Targeted Radiotherapy of Prostate Cancer with a Gastrin-Releasing Peptide Receptor Antagonist Is Effective as Monotherapy and in Combination with Rapamycin

Abstract

The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer and is an attractive target for radionuclide therapy. In addition, inhibition of the protein kinase mammalian target of rapamycin (mTOR) has been shown to sensitize various cancer cells to the effects of radiotherapy. Methods: To determine the effect of treatment with rapamycin and radiotherapy with a novel 177 Lu-labeled GRPr antagonist ( 177 Lu-RM2, BAY 1017858) alone and in combination, in vitro and in vivo studies were performed using the human PC-3 prostate cancer cell line. PC-3 cell proliferation and 177 Lu-RM2 uptake after treatment with rapamycin were assessed in vitro. To determine the influence of rapamycin on 177 Lu-RM2 tumor uptake, in vivo small-animal PET studies with 68 Ga-RM2 were performed after treatment with rapamycin. To study the efficacy of 177 Lu-RM2 in vivo, mice with subcutaneous PC-3 tumors were treated with 177 Lu-RM2 alone or after pretreatment with rapamycin. Results: Stable expression of GRPr was maintained after rapamycin treatment with doses up to 4 mg/kg in vivo. Monotherapy with 177 Lu-RM2 at higher doses (72 and 144 MBq) was effective in inducing complete tumor remission in 60% of treated mice. Treatment with 37 MBq of 177 Lu-RM2 and rapamycin in combination led to significantly longer survival than with either agent alone. No treatment-related toxicity was observed. Conclusion: Radiotherapy using a 177 Lu-labeled GRPr antagonist alone or in combination with rapamycin was efficacious in inhibiting in vivo tumor growth and may be a promising strategy for treatment of prostate cancer.

In Vitro and In Vivo Application of Radiolabeled Gastrin-Releasing Peptide Receptor Ligands in Breast Cancer

“…Up to now, GRP-R-based PRRT has been performed targeting prostate cancer, either in xenograft-bearing animals, with GRP-R agonists or antagonists (14,34), or in patients during a pilot study using 177 Lu-AMBA (24). However, GRP-R-based PRRT is not yet being applied in BC animal models or patients.…”

Radiopeptides for Imaging and Therapy: A Radiant Future

“…177 Lu-GRPR antagonists have not been tested in clinical studies thus far, even though they have shown promising results in preclinical studies (15). Radionuclide therapy using PSMA-targeted tracers has been more widely explored, as PSMA expression has been validated in advanced prostate cancer in several reports.…”

Targeted Radionuclide Therapy: Proceedings of a Joint Workshop Hosted by the National Cancer Institute and the Society of Nuclear Medicine and Molecular Imaging

“…Variability in toxicity, response, and organ dose has been identified but not yet entirely explained. Methods to account for these variabilities and accurately estimate delivered activity are under investigation, including the use of 111 In-based organ dosimetry (31).…”

“…Somatostatin receptors in NETs, particularly in carcinoids and gastroenteropancreatic tumors, were discussed with emphasis on the use of 111 In, 90 Y, and 177 Lu labels and theranostic agents. Somatostatin receptors, including the 5 subtypes (1, 2a and 2b, 3, 4, and 5) have been well described in the literature, and numerous studies have reported on the characteristics and affinities of radiolabeled somatostatin analogs, including 111 In-DTPA-octreotide (Octreoscan; Mallinckrodt Pharmaceuticals), 90 (86,87).…”

“…Somatostatin receptors, including the 5 subtypes (1, 2a and 2b, 3, 4, and 5) have been well described in the literature, and numerous studies have reported on the characteristics and affinities of radiolabeled somatostatin analogs, including 111 In-DTPA-octreotide (Octreoscan; Mallinckrodt Pharmaceuticals), 90 (86,87). Studies have addressed response rates, outcomes, the role of imaging (particularly PET/CT with 68 Ga-DOTATOC) in guiding therapeutic management, and the relative effectiveness of different radiolabeled somatostatin receptor agents (88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107).…”