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.

Outcomes:

In this study, we investigated side effects of a medical treatment called radioligand therapy (PRRT), which is used for treating metastatic neuroendocrine tumors by delivering radioisotopes to tumor cells. Recently, second generation radioligands targeting the NET biomarker SSTR2, have entered clinical evaluation. Those ligands can achieve better treatment effects due to higher tumor accumulation. However, during the initial clinical study, this treatment unexpectedly caused severe side effects and led to a toxic reduction of blood cells.

In this study, we investigated our hypothesis that the harmful effects were not simply due to the treatment circulating through the bloodstream but were instead caused by the radioligand specifically binding to hematopoietic stem cells. These stem cells are responsible for producing various blood cells in the bone marrow. To investigate this hypothesis, we developed fluorescent analogs of clinically used first (agonists) and second (antagonists) generation SSTR2-targeting radioligands, which enable characterization of their binding properties on a single cell basis. We created five different versions of the fluorescent compounds to select a lead candidate, which had similar characteristics to the clinical radioligands. We then proceed to characterize the binding of agonists and antagonists to bone marrow stem cells, which reside in very low number in the bone marrow. We found that the ligands specifically bound to very small subpopulations (0.1%) of mononuclear cells in the bone marrow niche. Since the antagonist exhibited higher binding level, it can be assumed that the clinical treatment leads to a higher-than-calculated exposure of these stem cells to the cytotoxic irradiation. Since these stem cells are very sensitive to irradiation, this could lead to the clinically observed bone marrow toxicity. Understanding the binding characteristics of these new compounds to bone marrow stem cell subpopulations is crucial for assessing potential risks associated with PRRT, particularly for hematological toxicities.

Our findings will hopefully contribute to increasing patient safety and the development of personalized treatment protocols for cancer patients. In conclusion, we successfully created multimodal variants of PRRT agents and identified a possible mechanism of the unexpected bone marrow toxicity of the antagonist 177Lu-DOTA-JR11. This knowledge will aid in improving cancer therapies and minimizing potential adverse effects.

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