Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study

Sankaranarayanan, Ramya Ambur; Peil, Jennifer; Vogg, Andreas; Bolm, Carsten; Terhorst, Steven; Claßen, Arno; Bauwens, Matthias; Maurer, Jochen; Mottaghy, Felix M.; Morgenroth, Agnieszka

doi:10.3390/cancers14010230

Cited by 14 publications

(18 citation statements)

References 58 publications

(68 reference statements)

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“…The same was demonstrated in the study by Miran et al ., with a fractionated therapy of 10 MBq Auger emitting nucleoside analogue following three applications with an interval of one week in an MDA-MB-231 xenografted mice model. Furthermore we observed DNA damage upon low dose PARPi application in our in-vitro experiments in the MDA-MB-231 cell line [ 17 ]. [ 18 F]FDG based PET image analysis did not show significant difference between control and therapy cohorts with respect to SUV values and tumour metabolic volumes (Additional file 1 : Fig.…”

Section: Resultsmentioning

confidence: 99%

PARP targeted Auger emitter therapy with [125I]PARPi-01 for triple-negative breast cancer

et al. 2022

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Background Triple-negative breast cancer (TNBC) lacks biomarkers for targeted therapy. Auger emitters display the best therapeutic effect, if delivered directly into the nucleus proximal to DNA. The nuclear protein Poly (ADP-ribose)-Polymerase 1 (PARP1) is a suitable target against which few inhibitors (PARPi) are clinically approved for treatment of breast cancer with germline BRCA mutation (BRCAmut). In this study, a theranostic approach was investigated in a TNBC xenografted mouse model by radiolabelling a close derivative of a PARPi Olaparib (termed PARPi-01) with the Auger emitters 123/125I. Methods TNBC cell line MDA-MB-231 was subcutaneously implanted in female NOD/SCID mice. At a tumour size of ~ 500mm3, [123I]PARPi-01 was administered intravenously, and SPECT/CT images were obtained at 4 h or 24 h post injection (p.i). A therapy study was performed with [125I]PARPi-01 in 4 doses (10 MBq/dose, 10 days apart). Tumour growth was monitored by CT scans longitudinally once per week. Upon reaching study endpoint, tissues were harvested and stained with TUNEL assay for detection of apoptosis induction. Results SPECT/CT images showed rapid hepatobiliary tracer clearance at 4 h post injection (p.i.). Retention in thyroid at 24 h p.i. suggested tracer deiodination in vivo. The tumour and liver uptake were 0.2%ID/g and 2.5%ID/g, respectively. The tumour: blood ratio was 1.3. Endogenous therapy induced a significant delay in tumour growth (doubling time increased from 8.3 to 14.2 days), but no significant survival advantage. Significantly higher apoptosis ratio was observed in [125I]PARPi-01 treated tumour tissues. No radiotoxicity was detected in the liver and thyroid. Conclusion Considering the radio-cytotoxic effect in the tumour tissue and a delay on tumour doubling time, [125I]PARPi-01 presents a potential radiotherapeutics for treatment of TNBC. Improvements to overcome the suboptimal pharmacokinetics are necessary for its potential clinical application.

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Section: Resultsmentioning

confidence: 99%

PARP targeted Auger emitter therapy with [125I]PARPi-01 for triple-negative breast cancer

et al. 2022

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“…While some cell lines already showed a sensitive response to [ 125 I]PARPi-01 monotherapy at lower concentrations than olaparib, the therapeutic response could be improved in non-responsive cell lines using a combinatorial treatment of [ 125 I]PARPi-01 with the chemotherapeutic drug Dox-NP. The observed responses were consistent across a panel of assays including cell cycle analysis, apoptosis quantification, and colony formation assays [ 102 ]. If these results could be confirmed in vivo, [ 125 I]PARPi-01 could be another interesting candidate for PARP radiotherapy.…”

Section: Current Status Of Parp-targeted Radiotherapymentioning

confidence: 67%

“…It is hypothesized that during excretion, metabolism confines the agent to the perinuclear region of the cell and therefore puts it outside the range of an Auger-emitter to achieve significant damage upon cellular DNA [99]. Recently, another therapeutic study of an Auger-emitting PARPi, [ 125 I]PARPi-01 (isotopologue of [ 131 I]I2-PARPi from [57]), was published (Morgenroth Lab) [102]. To assess the theranostic efficacy of the Auger electron emitter on triple negative breast cancer (TNBC), the tracer was evaluated in 11 different TNBC tumor cell lines, including BRCA-mutated and BRCA-wt cell lines.…”

Section: Rucaparib-like Radiotherapeuticsmentioning

confidence: 99%

“…Recently, another therapeutic study of an Auger-emitting PARPi, [ 125 I] PARPi-01 (isotopologue of [ 131 I]I2-PARPi from [ 57 ]), was published (Morgenroth Lab) [ 102 ]. To assess the theranostic efficacy of the Auger electron emitter on triple negative breast cancer (TNBC), the tracer was evaluated in 11 different TNBC tumor cell lines, including BRCA-mutated and BRCA-wt cell lines.…”

Section: Current Status Of Parp-targeted Radiotherapymentioning

confidence: 99%

“…To assess the theranostic efficacy of the Auger electron emitter on triple negative breast cancer (TNBC), the tracer was evaluated in 11 different TNBC tumor cell lines, including BRCA-mutated and BRCA-wt cell lines. Specifically, [ 125 I]PARPi-01 uptake was shown via olaparib blocking in MDA-MB-231 cells [ 102 ].…”

Section: Current Status Of Parp-targeted Radiotherapymentioning

confidence: 99%

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DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

Nguyen

Pacelli

Nader

et al. 2022

Cancers

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Since it was discovered that many tumor types are vulnerable to inhibition of the DNA repair machinery, research towards efficient and selective inhibitors has accelerated. Amongst other enzymes, poly(ADP-ribose)-polymerase 1 (PARP1) was identified as a key player in this process, which resulted in the development of selective PARP inhibitors (PARPi) as anti-cancer drugs. Most small molecule PARPi’s exhibit high affinity for both PARP1 and PARP2. PARPi are under clinical investigation for mono- and combination therapy in several cancer types and five PARPi are now clinically approved. In parallel, radiolabeled PARPi have emerged for non-invasive imaging of PARP1 expression. PARP imaging agents have been suggested as companion diagnostics, patient selection, and treatment monitoring tools to improve the outcome of PARPi therapy, but also as stand-alone diagnostics. We give a comprehensive overview over the preclinical development of PARP imaging agents, which are mostly based on the PARPi olaparib, rucaparib, and recently also talazoparib. We also report on the current status of clinical translation, which involves a growing number of early phase trials. Additionally, this work provides an insight into promising approaches of PARP-targeted radiotherapy based on Auger and α-emitting isotopes. Furthermore, the review covers synthetic strategies for PARP-targeted imaging and therapy agents that are compatible with large scale production and clinical translation.

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Current status and progress in using radiolabelled PARP-1 inhibitors for imaging PARP-1 expression in tumours

Wang

Zhang

2022

European Journal of Medicinal Chemistry

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Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study

Cited by 14 publications

References 58 publications

PARP targeted Auger emitter therapy with [125I]PARPi-01 for triple-negative breast cancer

PARP targeted Auger emitter therapy with [125I]PARPi-01 for triple-negative breast cancer

DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

Current status and progress in using radiolabelled PARP-1 inhibitors for imaging PARP-1 expression in tumours

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