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64Cu/177Lu-DOTA-diZD, a Small-Molecule-Based Theranostic Pair for Triple-Negative Breast Cancer
Yuqian Huang1,2, Zhen Yang1, Feng Li1
1Center for Bioenergetics, Houston Methodist Research Institute, Houston, Texas 77030, United States.
Abstract:
Despite advances in targeted therapies, the prognosis for patients with triple-negative breast cancer (TNBC) is poor because there are few actionable molecular targets. The dependence of solid tumor growth on angiogenesis prompted our development of angiogenic-receptor-targeted radionuclide therapy (TRT) to treat TNBC by targeted delivery of therapeutic doses of ionizing radiation to tumors. A high-affinity vascular endothelial growth factor receptor (VEGFR)-targeted agent, diZD, was synthesized and labeled with 177Lu and 64Cu by 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator giving the TRT agent, 177Lu-DOTA-diZD, and PET imaging agent, 64Cu-DOTA-diZD. We showed that "64Cu/177Lu"-DOTA-diZD radiotracers are a promising theranostic pair for TNBC. 4T1-bearing mice treated with 177Lu-DOTA-diZD-based TRT survived with a median of 28 days, which was significantly longer than that of control mice as 18 days. Anti-PD1 immunotherapy resulted in a shorter median survival of 16 days. This work presents for the first time that small-molecule VEGFR-oriented TRT is a promising therapeutic option to treat "immunogenic cold" TNBC.
Insights
New radionuclide therapy targeting VEGFR shows promise for triple-negative breast cancer (TNBC). This targeted radiation therapy significantly improved survival in mice, offering a new option for this difficult-to-treat cancer.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Triple-negative breast cancer (TNBC) has a poor prognosis due to limited targeted therapies.
- Tumor growth relies on angiogenesis, presenting a target for therapeutic intervention.
Purpose of the Study:
- To develop and evaluate a novel angiogenic-receptor-targeted radionuclide therapy (TRT) for TNBC.
- To assess the theranostic potential of a vascular endothelial growth factor receptor (VEGFR)-targeted agent.
Main Methods:
- Synthesis and radiolabeling of a VEGFR-targeted agent (diZD) with 177Lu (for therapy) and 64Cu (for imaging) using DOTA chelation.
- Evaluation of the theranostic pair (64Cu/177Lu)-DOTA-diZD in a 4T1 TNBC mouse model.
Main Results:
- The 177Lu-DOTA-diZD TRT significantly increased median survival in 4T1-bearing mice from 18 to 28 days compared to controls.
- 64Cu/177Lu-DOTA-diZD demonstrated theranostic potential for TNBC.
- Anti-PD1 immunotherapy showed a median survival of only 16 days in this model.
Conclusions:
- Small-molecule VEGFR-oriented TRT is a promising therapeutic strategy for "immunogenic cold" TNBC.
- Targeted radionuclide therapy offers a novel treatment avenue for TNBC, outperforming immunotherapy in this study.
