Project title: Target neuron-cancer interactions in NETs by non-invasive imaging of SV2A

Description 

Hao will develop oncological positron emission tomography (PET) imaging probes to detect synaptic vesicle protein 2A (SV2A) in NETs. 

What question will you try to answer through your research?

There has been a growing realization about the nervous system’s role in the growth and spread of cancer, with some clinical trials showing that blocking nerve signaling could slow cancer progression. NETs arise from the cells of the nervous and endocrine systems, which gives NET cancer cells traits of both nerve cells (neurons) and hormone-producing endocrine cells. However, the influence of neurons on the formation and progression of NETs remains unclear due to the lack of an effective tool to target neuron-cancer interactions. I will work on developing a non-invasive PET imaging tool to explore new diagnosis and treatment options for NETs by targeting these interactions.  

Why is this important?

The role of the nervous system in the growth and spread of cancer has long been overlooked. Research studies have shown “crosstalk” between tumors, nerves, and the tumor environment, and other studies have linked tumor nerve density with aggressiveness and prognosis in some NETs. SV2A PET imaging probes are currently used to measure and evaluate neurodegenerative diseases, and we will develop its oncological version of the probes to investigate the neuron-cancer interactions in NETs outside of the brain. 

What will you do as part of this research project?

We will measure and compare the expression of SV2A and other common NET biomarkers in a series of NET cell lines and tumors. We will develop new PET probes for SV2A in NETs to focus on improving the tumor localization and imaging. 

How might your research improve the treatment of NETs?

We expect that the new SV2A imaging tool will advance our knowledge of the role of the nervous system in NETs. The imaging tool may be used to screen NET patients to potentially start treatments earlier for better outcomes. It could also lead to new treatment options for NETs that can therapeutically target the interactions between neurons and cancer cells.

What is your next step?

As a pilot study, our project explores the ability to detect NET tumors by PET imaging of SV2A with newly developed probes. If the new imaging probes are promising, radionuclide therapy could be used to target SV2A in NETs. Also, the SV2A PET imaging may lead to a preclinical study of new treatment options that act on the interaction between neurons and cancer cells.

Outcomes:

There has been a growing realization of the role of the nervous system in the growth and spread of cancer, and nerve density within the tumor foci has been linked with aggressiveness and prognosis in some cancer types. Neuroendocrine tumors arise from the cells of the nervous and endocrine systems, which makes neuroendocrine tumor cells have traits of both nerve cells and hormone-producing endocrine cells. However, neuronal influences on tumorigenesis and progression of neuroendocrine tumors remains unclear due to the lack of informative targets and the right tools.

Synaptic vesicle protein 2 isoform A (SV2A) has been well recognized as the binding site for antiepileptic drugs and a non-invasive imaging biomarker for measuring synaptic density in neurodegenerative diseases. Like somatostatin receptors, the bioinformatic analyses revealed an amplified SV2A gene expression in neuroendocrine tumors and comparable patterns as synaptophysin. The SV2A protein measurement demonstrated that SV2A expression is in accordance with the gene expression data. SV2A holds the potential to be developed as an imaging diagnostic target and/or a therapeutic target by manipulating neural signals to the tumor microenvironment.

This project aims to explore such an opportunity by chemically designing and preparing new SV2A-specific radiotracers for evaluations. The initial tests with existing SV2A-specific neuroimaging radiotracer have demonstrated the positive tumor contrast and specificity to SV2A. With the recognition of the neuroimaging version of SV2A-specific radiotracers not optimal for cancer imaging, we prepared four new ligands with lower lipophilicity than currently existing SV2A specific ligands. We selected one of the compounds showing the highest binding affinity and have succeeded in its F-18 labeling. Now, we are in the process of further imaging evaluations.

Meanwhile, we explored an alternative chemistry strategy which can realize both the preferred lower lipophilicity and the multivalency effect for enhanced SV2A binding affinity and tumor retention. The Cu-64 radiolabeling of both monomeric and dimerized conjugates were successful. A lung tumor xenograft could be clearly visualized by both Cu-64 labeled monomeric and dimerized conjugates.

In conclusion, highly expressed in neuroendocrine tumors, SV2A can serve as a potential target for noninvasive imaging evaluation of neuroendocrine differentiation in vivo. Given the promising results with new structures, we believe it is the right direction of developing the oncological version of SV2A radiotracers to advance its diagnostic and/or therapeutic applications in neuroendocrine tumors. Overall, it is a new strategy to tackle neuroendocrine tumors.

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