Project title: Preclinical Toxicity and Therapy Study of 225Ac-crown-TATE

Description

Schaffer and his team will study a new chelate, or compound, that holds the radionuclinde called Ac-225. They are testing whether Ac-225-crown-TATE compound can safely and effectively treat tumors and prolong the survival of tumor-bearing models.

What question will the researchers try to answer?

Targeted radionuclide therapy involves developing tumor-specific drugs that can carry particle-emitting radioactive isotopes to tumors. The accumulation of these radiopharmaceuticals that contain toxic radionuclides will cause targeted cell death while sparing surrounding healthy tissue. Actinium-225 (Ac-225) is an alpha-emitting isotope that is showing significant clinical response in some advanced, untreatable cancers. A major hurdle in developing Ac-radiopharmaceuticals includes finding ways of attaching Ac-225 to drug carrier molecules. Dr. Schaffer’s research aims to demonstrate that a novel actinium chelate, or compound, can incorporate the radioisotope into molecules targeted toward the somatostatin receptor – an important cellular marker in some neuroendocrine tumors.

Why is this important?

Actinium is unstable, so drugs made with this isotope cannot be stockpiled. Dr. Schaffer and his team will demonstrate a chelate designed to incorporate the isotope under mild conditions, allowing pharmacists to easily produce and administer the radiopharmaceutical in a hospital setting. This project will also demonstrate the efficacy of the radiopharmaceutical for treating somatostatin-positive tumors.

What will researchers do?

Dr. Schaffer’s team will establish the radiopharmaceutical synthesis protocol and perform biodistribution studies to establish the toxicity and therapeutic response of somatostatin-positive neuroendocrine tumors. 

How might this improve the treatment of NETs?

Synthesizing actinium-labeled radiopharmaceuticals will enable the treatment of advanced, metastatic disease for which no other treatment options exist. 

What is the next step?

They will begin by synthesizing the drug precursors and label them with actinium produced at TRIUMF in Vancouver, Canada. Tumor-bearing models will receive escalating doses of the radiopharmaceutical to establish dose tolerance and tumor response. 

 

Outcomes:

Targeted therapy using peptides carrying radioactive payload has shown success in treating neuroendocrine tumors expressing somatostatin receptors. Clinical trials with 177Lu labeled peptide (octreotate) has demonstrated significant improved treatment outcome compared to high dose, long-lasting peptide (octreotide) by itself. However, for the 177Lu therapy, the response rate is only 18%, while 18-32% of patients are refractory to the therapy. Moreover, a majority of patients relapse after 2-3 years.

An alternative is to use an alpha-emitting radionuclide, such as 225Ac, as the radioactive payload, which has been used in treating late-stage prostate cancers and showed remarkable results. Current gold standard chelator for 225Ac is inefficient, requiring high peptide concentrations and extensive heating, and we have developed an Ac chelator that works at 100 lower peptide concentration at room temperature, ensuring the peptide is intact and can carry enough radioactive payload.

In this project, we evaluated the radiochemistry of making this novel radiopharmaceutical named [225Ac]Ac-crown-TATE, studied its distribution in tumor-bearing mice, evaluated toxicity to healthy organs, and most importantly, demonstrated the therapy efficacy of this drug in treating mice bearing somatostatin receptors positive tumors. Our work demonstrated that we can make [225Ac]Ac-crown-TATE reliably at high quality and purity. When injected in tumor-bearing mice, the radioactivity accumulated in tumor more than other healthy organs and tissues. When those tumor bearing mice were treated with this drug, they survive much longer compared to control groups where the tumor mice only received the tumor-targeting peptide. Overall, this work shows [225Ac]Ac-crown-TATE can be a candidate for clinical use in treating patients with somatostatin receptor-positive neuroendocrine tumors.

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