Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib

Abstract

Metastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with radiolabeled somatostatin analogues, resulting in strongly increased progression-free survival and quality of life. There is nevertheless still room for improvement, as very few patients can be cured at this stage of disease. We aimed to specifically sensitize replicating tumor cells without further damage to healthy tissues. Thereto we investigated the DNA damaging effects of PRRT with the purpose to enhance these effects through modulation of the DNA damage response. Although PRRT induces DNA double strand breaks (DSBs), a larger fraction of the induced lesions are single strand breaks (expected to be similar to those induced by external beam radiotherapy) that require poly-[ADP-ribose]-polymerase 1 (PARP-1) activity for repair. If these breaks cannot be repaired, they will cause replication fork arrest and DSB formation during replication. Therefore, we used the PARP-1 inhibitor Olaparib to increase the number of cytotoxic DSBs. Here we show that this new combination strategy synergistically sensitized somatostatin receptor expressing cells to PRRT. We observed increased cell death and reduced cellular proliferation compared to the PRRT alone. The enhanced cell death was caused by increased numbers of DSBs that are repaired with remarkably slow kinetics, leading to genome instability. Furthermore, we validated the increased DSB induction after PARP inhibitor addition in the clinically relevant model of living human NET slices. We expect that this combined regimen can thus augment current PRRT outcomes.

Combination of 5-Fluorouracil with Epigenetic Modifiers Induces Radiosensitization, Somatostatin Receptor 2 Expression, and Radioligand Binding in Neuroendocrine Tumor Cells In Vitro

“…To improve the therapeutic efficacy of PRRT in NETs, different strategies have been investigated as follows: several clinical studies using fluoropyrimidine-based chemotherapy regimens for PRCRT in NET patients (3,(5)(6)(7)(8), preclinical studies using epigenetic modifiers as DNMT inhibitors/HDAC inhibitors to upregulate SSTR expression (12,13) and radioligand binding (12,13), preclinical studies using novel molecular target compounds for PRCRT (17)(18)(19), and variation of radiopharmaceuticals by the use of the a-emitters 215 Act or 213 Bis (20) or by the use of somatostatin antagonists (21). In preclinical studies, Taelman et al (12) and Veenstra et al (13) reported that several DNMT inhibitors and HDAC inhibitors induce SSTR mRNA transcription and protein expression and enhance specific SSTR-mediated radioligand binding of NET cells.…”

Enhancing the therapeutic effects of in vitro targeted radionuclide therapy of 3D multicellular tumor spheroids using the novel stapled MDM2/X-p53 antagonist PM2

“…Similarly, potentiating the cytotoxic effects of radiotherapy through radiosensitization, the therapeutic effects of radiotherapy may be improved [13]. Compounds that target the DNA-damage response mechanisms initiated as a result of ionizing radiation are of particular interest for use in combination with radiotherapy [14,15]. At the very center of the radiation response pathways is the well-known transcription factor p53 [16].…”

New Developments in Peptide Receptor Radionuclide Therapy

“…Molecularly targeted therapeutics may be important to attain synergy with PRRT. For instance, concurrent inhibition of the DNA repair mechanisms with a poly-[ADP-ribose]-polymerase 1 inhibitor results in increased DNA double-strand breaks (23).…”