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DC10: ESTHER CALVIÑO SANLÉS (SP)

Partner of attachment: GIMM (Gulbenkian Institute for Molecular Medicine) PT

 

Supervisor: Dr Marta MARQUES

University of Attachment: FMUL (Faculty of Medicine of the University of Lisbon) PT

 

Director of Thesis : Prof. Gonçalo BERNARDES

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Human epidermal growth factor receptor-2 (HER2) is a protein that is usually found at very low levels in cells. However, some cancer patients have a higher level of this protein in tumor cells. Luckily, there are treatments targeting this protein that can improve the survival of these patients. The problem is that a tumor can include some cells with high levels of HER2 and others with normal levels but conventional diagnostic methods only analyze a small piece of the tumor. This sample may contain low levels of HER2 due to this heterogenicity, which will hinder the identification of patients susceptible to anti-HER2 treatments. To overcome this drawback, we aim to develop a diagnostic method that will allow us to obtain an image of the HER2 levels in the whole body using a scan (known as PET scan) after injecting a radioactive molecule that binds to HER2.

 

The molecule that we want to prepare that will be ultimately injected in patients to get an image showing their HER2 levels, has to contain two key elements: a motif that can bind to HER2 (that we can name as HER2 binder) and 18F, the radioactive atom which allows the PET detection.

 

Our strategy envisions these two elements glued together by a chemical bridge: on one side of the chemical bridge, there will be a piece that fits with the HER2 binder, and on the other side a piece that will allow the incorporation of the radioactive atom (that we can name as fluorination hotspot).

 

I first started working on the preparation of the chemical bridge. We decided to produce several chemical bridges: each with a different fluorination hotspot. This is because the fluorination hotspot can affect how fast the radioactive atom (18F) will be incorporated but we cannot know which fluorination hotspot will allow the fastest incorporation without testing it. This is a very important step since radioactive atoms lose radioactivity with time. If the incorporation of the radioactive atom is slow, there will be a long waiting time between the production of the radioactive atom and the obtention of the PET image. As a consequence of this long waiting time, the molecule will not be radioactive anymore. If this happens, it will not be possible to visualize the HER2 levels in the image because the molecule will not emit a radioactive signal that the PET scan can detect.

 

The preparation of the chemical bridges is still ongoing work. After achieving this step, I can assemble each chemical bridge with the HER2 binder and incorporate the radioactive atom. Subsequently, I can choose which chemical bridge is the best one and start studying how the radioactive molecule behaves in cells: if it binds to HER2, if it enters the cell and if the cells die in the presence of the radioactive molecule, among others. After studying the safety of the radioactive molecule, we can inject it in mice and attempt to obtain a PET image of the HER2 levels in tumor cells. In this way, we can determine if our method can be used for diagnosis.

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