Integrating Metabolic, Neo-Angiogenic, and HER2-Targeted Imaging to Characterize Breast Cancer in Preclinical Models

Integrating Metabolic, Neo-Angiogenic, and HER2-Targeted Imaging to Characterize Breast Cancer in Preclinical Models

Ngo, Minh Toan

Garai, Ildikó

Petrányi Gyula Klinikai immunológiai és allergológiai doktori iskola

Általános Orvostudományi Kar::Orvosi Képalkotó Intézet::Nukleáris Medicina Tanszék

2025-11-19T15:48:34Z

2025-11-19T15:48:34Z

2025/11/18

2025-12-02

breast cancer

positron emission tomography

HER2

52Mn

FDG

RGD

Klinikai orvostudományok

Orvostudományok

Background: Breast cancer is a highly heterogeneous disease, necessitating advanced imaging techniques for effective diagnosis and treatment. The visualization of metabolic activity, angiogenesis, and biomarkers such as HER2 expression provides critical insights into tumor behavior. This study integrates three molecular imaging approaches to explore tumor heterogeneity, focusing on metabolic activity, angiogenesis, their possible relationship, and HER2 expression in preclinical breast cancer models. Materials and Methods:(1) The relationship between metabolic activity and angiogenesis was assessed using [18F]FDG and [68Ga]Ga-NODAGA-c(RGDfK)2 (RGD) PET imaging in fast-growing 4T1 and slow-growing MDA-MB-HER2+ xenografts. Tumor/muscle ratios were analyzed using the Muscle-Spacing Correction Method. (2) HER2-targeted imaging with [52Mn]Mn-DOTAGA(anhydride)-trastuzumab was evaluated in orthotopic and ectopic MDA-MB-HER2+ and MDA-MB-468 (HER2-negative) xenografts. Tumor-to-background ratios were calculated, with melanoma xenografts serving as a specificity control. (3) A novel Mn(II) chelator, BPPA, was compared to DOTAGA-pSCN-Bn for [52Mn]Mn-trastuzumab labeling. Tumor-to-background ratios and tumor uptake were analyzed in 4T1 (HER2−) and MDA-MB-HER2+ xenografts. Results: (1) In the 4T1 group, both FDG and RGD imaging revealed highly heterogeneous tumor structures with correlations between uptake and tumor growth. FDG and RGD uptake showed relative linear correlations in all the tumors, with 4T1 showing higher FDG/RGD ratios compared to MDA-MB-HER2+. (2) [52Mn]Mn-DOTAGA(anhydride)-trastuzumab demonstrated higher tumor-to-background ratios in orthotopic HER2-positive tumors, showing consistently superior uptake compared to ectopic HER2-positive tumors, HER2-negative tumor and melanoma at all-time points. (3) The novel BPPA chelator significantly outperformed DOTAGA-pSCN-Bn in tumor imaging with [52Mn]Mn-BPPA-trastuzumab showing significantly superior tumor-to-background ratios. Using BPPA tracer, HER2+ tumor uptake remained higher than HER2− at all time points, with a 3–4 fold higher contrast over HER2− tumors by day 7, establishing its potential for extended imaging windows and earlier detection compared to the DOTAGA chelator. Conclusion: Integrating metabolic, angiogenic, and receptor-targeted imaging offers a comprehensive approach to characterizing breast cancer heterogeneity. The combination of [18F]FDG, RGD, and [52Mn]Mn-based radiotracers, especially with BPPA chelator, demonstrates the potential to improve imaging precision and optimize treatment strategies.

angol

PhD, doktori értekezés

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https://hdl.handle.net/2437/398903