Project title: Evaluation of Ac-225 dotatate for treatment of lung carcinoid tumors

What questions will the researchers try to answer?

Can we develop a PRRT drug for lung NETs with the precision to kill cancer cells without harming surrounding healthy lung tissue so that patients’ lung capacity is better preserved?

Why is this important?

When treating the lungs, it is vital to preserve as much healthy tissue as possible. Existing therapies can damage nearby healthy tissue in patients who already have compromised lung capacity.

What will researchers do?

Morse and colleagues will conduct laboratory tests of a novel radiotherapy called Ac-225 dotatate, which is a derivative of Lu-177 dotatate, in lung neuroendocrine tumors (NETs). This radiotherapy emits alpha particles instead of beta. Alpha particles are bigger, higher-powered, with a shorter reach, which researchers hope will be more effective in killing lung NET cells with decreased toxicity to surrounding healthy tissues. Morse will test Ac-225 dotatate in preclinical animal models to learn how well it kills lung NET cells without causing damage to surrounding tissue.

How might this improve the treatment of NETs?

Morse is optimistic about the potential of alpha particle treatment in lung NETs. He foresees probable improved outcomes over existing PRRT drugs. “Existing therapy has promising but modest success in lung NETs, delivering a partial response and stable disease. But we believe with the alpha particle emission— we’ll be able to increase that to complete response and longer overall survival.”

What is the next step?

The data produced by these laboratory tests could be paired with other research findings on Ac-225 dotatate to submit clinical research proposals for early testing of this radiotherapy in humans.

Disclaimer

NETRF funds laboratory research to understand the development of neuroendocrine tumors and translational research to explore new concepts in treatment. Research grant descriptions and research updates from NETRF are not intended to serve as medical advice. It can take years for research discoveries to be fully validated and approved for patient care. Always consult your health care providers about your treatment options.

Outcomes:

We have determined the binding affinity of La3+-DOTATATE, which is a chemically similar surrogate for 225Ac-DOTATATE. We have optimized the radiochemistry of 225Ac-DOTATATE with high yield, purity, specific activity and stability. We completed a toxicity study that demonstrated chronic renal toxicity at the higher doses, but no other significant toxicities. We determined the biodistribution, radiation dosimetry and pharmacokinetics of 225Ac and daughter radionuclides in the decay chain. We characterized two lung tumor lines (small-cell lung carcinoma and lung carcinoid) for high and low SSTR2 expression, and low and high expression heterogeneity, respectively. Efficacy studies demonstrated significant tumor growth delay and increased time to experimental endpoint for both tumor lines. All of the objectives of the pilot proposal were completed successfully.

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