Project title: Uncovering the cellular mechanisms that limit clinical application of PRRT

Susanne Kossatz, PhD, University Hospital “Klinikum rechts der Isar” at Technical University Munich, will investigate why a promising new radiopharmaceutical for therapy of metastatic neuroendocrine tumors caused unexpectedly severe side effects in its first clinical study. Understanding the underlying mechanisms will help develop safer evaluation protocols for radiopharmaceuticals and improved patient selection procedures.

What problem/questions will researchers try to answer?

Peptide receptor radionuclide therapy (PRRT) is a relatively new clinically available treatment option for patients with metastatic neuroendocrine tumors. A promising new PRRT candidate (¹⁷⁷Lu-DOTA-JR11) recently entered clinical evaluation having performed better in preclinical studies than the clinically-approved ¹⁷⁷Lu-DOTA-TOC. Unexpectedly, more than half of the patients developed severe side effects. Kossatz will try to identify the underlying cause of this toxicity with the goal of developing the protocols needed for patients to safely use this highly promising treatment.

Why is this important?

Patients with unresectable neuroendocrine tumors currently face limited treatment options and low survival rates. These tumors often show resistance to standard chemotherapy. PRRT is a therapeutic approach where cytotoxic radiation targets biomarker-expressing tumors while sparing biomarker-negative normal tissues. The relevant biomarker in our study is the Somatostatin-2-receptor (SSTR2), which is found in a majority of NETs. Improvement of the response rate to PRRT is key to improving outcomes and survival for many NET patients.

What will researchers do?

Kossatz will develop a fluorescent version of DOTA-JR11, which will allow it to be tracked using imaging methods. This will allow her lab to specifically investigate the cellular mechanisms of DOTA-JR11 responsible for the observed side effects and toxicity. Subsequently, her research aims to establish a strategy to assess the susceptibility of patients to these adverse side effects and develop effective protocols for improved radiopharmaceutical evaluation and patient selection.

How might this improve the treatment of NETs?

Since not all patients experienced severe side effects, Kossatz hypothesizes that she can develop a test to identify patients at risk for severe side effects and patients for whom treatment will be safe. In addition, her research aims to develop a general strategy to assess the safety of novel PRRT agents, based on the study’s results. All these efforts are aimed at providing better treatment options for patients with metastatic disease.

What is the next step?

Kossatz wants to improve treatment options for neuroendocrine tumor patients by developing general protocols that will predict how ¹⁷⁷Lu-DOTA-JR11 treatment may be optimized to mitigate harmful side effects while maximizing its full therapeutic potential.

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