Oncode Institute keeps investing in bringing insights from basic science into clinical practice. With the 12th grant awarded within the CPoC programme, Oncode Investigator Roland Kanaar together with Oncode researcher Julie Nonnekens (both Erasmus MC) will team up with a group of clinicians, a physicist and pharmacist for a project focused on gastroenteropancreatic neuroendocrine tumors (GEPNETs).
Oncode Institute is happy to announce that the 12th grant within the Clinical Proof of Concept programme has been awarded. Using this grant, Oncode Investigator Roland Kanaar together with Oncode researcher Julie Nonnekens (both Erasmus MC), in collaboration with 5 clinicians, namely H. Hofland, F. Eskens, W. de Herder, A. van der Veldt and T. Brabander (all Erasmus MC), and with physicist M. Konijnenberg and pharmacist S. Koolen, will focus on gastroenteropancreatic neuroendocrine tumors (GEPNETs), to determine the maximum tolerated dose (MTD) of a PARP inhibitor (PARPi) in combination with peptide receptor radionuclide therapy (PRRT) re-treatment in patients with well-differentiated advanced GEPNETs.
Although representing a relatively small percentage of cancers, incidence of NETs continues to increase, already between 3.6 and 4.8-fold over the last four decades. In the Netherlands, close to 500 GEPNET patients ae newly diagnosed annually.
Oncode Institute aims to link fundamental and clinical research to enable efficient translation of promising findings into novel diagnostic methods and clinical treatment strategies, and the project fits well within this mission. ‘This Proof-of-Concept study is a great opportunity to translate our laboratory discoveries into a novel treatment option for patients suffering from neuroendocrine tumors’ says Julie Nonnekens on behalf of the entire team. ‘We have preclinically shown that the combination of peptide receptor radionuclide therapy and PARP inhibitors is efficient and safe. With a multidisciplinary team of Erasmus MC researchers, physicians, pharmacists and physicists, we will now investigate the safety and potential of this combination treatment in a phase I study for patients with metastatic neuroendocrine tumors. Outcome of this project will hopefully lead to the availability of an improved treatment regimen for these patients’ she adds.
The way in which PRRT works is that a cell-targeting protein is combined with a small amount of radioactive material – radionuclide – creating a radiopeptide, which is a type of radiopharmaceutical. This radiopeptide, if injected in the patient’s bloodstream, travels to and binds to neuroendocrine tumor cells to directly deliver a targeted high dose of radiation. PRRT is therefore a site-directed targeted therapeutic strategy that uses radiolabeled peptides as biological targeting vectors made to deliver cytotoxic levels of radiation to cancer cells, that overexpress specific receptors.
In parallel, PARP-1 is fundamental for DNA single strand breaks (SSB) repair. When SSBs are not repaired they will be converted into double strand breaks (DSBs) during cell division. The combination of PRRT with PARPi will increase the rate of PRRT-induced DSBs and by that increase the tumor cell death rate.
This study will be followed by a proof of concept (PoC) study to assess the PRRT enhancement effect of the PARP inhibitor using the recommended phase II dose compared to PRRT monotherapy in historical controls.