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

Ramya Ambur Sankaranarayanan; Alexandru Florea; Susanne Allekotte; Andreas T J Vogg; Jochen Maurer; Laura Schäfer; Carsten Bolm; Steven Terhorst; Arno Classen; Matthias Bauwens; Agnieszka Morgenroth; Felix M Mottaghy

doi:10.1186/s13550-022-00932-9

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

EJNMMI Res. 2022 Sep 14;12(1):60. doi: 10.1186/s13550-022-00932-9.

Authors

Ramya Ambur Sankaranarayanan¹, Alexandru Florea^{1

2

3}, Susanne Allekotte¹, Andreas T J Vogg¹, Jochen Maurer⁴, Laura Schäfer¹, Carsten Bolm⁵, Steven Terhorst⁵, Arno Classen⁵, Matthias Bauwens^{1

2

6}, Agnieszka Morgenroth¹, Felix M Mottaghy^{7

8

9}

Affiliations

¹ Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074, Aachen, Germany.
² Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre (MUMC+), 6229HX, Maastricht, The Netherlands.
³ School for Cardiovascular Diseases (CARIM), Maastricht University, 6229HX, Maastricht, The Netherlands.
⁴ Clinic for Gynaecology and Obstetrics, University Hospital Aachen, RWTH Aachen University, 52074, Aachen, Germany.
⁵ Institute of Organic Chemistry, RWTH Aachen University, 52074, Aachen, Germany.
⁶ Research School NUTRIM, Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.
⁷ Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074, Aachen, Germany. fmottaghy@ukaachen.de.
⁸ Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre (MUMC+), 6229HX, Maastricht, The Netherlands. fmottaghy@ukaachen.de.
⁹ School for Cardiovascular Diseases (CARIM), Maastricht University, 6229HX, Maastricht, The Netherlands. fmottaghy@ukaachen.de.

Abstract

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 (BRCA^mut). 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.

Keywords: 123I; 125I; Auger emitter; PARP inhibitors; TNBC; Targeted radionuclide therapy.

Grants and funding

project number: 331065168 - GRK2375/Deutsche Forschungsgemeinschaft