The Somatostatin Analog ¹⁸⁸Re-P2045 Inhibits the Growth of AR42J Pancreatic Tumor Xenografts

Abstract

P2045 is a peptide analog of somatostatin with picomolar affinity for the somatostatin receptor subtype 2 (SSTR2) upregulated in some pancreatic tumors. Studies were conducted in rat AR42J pancreatic tumor-xenograft mice to determine if Re-188-P2045 could inhibit the growth of pancreatic cancer in an animal model. Methods Re-188-P2045 was intravenously administered every 3 days for 16 days to nude mice with AR42J tumor-xenografts that were ≈ 20 mm3 at study initiation. Tumor volumes were recorded throughout the dosing period. At necropsy all tissues were assessed for levels of radioactivity and evaluated for histological abnormalities. Clinical chemistry and hematology parameters were determined from terminal blood samples. The affinity of non-radioactive Re-185/187-P2045 for somatostatin receptors was compared in human NCI-H69 and rat AR42J tumor-cell membranes expressing predominantly SSTR2. Results In the 1.85 and 5.55 mBq groups tumor growth was inhibited in a dose-dependent fashion. In the 11.1 mBq group tumor growth was completely inhibited throughout the dosing period and for 12 days after the last administered dose. The radioactivity level in tumors 4 hours post-injection was 10%ID/g, which was 2-fold higher than in the kidneys. Re-188-P2045 was well tolerated in all dose-groups with no adverse clinical, histological, or hematological findings. The non-radioactive Re-185/187-P2045 bound more avidly (0.2 nM) to SSTR2 in human than rat tumor membranes suggesting that these studies are relevant to human studies. Conclusion Re-188-P2045 is a promising therapeutic candidate for patients with somatostatin-receptor-positive cancer.

Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy

“…This optimization led to P2045, which showed better accumulation in the tumor, weaker retention in the kidneys, and faster urinary excretion than [ 99m Tc]-depreotide [ 186 ]. This new rhenium-based analog of depreotide, [ 188 Re]-P2045 ( Figure 11 ), went up to phase I in therapy for small cell lung cancer [ 187 ] and has shown promising in vivo results in the treatment of pancreatic tumors in mice [ 188 ]. To the best of our knowledge, no HYNIC-TOC/TATE or demotate derivatives have yet been radiolabeled with rhenium.…”

Rhenium-188 Radiochemistry: Challenges and Prospects

“…3+ core (and its Tc analogue) directly has been problematic; either they are poorly characterised [15] or studies using mass spectrometry and molecular modelling have shown that it leads to heterogeneous mixtures of multiple isomers and monomeric and dimeric structures [16][17][18][19]. This direct labelling approach is therefore not recommended as a strategy for peptide labelling.…”