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Radionuclide Molecular Imaging of EpCAM Expression in Triple-Negative Breast Cancer Using the Scaffold Protein DARPin Ec1.

ABSTRACT: Efficient treatment of disseminated triple-negative breast cancer (TNBC) remains an unmet clinical need. The epithelial cell adhesion molecule (EpCAM) is often overexpressed on the surface of TNBC cells, which makes EpCAM a potential therapeutic target. Radionuclide molecular imaging of EpCAM expression might permit selection of patients for EpCAM-targeting therapies. In this study, we evaluated a scaffold protein, designed ankyrin repeat protein (DARPin) Ec1, for imaging of EpCAM in TNBC. DARPin Ec1 was labeled with a non-residualizing [125I]I-para-iodobenzoate (PIB) label and a residualizing [99mTc]Tc(CO)3 label. Both imaging probes retained high binding specificity and affinity to EpCAM-expressing MDA-MB-468 TNBC cells after labeling. Internalization studies showed that Ec1 was retained on the surface of MDA-MB-468 cells to a high degree up to 24 h. Biodistribution in Balb/c nu/nu mice bearing MDA-MB-468 xenografts demonstrated specific uptake of both [125I]I-PIB-Ec1 and [99mTc]Tc(CO)3-Ec1 in TNBC tumors. [125I]I-PIB-Ec1 had appreciably lower uptake in normal organs compared with [99mTc]Tc(CO)3-Ec1, which resulted in significantly (p < 0.05) higher tumor-to-organ ratios. The biodistribution data were confirmed by micro-Single-Photon Emission Computed Tomography/Computed Tomography (microSPECT/CT) imaging. In conclusion, an indirectly radioiodinated Ec1 is the preferable probe for imaging of EpCAM in TNBC.

SUBMITTER: Vorobyeva A

PROVIDER: S-EPMC7587533 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Radionuclide Molecular Imaging of EpCAM Expression in Triple-Negative Breast Cancer Using the Scaffold Protein DARPin Ec1.

Vorobyeva Anzhelika A Bezverkhniaia Ekaterina E Konovalova Elena E Schulga Alexey A Garousi Javad J Vorontsova Olga O Abouzayed Ayman A Orlova Anna A Deyev Sergey S Tolmachev Vladimir V

Molecules (Basel, Switzerland) 20201014 20

Efficient treatment of disseminated triple-negative breast cancer (TNBC) remains an unmet clinical need. The epithelial cell adhesion molecule (EpCAM) is often overexpressed on the surface of TNBC cells, which makes EpCAM a potential therapeutic target. Radionuclide molecular imaging of EpCAM expression might permit selection of patients for EpCAM-targeting therapies. In this study, we evaluated a scaffold protein, designed ankyrin repeat protein (DARPin) Ec1, for imaging of EpCAM in TNBC. DARPi ...[more]

PMID: 33066684

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Project description:There is a clinically unmet need for effective treatments for triple-negative breast cancer (TNBC), as it remains the most aggressive subtype of breast cancer. Herein, we demonstrate a promising strategy using a tumor-targeting alkylphosphocholine (NM600) for targeted radionuclide therapy of TNBC. Methods: NM600 was radiolabeled with 86Y for PET imaging and 177Lu for targeted radionuclide therapy. 86Y-NM600 PET imaging was performed on female BALB/C mice bearing syngeneic 4T07 (nonmetastatic) and 4T1 (metastatic) TNBC tumor grafts (n = 3-5). Quantitative data derived from a PET-image region-of-interest analysis, which was corroborated by ex vivo biodistribution, were used to estimate the dosimetry of 177Lu-NM600 treatments. Weight measurement, complete blood counts, and histopathology analysis were performed to determine 177Lu-NM600 toxicity in naïve BALB/C mice administered 9.25 or 18.5 MBq. Groups of mice bearing 4T07 or 4T1 grafts (n = 5-6) received excipient or 9.25 or 18.5 MBq of 177Lu-NM600 as a single or fractionated schedule, and tumor growth and overall survival were monitored. Results: Excellent tumor targeting and rapid normal-tissue clearance of 86Y-NM600 were noted in both 4T07 and 4T1 murine models. Ex vivo biodistribution corroborated the accuracy of the PET data and validated 86Y-NM600 as a surrogate for 177Lu-NM600. 177Lu-NM600 dosimetry showed absorbed doses of 2.04 ± 0.32 and 1.68 ± 0.06 Gy/MBq to 4T07 and 4T1 tumors, respectively, which were larger than those delivered to liver (1.28 ± 0.09 Gy/MBq) and to bone marrow (0.31 ± 0.05 Gy/MBq). The 177Lu-NM600 injected activities used for treatment were well tolerated and resulted in significant tumor growth inhibition and prolonged overall survival in both tested TNBC models. A complete response was attained in 60% of treated mice bearing 4T07 grafts. Conclusion: Overall, our results suggest that 177Lu-NM600 targeted radionuclide therapy has potential for TNBC and merits further exploration in a clinical setting.

Project description:BackgroundTriple-negative breast cancer is a subtype of breast cancer with aggressive tumor behavior and distinct disease etiology. Due to the lack of an effective targeted medicine, treatment options for triple-negative breast cancer are few and recurrence rates are high. Although various multi-gene prognostic markers have been proposed for the prediction of breast cancer outcome, most of them were proven clinically useful only for estrogen receptor-positive breast cancers. Reliable identification of triple-negative patients with a favorable prognosis is not yet possible.Methodology/principal findingsClinicopathological information and microarray data from 157 invasive breast carcinomas were collected at National Taiwan University Hospital from 1995 to 2008. Gene expression data of 51 triple-negative and 106 luminal breast cancers were generated by oligonucleotide microarrays. Hierarchical clustering analysis revealed that the majority (94%) of triple-negative breast cancers were tightly clustered together carrying strong basal-like characteristics. A 45-gene prognostic signature giving 98% predictive accuracy in distant recurrence of our triple-negative patients was determined using the receiver operating characteristic analysis and leave-one-out cross validation. External validation of the prognostic signature in an independent microarray dataset of 59 early-stage triple-negative patients also obtained statistical significance (hazard ratio 2.29, 95% confidence interval (CI) 1.04-5.06, Cox P=0.04), outperforming five other published breast cancer prognostic signatures. The 45-gene signature identified in this study revealed that TGF-? signaling of immune/inflammatory regulation may play an important role in distant metastatic invasion of triple-negative breast cancer.Conclusions/significanceGene expression data and recurrence information of triple-negative breast cancer were collected and analyzed in this study. A novel set of 45-gene signature was found to be statistically predictive in disease recurrence of triple-negative breast cancer. The 45-gene signature, if further validated, may be a clinically useful tool in risk assessment of distant recurrence for early-stage triple-negative patients.

Dataset Information

Radionuclide Molecular Imaging of EpCAM Expression in Triple-Negative Breast Cancer Using the Scaffold Protein DARPin Ec1.

Publications

Radionuclide Molecular Imaging of EpCAM Expression in Triple-Negative Breast Cancer Using the Scaffold Protein DARPin Ec1.

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