Cholecystokinin‐B (CCK‐B)/gastrin receptor targeting peptides for staging and therapy of medullary thyroid cancer and other CCK‐B receptor expressing malignancies
Authors: Béhé Martin , Behr Thomas M. 
Published: March 2003

Nuclear medicine is engaged with the detection of pathological processes with the help of radionuclides. An interesting approach is to target antigens, symporters, or receptors with diagnostic and therapeutic radionuclides.

Different peptide receptors like somatostatin, bombesin/GRP or VIP are (over)expressed on cancer cells, and are therefore an ideal target for the diagnosis and therapy in nuclear medicine with radiolabeled peptides. The somatostatin analogue OctreoScan [octreotide coupled with diethylene–triamine–pentaacetate (DTPA)] can be labeled with In‐111 and is widely used in nuclear oncology for the staging of different tumors (e.g., carcinoids). Other peptides like neurotensin, bombesin/GRP, and VIP are under (pre)clinical investigations.

The staging of metastatic medullary thyroid cancer (MTC) with the conventional radiological procedures is sometimes difficult. The high sensitivity of the pentagastrin stimulation test in detecting primary or metastatic MTC indicates the presence of tumor, but its localization is often not possible. This reaction of the tumor cells to the pentagastrin stimulation test suggests a widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies demonstrated cholecystokinin (CCK)‐B/gastrin receptors not only in over 90% of MTCs, but in a high percentage of small cell lung cancers, stromal ovarian, and potentially a variety of other tumors, including gastrointestinal adenocarcinomas, neuroendocrine tumors, and malignant glioma.

The aim of our recent work was to develop and systematically optimize suitable radioligands for targeting CCK‐B receptors in vivo and to investigate their role in the staging and therapy of MTC and other CCK‐B receptor expressing malignancies. For this purpose, a variety of CCK/gastrin‐related peptides, all having in common the C‐terminal CCK receptor binding tetrapeptide sequence TrpMetAspPheNH2 or derivatives thereof, were investigated. They were members of the gastrin‐ or cholecystokinin families, or possessed characteristics of both, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied and optimized in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in preclinical models. Best tumor uptake and tumor‐to‐nontumor ratios were obtained with members of the gastrin family, due to their superior selectivity and affinity for the CCK‐B receptor subtype. Radiometal‐labeled derivatives of minigastrin showed excellent targeting of CCK‐B receptor expressing tissues in animals and healthy human volunteers. Preclinical therapy experiments in MTC‐bearing animals showed significant antitumor efficacy.

In a subsequent clinical study, 75 MTC patients with metastatic MTC were investigated; 43 suffered of known, 32 of occult disease. CCK‐B receptor scintigraphy was performed with 111In–DTPA–D‐Glu1–minigastrin. The normal organ uptake was essentially confined to the stomach (and to a lower extent, to the gallbladder and, in premenopausal women, to normal breast tissue) as a result of CCK‐B receptor specific binding, and to the kidneys as excretory organs. All tumor manifestations known from conventional imaging were visualized as early as 1 h p.i., with increasing tumor‐to‐background ratios over time; at least one lesion was detected in 29/32 patients with occult disease (patient‐based sensitivity 91%). Among them were local recurrences, lymph node, pulmonary, hepatic, splenic, and bone (marrow) metastases.

Eight patients with advanced metastatic disease were injected in a dose‐escalation study with potentially therapeutic activities of a 90Y‐labeled minigastrin derivative at 4–6‐weekly intervals (30–50 mCi/m2 per injection for a maximum of four injections). Hematologic and renal were identified as the dose‐limiting toxicities at the 40 and 50 mCi/m2 levels. Two patients experienced partial remissions, 4 stabilization of their previously rapidly progressing disease.

These data suggest that CCK‐B receptor ligands may be a useful new class of receptor binding peptides for diagnosis and therapy of a variety of (CCK‐B receptor expressing) tumor types. They allow for a sensitive and reliable staging of patients with metastatic MTC. Initial therapeutic results are promising, but nephrotoxicity is a major concern to be solved. © 2003 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 66: 399–418, 2002