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Efficacy of a HER2-Targeted Thorium-227 Conjugate in a HER2-Positive Breast Cancer Bone Metastasis Model
Jenny Karlsson1, Urs B Hagemann2, Véronique Cruciani1
1Targeted Radiopharmaceuticals, Bayer AS, 0283 Oslo, Norway.
Abstract:
Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-30% of breast cancers but has low expression in normal tissue, making it attractive for targeted alpha therapy (TAT). HER2-positive breast cancer typically metastasizes to bone, resulting in incurable disease and significant morbidity and mortality. Therefore, new strategies for HER2-targeting therapy are needed. Here, we present the preclinical in vitro and in vivo characterization of the HER2-targeted thorium-227 conjugate (HER2-TTC) TAT in various HER2-positive cancer models. In vitro, HER2-TTC showed potent cytotoxicity in various HER2-expressing cancer cell lines and increased DNA double strand break formation and the induction of cell cycle arrest in BT-474 cells. In vivo, HER2-TTC demonstrated dose-dependent antitumor efficacy in subcutaneous xenograft models. Notably, HER2-TTC also inhibited intratibial tumor growth and tumor-induced abnormal bone formation in an intratibial BT-474 mouse model that mimics breast cancer metastasized to bone. Furthermore, a match in HER2 expression levels between primary breast tumor and matched bone metastases samples from breast cancer patients was observed. These results demonstrate proof-of-concept for TAT in the treatment of patients with HER2-positive breast cancer, including cases where the tumor has metastasized to bone.
Insights
Targeted alpha therapy (TAT) using a novel HER2-targeted thorium-227 conjugate (HER2-TTC) shows promise for treating HER2-positive breast cancer. This therapy effectively reduced tumor growth and bone metastasis in preclinical models.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Biology
Background:
- Human epidermal growth factor receptor 2 (HER2) overexpression occurs in 15-30% of breast cancers, presenting a therapeutic target.
- HER2-positive breast cancer frequently metastasizes to bone, leading to poor prognosis and high mortality.
- Current HER2-targeting therapies have limitations, necessitating novel treatment strategies.
Purpose of the Study:
- To evaluate the preclinical efficacy of a HER2-targeted thorium-227 conjugate (HER2-TTC) for targeted alpha therapy (TAT).
- To assess HER2-TTC's activity against HER2-positive breast cancer, including bone metastases.
Main Methods:
- In vitro characterization of HER2-TTC cytotoxicity and DNA damage induction in HER2-expressing cancer cell lines.
- In vivo assessment of HER2-TTC's antitumor efficacy in subcutaneous xenograft models.
- Evaluation of HER2-TTC's effect on intratibial tumor growth and bone formation in a preclinical bone metastasis model.
Main Results:
- HER2-TTC demonstrated potent in vitro cytotoxicity and induced DNA double-strand breaks and cell cycle arrest.
- In vivo studies showed dose-dependent antitumor efficacy of HER2-TTC in xenograft models.
- HER2-TTC significantly inhibited tumor growth and bone abnormalities in a bone metastasis mouse model, with matched HER2 expression observed in patient samples.
Conclusions:
- HER2-TTC represents a viable targeted alpha therapy (TAT) for HER2-positive breast cancer.
- The study provides proof-of-concept for HER2-TTC in treating primary and bone-metastatic HER2-positive breast cancer.
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