The Balance Between the Therapeutic Efficacy and Safety of [177Lu]Lu-NeoB in a Preclinical Prostate Cancer Model

Abstract

Purpose: Radiolabeled NeoB is a promising gastrin-releasing peptide receptor (GRPR)-targeting radiopharmaceutical for theranostics of GRPR-expressing malignancies, e.g., prostate cancer (PCa). The aim of this study was to evaluate the effect of different doses of [¹⁷⁷Lu]Lu-NeoB on the balance between therapeutic efficacy and safety in a preclinical PCa model.

Procedures: To determine the efficacy of [¹⁷⁷Lu]Lu-NeoB, PC-3 xenografted mice received 3 sham injections (control group) or 3 injections of 30 MBq/300 pmol, 40 MBq/400 pmol, or 60 MBq/600 pmol [¹⁷⁷Lu]Lu-NeoB (groups 1, 2, and 3, respectively) 1 week apart. To quantify tumor uptake, single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed 4 h after the first, second, and third injection on a separate group of animals. For safety evaluations, pancreatic and renal tissues of non-tumor-bearing mice treated with the abovementioned [¹⁷⁷Lu]Lu-NeoB doses were evaluated 12 and 24 weeks post-treatment.

Results: Treatment of PC-3 tumors with all three studied [¹⁷⁷Lu]Lu-NeoB doses was effective. Median survival times were significantly (p < 0.0001) improved for treatment groups 1, 2, and 3 versus the control group (82 days, 89 days, 99 days versus 19 days, respectively). However, no significant differences were observed between treatment groups. Quantification of SPECT/CT images showed minimal differences in the average absolute radioactivity uptake, especially after the third injection. Histopathological analysis revealed no clear signs of treatment-related pancreatic toxicity. For the kidneys, atrophy and fibrosis were observed for one animal from group 1 and a chronic inflammatory response was observed for both animals from group 3 at 24 weeks post-treatment.

Conclusions: Treatment with [¹⁷⁷Lu]Lu-NeoB is effective in a preclinical PCa model. Adjusting the administered dose could positively impact the risk-benefit balance as a higher dose might not lead to an increased therapeutic effect, but it may lead to an increase in toxicological effects in healthy organs such as the kidneys.

Keywords: Efficacy; Gastrin-releasing peptide receptor (GRPR); Prostate cancer; Theranostics; Toxicity; [177Lu]Lu-NeoB.

Fig. 1

Tumor volume (A), extrapolated tumor volume (B), and percent of survival (C) of PC-3 tumor-bearing mice untreated/sham-treated (control), or treated with 3 injections of 30 MBq/300 pmol (group 1), 40 MBq/400 pmol (group 2), or 60 MBq/600 pmol of [¹⁷⁷Lu]Lu-NeoB (group 3) on day 0, 7, and 14. The mean tumor volume with 95% confidence interval is presented for the time period that all data points of the group were available (i.e., tumor volume of no animal in the group exceeded 2000 mm³) (A) or for the duration until the tumor limit of 2000 mm³ was reached based on extrapolated growth curves (B). The dotted line indicates the start of treatment. *p < 0.05, ****p < 0.0001

Fig. 2

Representative SPECT/CT images (A) acquired 4 h post the first, second, and third injection of animals treated with 3 × 30 MBq/300 pmol (group 1), 3 × 40 MBq/400 pmol (group 2), or 3 × 60 MBq/600 pmol of [¹⁷⁷Lu]Lu-NeoB (group 3). Images show an overlay of a CT slice and the corresponding SPECT slice on which the cross-section of the tumor is clearly visible. Arrows indicate the tumor and the scale bar shows the linear scaling running from min-max of the signal present in the images. The mean quantified tumor uptake with the range is expressed as %IA/mL (B) and MBq/mL (C) (n = 2 per group)

Fig. 3

Animal weight before and after treatment with 3 × sham injection (control) or 3 × 30 MBq/300 pmol (group 1), 3 × 40 MBq/400 pmol (group 2), and 3 × 60 MBq/600 pmol of [¹⁷⁷Lu]Lu-NeoB (group 3) up to 12 weeks (A) and 24 weeks (B). ID numbers represent the identification number for each individual animal

Fig. 4

Representative H&E staining of pancreatic tissue from untreated (control) and treated animals (3× 30 MBq/300 pmol (group 1), 3× 40 MBq/400 pmol (group 2), and 3× 60 MBq/600 pmol of [¹⁷⁷Lu]Lu-NeoB (group 3)) after 12 and 24 weeks. ID numbers represent the identification number of the animal

Fig. 5

Representative H&E staining of renal tissue from untreated (control) and treated animals (3× 30 MBq/300 pmol (group 1), 3× 40 MBq/400 pmol (group 2), and 3× 60 MBq/600 pmol of [¹⁷⁷Lu]Lu-NeoB (group 3)) after 12 and 24 weeks. Areas circled in black indicate regions with low (ID: B, 6 and 8) or high (ID: 11) lymphocyte infiltration. The area circled in blue shows a region of atrophy and fibrosis (ID: 3). ID numbers represent the identification number of the animal