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Cholecystokinin 2 Receptor Agonist 177Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study.

ABSTRACT: Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177Lu-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH2 (177Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (?80 ?g) of 177Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of 177Lu-PP-F11N to assess safety. Results: In all patients, 177Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85-1.04), 0.42 (IQR: 0.25-1.01), 0.11 (IQR: 0.07-0.13), and 0.028 (IQR: 0.026-0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11-14.4) without SG and 13.0 (IQR: 10.2-18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14-4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: 177Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, 177Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177Lu-PP-F11N.

SUBMITTER: Rottenburger C

PROVIDER: S-EPMC7198370 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Cholecystokinin 2 Receptor Agonist 177Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study.

Rottenburger Christof C Nicolas Guillaume P GP McDougall Lisa L Kaul Felix F Cachovan Michal M Vija A Hans AH Schibli Roger R Geistlich Susanne S Schumann Anne A Rau Tilman T Glatz Katharina K Behe Martin M Christ Emanuel R ER Wild Damian D

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20190913 4

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177Lu-DOTA-(d-Glu)6-Ala- ...[more]

PMID: 31519804

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Project description:Rationale: A high tumor-to-healthy-tissue uptake ratio of radiolabeled ligands is an essential prerequisite for safe and effective peptide receptor radionuclide therapy (PRRT). In the present study, we searched for novel opportunities to increase tumor-specific uptake of the radiolabeled minigastrin analogue [177Lu]Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2 ([177Lu]Lu-PP-F11N), that targets the cholecystokinin B receptor (CCKBR) in human cancers. Methods: A kinase inhibitor library screen followed by proliferation and internalization assays were employed to identify compounds which can increase uptake of [177Lu]Lu-PP-F11N in CCKBR-transfected human epidermoid carcinoma A431 cells and natural CCKBR-expressing rat pancreatic acinar AR42J cells. Western blot (WB) analysis verified the inhibition of the signaling pathways and the CCKBR level, whereas the cell-based assay analyzed arrestin recruitment. Biodistribution and SPECT imaging of the A431/CCKBR xenograft mouse model as well as histological analysis of the dissected tumors were used for in vivo validation. Results: Our screen identified the inhibitors of mammalian target of rapamycin complex 1 (mTORC1), which increased cell uptake of [177Lu]Lu-PP-F11N. Pharmacological mTORC1 inhibition by RAD001 and metformin increased internalization of [177Lu]Lu-PP-F11N in A431/CCKBR and in AR42J cells. Analysis of protein lysates from RAD001-treated cells revealed increased levels of CCKBR (2.2-fold) and inhibition of S6 phosphorylation. PP-F11N induced recruitment of β-arrestin1/2 and ERK1/2 phosphorylation. In A431/CCKBR-tumor bearing nude mice, 3 or 5 days of RAD001 pretreatment significantly enhanced tumor-specific uptake of [177Lu]Lu-PP-F11N (ratio [RAD001/Control] of 1.56 or 1.79, respectively), whereas metformin treatment did not show a significant difference. Quantification of SPECT/CT images confirmed higher uptake of [177Lu]Lu-PP-F11N in RAD001-treated tumors with ratios [RAD001/Control] of average and maximum concentration reaching 3.11 and 3.17, respectively. HE staining and IHC of RAD001-treated tumors showed a significant increase in necrosis (1.4% control vs.10.6% of necrotic area) and the reduction of proliferative (80% control vs. 61% of Ki67 positive cells) and mitotically active cells (1.08% control vs. 0.75% of mitotic figures). No significant difference in the tumor vascularization was observed after five-day RAD001 or metformin treatment. Conclusions: Our data demonstrates, that increased CCKBR protein level by RAD001 pretreatment has the potential to improve tumor uptake of [177Lu]Lu-PP-F11N and provides proof-of-concept for the development of molecular strategies aimed at enhancing the level of the targeted receptor, to increase the efficacy of PRRT and nuclear imaging.

Project description:Abstract Introduction: Despite the introduction of new molecular targeted therapies, there is still an unmet need for an effective systemic therapy for advanced medullary thyroid carcinoma (MTC). As MTC expresses cholecystokinine-2 (CCK-2) receptors at a high incidence and density, targeting the CCK-2 receptor with radiolabelled gastrin analogues is a potential approach for radionuclide therapy. Unfortunately, kidney and bone marrow toxicity precluded therapeutic applications of CCK-2 receptor specific radiotracers until now. The aim of this prospective study is the feasibility testing of targeting CCK-2 receptors with the novel gastrin analogue [177Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nleu-Asp-PheNH2] (177Lu-PP-F11N) in six patients with advanced MTC (ClinicalTrials.gov: NCT02088645). Subjects and Methods: Six patients received two injections of 1 GBq 177Lu-PP-F11N, one injection with and the other without Physiogel (Gelofusin = plasma expander for nephroprotection) infusion. Planar scintigraphy and SPECT/CT scans were performed at several time points for up to 72 h post injection in order to calculate tumour- and organ doses using 3D voxel- and MIRD based dosimetry (Dosimetry Research Tool v5.2, Siemens Medical Solutions, USA). Blood samples were taken for bone marrow dose calculations. ECG, blood count and blood chemistry were measured up to 12 weeks after the second administration of 177Lu-PP-F11N in order to evaluate adverse events. Results: Adverse reactions (mainly hypotension, flushing and hypokalemia) were self-limiting and not higher than grade 1, according to CTCAE version 4.03. In all patients, 177Lu-PP-F11N accumulation was visible in tumor tissue, in the kidneys, stomach and the colon. Altogether, 14 tumours were eligible for dosimetry. The median (range) radiation dose for tumours, kidneys and bone marrow was 0.88 Gy/GBq (0.69-2.85), 0.090 (0.045-0.115) and 0.010 (0.008-0.016). These resulted in median tumour-to-kidney dose ratios of 12.8 (6.0-52.4) (without Physiogel) and 12.4 (6.4-29.8) (with Physiogel), which was not significantly different. The median tumour-to-bone marrow dose ratio was 87.9 (52.8-316.4). Discussion/Conclusion: The administration of the novel CCK-2 receptor ligand 177Lu-PP-F11N was safe in all six examined patients. Visualization of metastasized/recurrent disease in all patients provides evidence that CCK-2 receptor targeting with 177Lu-PP-F11N is feasible in patients with MTC. The dosimetry results indicate tumour doses that could enable radionuclide therapy. Dosimetry results for kidneys and bone marrow revealed low organ doses, as well as excellent tumour-to-kidney and tumour-to-bone marrow ratios. Further studies will be necessary to evaluate the theranostic potential of 177Lu-PP-F11N in patients with CCK-2 receptor expressing tumours.

Dataset Information

Cholecystokinin 2 Receptor Agonist 177Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study.

Publications

Cholecystokinin 2 Receptor Agonist <sup>177</sup>Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study.

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