LAT1-Targeted Alpha Therapy Using ²¹¹At-AAMT for Bone and Soft Tissue Sarcomas

Area of Science:

• Oncology
• Radiopharmaceutical Therapy
• Molecular Targeting

Background:

• Malignant bone and soft tissue sarcomas often resist conventional treatments, especially in advanced or metastatic stages.
• L-type amino acid transporter 1 (LAT1) is overexpressed in sarcomas, presenting a viable target for novel therapeutic strategies.
• Targeted alpha therapy offers a potent and localized treatment modality for cancer.

Purpose of the Study:

• To evaluate the therapeutic efficacy of a novel LAT1-targeted alpha therapy agent, 211At-AAMT, in bone and soft tissue sarcomas.
• To assess the LAT1-dependency and specificity of 211At-AAMT uptake in sarcoma cell lines.
• To compare the in vivo antitumor efficacy and toxicity of 211At-AAMT with doxorubicin in xenograft models.

Main Methods:

• LAT1 expression was analyzed in sarcoma cell lines.
• Uptake of 211At-AAMT was measured to confirm LAT1-mediated delivery.
• In vitro antiproliferative effects were assessed via cell viability and colony formation assays.
• DNA damage was evaluated using γH2AX immunostaining.
• In vivo efficacy was tested in xenograft mouse models, comparing 211At-AAMT to doxorubicin.

Main Results:

• LAT1 was highly expressed in all tested bone and soft tissue sarcoma cell lines.
• 211At-AAMT uptake was confirmed to be LAT1-dependent and significant.
• 211At-AAMT demonstrated dose-dependent inhibition of cell proliferation, comparable to doxorubicin.
• In vivo studies showed significant tumor growth inhibition by 211At-AAMT with no systemic toxicity, unlike doxorubicin.
• Histopathological analysis revealed reduced cell density, inhibited proliferation, and extensive DNA damage in tumors treated with 211At-AAMT.

Conclusions:

• LAT1-targeted alpha therapy using 211At-AAMT exhibits significant antitumor efficacy against bone and soft tissue sarcomas.
• The efficacy of 211At-AAMT is comparable to first-line chemotherapy agents like doxorubicin, but with a superior safety profile.
• Sustained LAT1 expression in residual tumors suggests potential for repeated or combination therapies, positioning 211At-AAMT as a promising novel treatment for advanced, treatment-resistant sarcomas.