40-fold increase in affinity for the Somatostatin Receptor 5 compared to the other two agents. Pasireotide is mainly used when a tumor cannot be removed surgically or fails to respond to other somatostatin analogues. Structure of pasireotide (SigniforTM).
Non-Obstructing Small Bowel Neuroendocrine Tumor with Liver Metastasis
Published in Savio George Barreto, Shailesh V. Shrikhande, Dilemmas in Abdominal Surgery, 2020
Mufaddal Kazi, Manish S. Bhandare, Vikram A. Chaudhari, Shailesh V. Shrikhande
Somatostatin receptor-based imaging is recommended to assess the receptor expression of the tumors in order to determine the benefit of octreotide-based treatment. Somatostatin receptor scintigraphy with Indium-111 labeled pentreotide, also known as Octreoscan, has been supplanted by Gallium (Ga)-68 DOTA positron emission tomography scans. Somatostatin receptor expression is a predictive marker for response to peptide receptor radionuclide therapy. In poorly differentiated or grade 3 neuroendocrine tumors, somatostatin avidity decreases with concomitant increase in 18-fludeoxyglucose uptake. In such situations, a combined DOTA and fluorodeoxyglucose scan can be ordered. Figure 22.1
Regulation of the Pituitary Gland by Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
GHRH was originally isolated from a pancreatic tumor taken from a patient with acromegaly and somatotroph hyperplasia. GHRH is derived from a 108-amino acid prepro-hormone, which gives rise to GBRH(l–40) and [1–44], both of which are found in the human hypothalamus. GHRH binds to a GPCR-type receptor, activates adenylate cyclase and stimulates transcription of the GH gene and GH release. Somatostatin [also called somatotropin release inhibitory factor (SRIF)] is derived from a 116-amino acid prohormone that gives rise to two forms, somatoatatin-28 and -14, both of which are cyclic peptides due to an intramolecular disulfide bond. Somatostatin inhibits GH secretion directly from the somatotrophs and also reduces the impact of ghrelin by inhibiting its secretion from the stomach. There are five somatostatin receptor (SSTR) subtypes, with SSTR2 and 5 the most abundant in the pituitary.
Piflufolastat F-18 (18F-DCFPyL) for PSMA PET imaging in prostate cancer
Published in Expert Review of Anticancer Therapy, 2022
Andrew F. Voter, Rudolf A. Werner, Kenneth J. Pienta, Michael A. Gorin, Martin G. Pomper, Lilja B. Solnes, Steven P. Rowe
The power of molecular imaging, including PSMA-PET, derives from the exquisite precision of the agents in combination with their modularity. While 18F-DCFPyL is exclusively an imaging agent, different warheads can be loaded onto the PSMA inhibitor delivery vehicle to address a range of clinical scenarios. This approach has been validated in neuroendocrine tumors. Somatostatin receptor PET/CT with 68Ga-labelled somatostatin analogues rapidly replaced 111In-based somatostatin receptor scintigraphy scans for imaging and staging of neuroendocrine tumors [108]. However, replacement of the gallium-68 PET imaging radionuclide with a lutetium-177 warhead yielded a therapeutic agent that has revolutionized the treatment of carcinoid tumors [109]. Similar efforts are underway for the PSMA agents, with initial trials showing favorable results for the treatment of metastatic castration-resistant prostate cancer [110–112]. The VISION trial, a prospective, phase III randomized trial, demonstrated that men with metastatic castration-resistant, PSMA-positive prostate cancer who were treated with 177Lu-PSMA-617 in addition to standard of care therapies had a significantly increased overall survival. This led to the FDA approval of 177Lu-PSMA-617 for use in this population in 2022 [113]. Further trials to explore the potential role of this agent earlier in the disease course are currently underway.
Metastatic neuroendocrine carcinoma presenting with left lateral rectus enlargement and orbital cellulitis
Published in Baylor University Medical Center Proceedings, 2021
Kevin Garrett Tayon, Vishal Kaila, Deepak Sobti, Ivan Vrcek
The patient underwent transconjunctival left orbitotomy with incisional biopsy and debulking of the lateral rectus lesion. Histopathologic analysis showed well-differentiated NET with uniform cells and regular nuclei with expression of neuroendocrine markers including chromogranin A and synaptophysin. Immunostaining revealed expression of CDX2 and villin, found in small intestine primary tumors (Figure 2). The Ki-67 proliferative index was low. Subsequent staging computed tomography (CT) revealed a 10 mm enhancing nodule in the small bowel mesentery. A 68Ga-DOTATATE scan revealed the focus of activity within the lateral aspect of the left orbit, the distal ileum, and an ileocolic mesenteric lymph node. Somatostatin receptor scintigraphy demonstrated no somatostatin-receptor positivity. At 2-month follow-up, the patient’s headache, diplopia, and afferent pupillary defect had resolved. Given the low volume of residual disease, further surgical debulking and systemic therapies were deferred.
Identification of somatostatin receptors using labeled PEGylated octreotide, as an active internalization
Published in Drug Development and Industrial Pharmacy, 2019
Somatostatin receptors (SSTRs) are memberships of the G-protein coupled receptor, GPCRs great family [1,2]. There are five subtypes of somatostatin receptors (SSTR1–5), while SSTR2 is classified into two subtypes, SSTR2A and SSTR2B [3,4]. The natural SST and its analogs bind with the receptor at a little nanomolar activity to yield distinct biological effects in all cells [2,5]. The SSTRs can be blocked with an antagonist to suppress the interaction with the receptor [6]. SSTRs are expressed in normal tissues such as monocytes, lymphocytes, duodenum, ovary, and myocardium. Moreover, SSTR2A is particularly expressed in many cells such as brain, pituitary, islet, stomach, and kidney [4,7]. Also, SSTRs are also expressed in numerous tumor cells such as small cell lung cancer [8–10], neuroendocrine cancer [11], breast cancer [12], and colorectal cancer [13]. Further, SSTR2 is expressed in numerous cancer such as glucagonoma 2 [14], metastatic lymph nodes [15], insulinoma [14,16–18], and pheochromocytoma [19]. Nevertheless, the majority of human tumors are mostly positive for SSTRs expression [20]. So, the identification of SSTR2 would be a favorable target for normal and diseased cells using branched labeled PEG as a very big molecule with nonspecific internalization [21]. These labeled branched PEGs would be useful also for the identification of cancer cells after attaching of the somatostatin analog octreotide, OCT. OCT was chosen as a ligand, as it is known for selectively bind to SSTR2.