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

Sankaranarayana et al.

Research question

Triple-negative breast cancer (TNBC) is an invasive form of breast cancer. Because of the lack of known therapeutic targets to day, the number of biomarkers for targeted radiotherapy is limited. The nuclear protein Poly (ADP-ribose)-Polymerase 1 (PARP1) is a suitable target against which few inhibitors (PARPi) are clinically approved for treatment of triple-negative breast cancer with germline BRCA mutation. In the current study, a theranostic agent is proposed that targets the PARP1 receptor.


A theranostic approach was investigated in a TNBC xenograft mouse model by radiolabelling a close derivative of a PARPi Olaparib (termed PARPi-01) with the Auger emitters 123/125I. It is known that Auger emitters display optimal therapeutic effect, if delivered directly into the nucleus proximal to DNA. Longitudinal SPECT/CT imaging was performed to evaluate the biodistribution of the compound 4h and 24h post-injection. In addition, a therapy study was performed with [125I]PARPi-01 in 4 doses (10 MBq/dose, 10 days apart). During the therapy study, 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.


In this study the in vivo biodistribution and therapeutic effect of the Auger emitter coupled PARP inhibitor [125I]PARPi-01 was evaluated in a subcutaneous TNBC model.The SPECT/CT biodistribution study showed rapid hepatobiliary tracer clearance and low intra-tumoural uptake.  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. Although the tumor uptake is limited, 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.

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. However, for clinical application further improvements regarding the tumour uptake, blood stability, and fast clearance need to be addressed. This may be done by employment of an adequate drug delivery system loaded with [125I]PARPi-01.