Imaging Cell Death: Focus on Early Evaluation of Tumor Response to Therapy

Zhang, Dongjian; Jin, Qiaomei; Jiang, Cuihua; Gao, Meng; Ni, Yicheng; Zhang, Jian

doi:10.1021/acs.bioconjchem.0c00119

Cited by 22 publications

(22 citation statements)

References 315 publications

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“…Conventionally, therapy response monitoring relies on categorizing measurements of predefined changes in either tumor size (Eisenhauer et al 2009) or tumor FDG uptake by PET (Wahl et al 2009;Peacock et al 2019). However, given that tumor cell death is a desired endpoint of anticancer therapies, specific and robust in vivo measures are being intensively investigated preclinically and clinically (Smith and Smith 2012;Zhang et al 2019;Zhang et al 2020). Among the cited in vivo tumor cell death detection technologies is the mAb DAB4.…”

Section: Introductionmentioning

confidence: 99%

Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®

Liapis

Tieu

Rudd

et al. 2020

EJNMMI radiopharm. chem.

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Purpose The chimeric monoclonal antibody (mAb) chDAB4 (APOMAB®) targets the Lupus associated (La)/Sjögren Syndrome-B (SSB) antigen, which is over-expressed in tumors but only becomes available for antibody binding in dead tumor cells. Hence, chDAB4 may be used as a novel theranostic tool to distinguish between responders and nonresponders early after chemotherapy. Here, we aimed to ascertain which positron emitter, Zirconium-89 ([89Zr]ZrIV) or Iodine-124 ([124I]I), was best suited to label chDAB4 for post-chemotherapy PET imaging of tumor-bearing mice and to determine which of two different bifunctional chelators provided optimal tumor imaging by PET using [89Zr]ZrIV-labeled chDAB4. Methods C57BL/6 J mice bearing subcutaneous syngeneic tumors of EL4 lymphoma were either untreated or given chemotherapy, then administered radiolabeled chDAB4 after 24 h with its biodistribution examined using PET and organ assay. We compared chDAB4 radiolabeled with [89Zr] ZrIV or [124I] I, or [89Zr]Zr-chDAB4 using either DFO-NCS or DFOSq as a chelator. Results After chemotherapy, [89Zr]Zr-chDAB4 showed higher and prolonged mean (± SD) tumor uptake of 29.5 ± 5.9 compared to 7.8 ± 1.2 for [124I] I -chDAB4. In contrast, antibody uptake in healthy tissues was not affected. Compared to DFO-NCS, DFOSq did not result in significant differences in tumor uptake of [89Zr]Zr-chDAB4 but did alter the tumor:liver ratio in treated mice 3 days after injection in favour of DFOSq (8.0 ± 1.1) compared to DFO-NCS (4.2 ± 0.7). Conclusion ImmunoPET using chDAB4 radiolabeled with residualizing [89Zr] ZrIV rather than [124I] I optimized post-chemotherapy tumor uptake. Further, PET imaging characteristics were improved by DFOSq rather than DFO-NCS. Therefore, the radionuclide/chelator combination of [89Zr] ZrIV and DFOSq is preferred for the imminent clinical evaluation of chDAB4 as a selective tumor cell death radioligand.

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Section: Introductionmentioning

confidence: 99%

Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®

Liapis

Tieu

Rudd

et al. 2020

EJNMMI radiopharm. chem.

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“…Nevertheless, the sensitivity and speci city of FDG-PET/CT for therapy response monitoring may be limited by such tumor variables as expression of glucose transport exporters [8] or tissue in ammation or infection both of which may also be FDG avid [9]. Therefore, there has been great interest in the eld of molecular imaging to develop selective, robust, and clinically applicable in vivo imaging markers of therapy-induced tumor cell death [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Positron Emission Tomographic imaging of tumor cell death using Zirconium-89-labeled APOMAB® following cisplatin chemotherapy in lung and ovarian cancer xenograft models

