Abstract
Peptide receptor radionuclide therapy (PRRT) is an important treatment option for patients with somatostatin receptor-2 (SSTR2)-expressing neuroendocrine tumour (NET) though tumour regression occurs in only a minority of patients. Therefore, novel PRRT regimens with improved therapeutic activity are needed. Radiation induced DNA damage repair is an attractive therapeutic target to increase PRRT efficacy and consequently, we have characterised a panel of preclinical models for their SSTR2 expression, in vivo growth properties and response to 177Lu-DOTA-octreotate (LuTate) PRRT to identify models with features suitable for evaluating novel therapeutic combinations. In vitro studies using the SSTR2 expressing AR42J model demonstrate that the combination of LuTate and the small molecule Poly(ADP-ribose) polymerase-1 (PARP) inhibitor, talazoparib led to increased DNA double strand breaks, as assessed by γ-H2AX foci formation, as compared to LuTate alone. Furthermore, using the AR42J tumour model in vivo we demonstrate that the combination of LuTate and talazoparib significantly improved the anti-tumour efficacy of LuTate alone. These findings support the clinical evaluation of the combination of LuTate and PARP inhibition in SSTR2-expressing NET.
Highlights
Peptide receptor radionuclide therapy (PRRT) is an important treatment option for patients with somatostatin receptor-2 (SSTR2)-expressing neuroendocrine tumour (NET) though tumour regression occurs in only a minority of patients
When the cells were grown as tumour xenografts in vivo, SSTR2 expression was primarily localised to the cell membrane (Fig. 1b, lower)
We demonstrated the preclinical efficacy of combining LuTate with the PARPi, talazoparib
Summary
Peptide receptor radionuclide therapy (PRRT) is an important treatment option for patients with somatostatin receptor-2 (SSTR2)-expressing neuroendocrine tumour (NET) though tumour regression occurs in only a minority of patients. We have demonstrated that patients selected on the basis of uncontrolled symptoms or progression within 12 months on conventional therapy can achieve high objective response rates and prolonged progression-free survival following peptide chemoradionuclide therapy[19] These results were recapitulated in a group of patients with a more aggressive phenotype based on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)[20]. Preclinical anti-tumour activity of PARP inhibitors has been observed in combination with chemotherapy and beta particle emitting targeted radiotherapy agents[29,30] and more recently, PARP inhibitors have been shown to enhance the formation and persistence of cytotoxic double strand DNA breaks and potentiate the cytotoxicity of LuTate in vitro[31,32]
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