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DC4: MALAMATENIA PAPAVASILEIOU (GR)

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

 

Supervisor: Dr. Rafael GOMES

 

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

 

Director of Thesis : Prof. Gonçalo BERNARDES

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Cancer is the second most common cause of death, after cardiovascular diseases. Early cancer diagnosis is key since it is more likely to be treated successfully. Screening programs such as Blood tests or PET-CT Technology show promise in early detection. Technological advancements in cancer diagnostics are crucial for better patient outcomes. This project aims to develop a tool that will allow early-stage cancer detection employing three main areas: chemistry, protein engineering, and cancer biology. Briefly, we will use rationally designed mini-proteins that bind to protein targets overexpressed in cancer cells.

 

Proteins can be seen as a pearl necklace. Each pearl is an amino acid; a group of molecules with special chemical properties that determine the protein’s structure and function. Having in mind that every amino acid exhibits different properties, we aim to modify the specific ones that will allow us to insert extra features to our protein-target.

 

Specifically, the goal of this project is to develop a strategy to incorporate an isotope of fluorine, 18F, into our protein mini-binder. Fluorine-18 is widely used in medicine and drug development due to its special chemical and nuclear properties, like a glow-in-the-dark sticker. Back to the pearl necklace example, the challenge that we need to address is to find a delicate enough process to incorporate the glow-in-the-dark sticker into one specific pearl, without breaking the necklace or disrupting its folded (3D) structure. Our chemical modification strategy needs to be suitable to our protein targets, avoiding harsh conditions that would unfold our mini-binder and fast enough, before the “glowing” effect is gone.

 

To this day, we have successfully produced and characterized our protein mini-binder. In the meantime, some fluorination strategies have also been tested. The next steps are the optimization of the fluorination process, protein engineering of our model mini-binder, and in-vitro tests with cancer cell lines to assess binding and internalization. After all the in vitro characterization, the in- vivo tests with tumor-bearing mice will be performed to study the metabolic fate and the accumulation profile of our fluorinated mini-binder.

 

One of the main applications of 18F-radiolabeling biomolecules can be in non-invasive imaging techniques such as positron emission tomography (PET). A PET tracer is a special type of substance used in medical imaging. Think of a PET tracer as a tiny detective that helps doctors see what's happening inside your body. The human body can be compared to a city at night. The PET tracer is like a dye that highlights certain buildings (organs or tissues) based on their activity level. The PET scan is like a special camera that can see the glow from this dye, showing doctors a map of how different parts of your body are functioning.

 

PET tracers are an invaluable tool in doctors’ hands to identify cancerous tumors, showing where they are and how big they are, but they are also useful in other diseases like heart-related issues or brain disorders. By developing a strategy to successfully 18F-radiolabel and bio-engineer disease-related mini-binders, we can help doctors detect malfunctioning tissues and select the most suitable therapy.

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