Breast cancer theranostics: A preclinical evaluation of RM26 targeting the gastrin-releasing peptide receptor for molecular imaging and therapy

Christina Baun*

*Corresponding author for this work

Research output: ThesisPh.D. thesis

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Abstract

Breast cancer patients with advanced metastatic disease must receive treatment for the rest of their life. Unfortunately, most patients will develop acquired resistance to the standard of care treatment over time, leading to uncontrolled progression, as no curative therapies currently exist for these patients. The gastrin-releasing peptide receptor (GRPR) is overexpressed in breast cancer and comprises an interesting novel treatment target. This thesis aimed to investigate the theranostic value of the peptide RM26 targeting the GRPR in estrogen receptor-positive breast cancer to overcome acquired resistance.

The first Manuscript included a comparative evaluation of the two radioligands [ 64Cu]CuNOTA-RM26 and [ 64Cu]Cu-NODAGA-RM26 in comparison to their cobalt-55-labeled counterparts to identify the optimal radioligand for next-day PET imaging. The cobaltlabeled radioligand demonstrated an overall better performance compared to the copperlabeled counterpart. Hence, the radionuclide cobalt-55 was selected for the further evaluation of RM26 in breast cancer.

The second Manuscript comprised a systematic scoping review focusing on the role of GRPR as a theranostic target in breast cancer. The findings revealed that GRPR-targeting antagonists could be particularly advantageous in the theranostic approach for estrogen receptor-positive breast cancer patients. Furthermore, the review highlighted a need for further studies exploring GRPR-targeting radioligand therapy.

The third Manuscript evaluated the theranostic potential of [ 55Co]Co/[177Lu]Lu-DOTARM26 in vitro in estrogen receptor-positive breast cancer. Furthermore, it aimed to assess the diagnostic potential of [ 55Co]Co-DOTA-RM26 in vivo. The results demonstrated high specific binding of both radioligands to breast cancer cells and a significant, dosedependent reduction in cell viability after treatment with [ 177Lu]Lu-DOTA-RM26. In vivo studies confirmed specific targeting of [ 55Co]Co-DOTA-RM26 to GRPR-expressing breast cancer tumors with increasing tumor-to-organ ratios over time, confirmed by PET imaging that showed optimal tumor visualization 24 h pi.

The fourth Manuscript extended the preclinical evaluation of [ 55Co]Co/[177Lu]Lu-DOTARM26 theranostics to breast cancer with acquired resistance. The results demonstrated reduced but specific radioligand uptake in the treatment-resistant breast cancer cells, suggesting lower GRPR expression than treatment-sensitive cells. Evaluation of [ 177Lu]Lu-DOTA-RM26 in these cells significantly reduced tumor cell viability, albeit with decreased treatment response compared to the treatment-sensitive breast cancer cells.

The additional in vivo data aimed to establish and refine an orthotopic model of estrogen receptor-positive breast cancer with acquired resistance in mice. The results showed that the model proved challenging and comprised several iterations for refinement. The results indicate that estrogen supplementation is required to stimulate tumor growth, which can lead to severe side effects in mice, with some strains being more sensitive than others. However, the Balb/c nude mouse appears to be a viable option, and estrogen supplementation in drinking water seems preferable to avoid hormone-related side effects.

The overall results of this thesis suggest that [ 55Co]Co/[177Lu]Lu-DOTA-RM26 holds promising potential for the theranostic approach of estrogen receptor-positive breast cancer, even in the context of acquired resistance. This thesis contributes valuable preclinical insights into GRPR-targeted theranostics for breast cancer.
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Thisgaard, Helge, Principal supervisor
  • Olsen, Birgitte B., Co-supervisor
  • Dam, Johan H., Co-supervisor
  • Orlova, Anna, Co-supervisor, External person
Date of defence8. Jan 2025
Publisher
DOIs
Publication statusPublished - 1. Nov 2024

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