Inhibition of Poly(ADP-ribose) Polymerase Sensitizes [<sup>177</sup>Lu]Lu-DOTAGA.(SA.FAPi)<sub>2</sub>-Mediated Radiotherapy in Triple-Negative Breast Cancer

Bao, Guangfa; Zhou, Huimin; Zou, Sijuan; Chen, Lixing; Zhang, Buchuan; Wang, Ziqiang; Moon, Euy Sung; Zhao, Jun; Roesch, Frank; Zhu, Xiaohua

doi:10.1021/acs.molpharmaceut.2c01051

Cited by 5 publications

(1 citation statement)

References 29 publications

(49 reference statements)

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“…However, it is important to consider two caveats. First, the regrowth of the tumors even in the high-dose cohort suggests that the clinical efficacy of [ 177 Lu]Lu-DTPA-A″-CHX-αCD133 may depend upon using higher doses, adopting a fractionated dosing schema, or combining the radioimmunoconjugate with chemo- or immunotherapeutics. − Second, the expression of CD133 by human stem cells raises the spectre of hematopoietic toxicity in patients, and the hematological data from the murine therapy study support the notion that doses may need to be carefully selected in the clinic. If hematotoxicity proves to be a concern, strategies such as fractionated dosing and in vivo pretargeting may be adopted to reduce radiation dose rates to healthy tissues. , Of course, the translational relevance of either issue cannot be truly known until biodistribution and dosimetry data from patients are obtained in a pilot, first-in-human study.…”

Section: Resultsmentioning

confidence: 99%

Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer

Sarrett,

Rodriguez,

Delaney

et al. 2024

Mol. Pharmaceutics

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Despite decades of work, small-cell lung cancer (SCLC) remains a frustratingly recalcitrant disease. Both diagnosis and treatment are challenges: low-dose computed tomography (the approved method used for lung cancer screening) is unable to reliably detect early SCLC, and the malignancy’s 5 year survival rate stands at a paltry 7%. Clearly, the development of novel diagnostic and therapeutic tools for SCLC is an urgent, unmet need. CD133 is a transmembrane protein that is expressed at low levels in normal tissue but is overexpressed by a variety of tumors, including SCLC. We previously explored CD133 as a biomarker for a novel autoantibody-to-immunopositron emission tomography (PET) strategy for the diagnosis of SCLC, work that first suggested the promise of the antigen as a radiotheranostic target in the disease. Herein, we report the in vivo validation of a pair of CD133-targeted radioimmunoconjugates for the PET imaging and radioimmunotherapy of SCLC. To this end, [89Zr]Zr-DFO-αCD133 was first interrogated in a trio of advanced murine models of SCLCi.e., orthotopic, metastatic, and patient-derived xenograftswith the PET probe consistently producing high activity concentrations (>%ID/g) in tumor lesions combined with low uptake in healthy tissues. Subsequently, a variant of αCD133 labeled with the β-emitting radiometal 177Lu[177Lu]Lu-DTPA-A″-CHX-αCD133was synthesized and evaluated in a longitudinal therapy study in a subcutaneous xenograft model of SCLC, ultimately revealing that treatment with a dose of 9.6 MBq of the radioimmunoconjugate produced a significant increase in median survival compared to a control cohort. Taken together, these data establish CD133 as a viable target for the nuclear imaging and radiopharmaceutical therapy of SCLC.

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Section: Resultsmentioning

confidence: 99%

Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer

Sarrett,

Rodriguez,

Delaney

et al. 2024

Mol. Pharmaceutics

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Targeting CXCR4/CXCL12 axis via [177Lu]Lu-DOTAGA.(SA.FAPi)2 with CXCR4 antagonist in triple-negative breast cancer

Bao,

Wang,

Liu

et al. 2024

Eur J Nucl Med Mol Imaging

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Purpose Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2, a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC). Methods Public database was first interrogated to reveal the correlation between CAFs’ scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18F-FDG, [18F]AlF-NOTA-FAPI-04, and [68Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen. Results CAFs’ scores negatively correlated with the survival of TNBC patients (p < 0.05). The expression of CXCR4 and FAP was both significantly higher in tumors than in normal tissues. The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18F-FDG and [18F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12. Conclusion The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs.

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Development, preclinical evaluation and preliminary dosimetry profiling of SB03178, a first-of-its-kind benzo[h]quinoline-based fibroblast activation protein-α-targeted radiotheranostic for cancer imaging and therapy

Bendre,

Merkens,

Kuo

et al. 2024

European Journal of Medicinal Chemistry

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Inhibition of Poly(ADP-ribose) Polymerase Sensitizes [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂-Mediated Radiotherapy in Triple-Negative Breast Cancer

Cited by 5 publications

References 29 publications

Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer

Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer

Targeting CXCR4/CXCL12 axis via [177Lu]Lu-DOTAGA.(SA.FAPi)2 with CXCR4 antagonist in triple-negative breast cancer

Development, preclinical evaluation and preliminary dosimetry profiling of SB03178, a first-of-its-kind benzo[h]quinoline-based fibroblast activation protein-α-targeted radiotheranostic for cancer imaging and therapy

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Inhibition of Poly(ADP-ribose) Polymerase Sensitizes [177Lu]Lu-DOTAGA.(SA.FAPi)2-Mediated Radiotherapy in Triple-Negative Breast Cancer

Cited by 5 publications

References 29 publications

Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer

Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer

Targeting CXCR4/CXCL12 axis via [177Lu]Lu-DOTAGA.(SA.FAPi)2 with CXCR4 antagonist in triple-negative breast cancer

Development, preclinical evaluation and preliminary dosimetry profiling of SB03178, a first-of-its-kind benzo[h]quinoline-based fibroblast activation protein-α-targeted radiotheranostic for cancer imaging and therapy

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Inhibition of Poly(ADP-ribose) Polymerase Sensitizes [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂-Mediated Radiotherapy in Triple-Negative Breast Cancer