Liapis

Tieu

Wittwer

et al. 2020

Preprint

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Purpose. There are no currently approved non-invasive methods for detecting tumor treatment responses within the first few days of treatment. The monoclonal antibody, DAB4, or its chimeric derivative, chDAB4 (APOMAB®), targets the Lupus-associated or Sjögren Syndrome-B antigen (La/SSB). La/SSB is over-expressed in malignancy and is selectively targeted by chDAB4 in cancer cells that have died after DNA-damaging treatment. Therefore, chDAB4 could be used to distinguish between chemotherapy responsive and non-responsive patients. In this study, we performed preclinical validation studies using whole-body Positron-Emission Tomography (PET) to examine tumor and normal tissue uptake of 89Zr-labeled chDAB4 in lung or ovarian tumor-bearing mice, which were left untreated or given cisplatin chemotherapy.Methods. The binding of chDAB4 and its conjugates to dead cisplatin-treated human lung and ovarian cancer cells was assessed in vitro as well as its Fc-dependent effector functions. Mice bearing xenografts of H460 lung cancer or A2780 ovarian cancer cells were untreated or given cisplatin chemotherapy followed 24 hours later by 89Zr-labeled chDAB4. Post-cisplatin tumor responses were monitored using bioluminescence imaging and caliper measurements and 89Zr-labeled chDAB4 tumor uptake was measured using an Albira SI PET imager and PMOD analysis software. On completion of experiments, organs were dissected and biodistribution of 89Zr-labeled chDAB4 was measured using a Hidex gamma-counter.Results. The chDAB4 antibody bound only to dead A2780 and H460 cells, and its binding increased with cisplatin treatment in vitro. The chDAB4 antibody did not exhibit Fc-dependent effector functions. Chemotherapy significantly increased uptake of 89Zr-labeled chDAB4 in tumors but not in normal tissues for each tumor model. The greatest differences in average uptake of 89Zr-labeled chDAB4 in subcutaneous tumors were observed 3 days post-cisplatin chemotherapy compared to untreated mice, and before tumor shrinkage was evident.Conclusion. After administration of cisplatin chemotherapy, tumor xenograft uptake of 89Zr-labeled chDAB4 was detected in vivo by PET imaging. Given that the chDAB4 mAb lacked effector activity and that malignant rather than normal tissues were targeted after chemotherapy, these results support clinical development of chDAB4 as both a predictive marker of chemotherapy response and a theranostic imaging agent, which may guide subsequent delivery of chDAB4-directed antibody drug or radio-conjugate anticancer therapies.

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“…However, no differences in tumor size were detected in either cell line or treatment condition ( Figure 2 B–I,M). The induction of apoptosis has been described as a surrogate of treatment response preceding changes in tumor size—acting as an early monitor of tumor response—and thus allowing for shorter assays that can be easily included in the clinical decision-making time regarding treatment selection [ 58 , 59 ]. Thus, we anticipate that if the assay were to be extended, the tumor size effect would emerge, as we recently observed in other studies [ 60 ].…”

Section: Resultsmentioning

confidence: 99%

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

Varanda

Martins-Logrado

Ferreira

et al. 2020

Cancers

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Poly (ADP-ribose) polymerase (PARP) inhibition in BRCA-mutated cells results in an incapacity to repair DNA damage, leading to cell death caused by synthetic lethality. Within the treatment options for advanced triple negative breast cancer, the PARP inhibitor olaparib is only given to patients with BRCA1/2 mutations. However, these patients may show resistance to this drug and BRCA1/2 wild-type tumors can show a striking sensitivity, making BRCA status a poor biomarker for treatment choice. Aiming to investigate if the zebrafish model can discriminate sensitivities to olaparib, we developed zebrafish xenografts with different BRCA status and measured tumor response to treatment, as well as its impact on angiogenesis and metastasis. When challenged with olaparib, xenografts revealed sensitivity phenotypes independent of BRCA. Moreover, its combination with ionizing radiation increased the cytotoxic effects, showing potential as a combinatorial regimen. In conclusion, we show that the zebrafish xenograft model may be used as a sensitivity profiling platform for olaparib in monotherapy or in combinatorial regimens. Hence, this model presents as a promising option for the future establishment of patient-derived xenografts for personalized medicine approaches beyond BRCA status.

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Imaging Cell Death: Focus on Early Evaluation of Tumor Response to Therapy

Cited by 22 publications

References 315 publications

Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®

Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®

WITHDRAWN: Positron Emission Tomographic imaging of tumor cell death using Zirconium-89-labeled APOMAB® following cisplatin chemotherapy in lung and ovarian cancer xenograft models

Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

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