Project title: Novel radioligands to improve radiotherapy of NETs

General Description

Scientists will explore a novel, very stable compound that binds to NET cells’ somatostatin receptors (SSTR2) more tightly than lutetium 177 (Lu-177) dotatate. This new radiopharmaceutical will be compared with Lu-177 dotatate in disease models. Researchers hope tighter binding of this radiotherapeutic agent to cancer cell receptors will lead to higher radiation accumulation and improved cancer response.

What question(s) will researchers ask?

Is there a way to improve the binding of radiotherapeutic agents to neuroendocrine tumor (NET) cells to enhance radiation exposure during Peptide Receptor Radionuclide Therapy (PRRT)?

Why is this important?

While PRRT is an effective treatment for many patients, not everyone responds equally well. Principal investigator Kuo-Shyan Lin, PhD, BC Canada, says he thinks a low response in some patients may be due to an ineffective interaction between the radiotherapeutic agent and the tumor cells. Lin believes that loose, unstable tumor cell-binding of the drug may be partly to blame. The first FDA-approved PRRT agent binds to the somatostatin receptors on the surface of NET cells. Dr.Lin says a tighter, stronger binding of the drug to those receptors could increase the killing potency of its radiation, helping improve the treatment response to PRRT.

What will researchers do?

Dr. Lin will use a new kind of small molecule for the design of radiotherapeutic agents which bind more tightly to the somatostatin receptors found on NET cells.

Testing a novel agent as an imaging tracer

First, researchers at Dr. Lin’s laboratory will try to attach an imaging radio-tag to the small molecule, which Lin hopes will bind the somatostatin receptor, and allow its location and distribution within the body to be tracked by PET scan. Unlike the radiotherapeutic agents, the radio-tag on the imaging agents allows the visualization of the small molecule but does not effectively kill cells. He will inject the imaging agent into tumor-bearing mice and use PET scans to show how well the agent targets and binds to NET cells. This will be monitored by its accumulation in the animal’s tumors.

Testing novel agent as a possible treatment

If the first tests are successful and improved cell binding is observed, the researchers will replace the imaging radio-tag with a radiotherapeutic component and evaluate the new radiotherapeutic agent’s cancer-cell killing effectiveness in tumor-bearing mice.

How might this research affect NET treatment in the future?

Dr. Lin hopes his research could contribute to the discovery of a novel class of radiotherapeutic agents that more effectively bind and treat NETs.

What is the next step?

If Dr. Lin’s concept shows feasibility, it would then undergo comprehensive laboratory testing to look for toxicity and other side effects. If extensive laboratory studies show it is safe to test in humans, it would advance into clinical trials, a three-phased regulated series of studies in increasingly larger patient pools to generate the data needed to apply for drug approval.

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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:

The goal of this project is to develop more effective radiotherapeutic agents to treat metastatic neuroendocrine tumors. Currently, Lutathera is the only radiotherapeutic agent approved by FDA to treat metastatic neuroendocrine tumors. Once injected into patients, Lutathera is carried by blood, and gradually accumulated into tumors. The radioactive tag on Lutathera can then emit radiation to kill cancer cells. However, Lutathera is effective in only a few patients (18%), and the majority of patients do not respond to the Lutathera treatment. The major cause of this suboptimal treatment efficacy is due to the decomposition of Lutathera in the body, leading to low accumulation of Lutathera in tumors. The target of Lutathera is a protein called somatostatin receptor subtype 2 which is abundantly present on the cell membranes of neuroendocrine tumor cells.

To improve treatment efficacy, we proposed to develop novel radiotherapeutic agents based on a more stable molecule which is less likely to decompose in the body. In addition, this small molecule has also been shown to bind to somatostatin receptor subtype 2 more tightly than Lutathera. We successfully synthesized this molecule, and attached a radioactive tag to this molecule. We made a total of three different radioactive drugs and each of them has a different way to attach the radioactive tag to the small molecule. All of these three radioactive drugs were prepared with good yields and good purity. We also investigated if these three radioactive drugs could decompose in the body. We injected them into mice, and after 15 minutes we took their blood samples for analysis. All these three radioactive drugs show very good stability in the body with no observed degradation. Next, we injected these three radioactive drugs into mice with an implanted neuroendocrine tumor to see if these drugs can accumulate into tumors. The results showed that two of these three radioactive drugs have good accumulation into tumors. We chose the best candidate and compared it with Lutathera. We injected our top candidate into mice implanted with a neuroendocrine tumor, and measured/calculated which one can deliver more radioactive drugs to the tumors. The results showed compared to Lutathera, our top candidate delivered less radiation dose to tumors. This is consistent with its weaker binding to the targeted somatostatin receptor subtype 2.

Our data demonstrate that despite the reported high binding affinity of the investigated small molecule, attaching the radio-tag jeopardizes its binding to the somatostatin receptor subtype 2. To preserve its high binding affinity, more work needs to be done to fine tune the position on the small molecule to attach the radio-tag.

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