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8 juni 2019: Bron: persbericht van EANM (impressum health & science communication)

Een nieuwe manier van het maken van een petscan - Positron emission tomography maakt uitzaaiingen van verschillende solide tumoren veel beter zichtbaar en geeft ook betere informatie hoe en welke personalised medicine zouden kunnen worden ingezet. De nieuwe methode houdt in dat de petscan wordt gegeven samen met een contrast vloeistof die zich richt op een bepaald eiwit, een zogeheten fibroblast activation protein (FAP). 

 “By targeting a particular enzyme found on the membrane of cancer-associated fibroblasts we may achieve a better outcome than with the methods used so far,” says Professor Uwe Haberkorn, expert of the European Association of Nuclear Medicine (EANM)

Dit enzyme wordt veel waargenomen op het membraan, de schil van aan kanker geassocieerde fibroblasten. Deze cellen (fibroblasten - CAF's) zijn aanwezig in meer dan 90 procent van plaveiseltumoren, waaronder bijvoorbeeld bij vormen van  alvleesklierkanker, eierstokkanker, darmkanker en borstkanker.

Veelvuldig aanwezig zijn van het fibroblast activation protein (FAP) duidt op een slechte prognose van de ziekte. Hoewel CAF's betrokken zijn bij de groei en verspreiding van de tumorcellen, zijn ze zelf geen kankercellen. Omdat ze genetisch stabieler zijn dan kankercellen, ontwikkelen ze minder vaak therapieresistentie. 

Al deze kenmerken maken het fibroblast activation protein (FAP) een veelbelovend doelwit voor zowel nucleaire medische diagnostiek als therapeutische benaderingen,” zegt EANM expert Prof. Uwe Haberkorn die deze nieuwe manier van Petscan diagnostiek ontwikkelde met zijn collega's uit Heidelberg.

Het persbericht: Fighting cancer: New PET-imaging method improves diagnosis and treatment of widespread carcinomas is als PDF aan te klikken.

Het studierapport: Development of novel FAP‐targeted radiotracers with improved tumor retention is volledig en gratis in te zien.

Onderaan artikel het abstract van de studie:

Hier het persbericht:

EANM PRESS RELEASE Fighting cancer: New PET-imaging method improves diagnosis and treatment of widespread carcinomas
(Vienna, March 19, 2019) In fighting cancer an early and accurate diagnosis is crucial.  A new nuclear medicine imaging method within the field of Positron emission tomography (PET) facilitates a more precise diagnosis of widespread carcinomas such as breast, colon, pancreas or lung cancer. Moreover, the novel imaging technique can combine the detection of the tumor with its treatment according to the patient’s individual needs. “By targeting a particular enzyme found on the membrane of cancer-associated fibroblasts we may achieve a better outcome than with the methods used so far,” says Professor Uwe Haberkorn, expert of the European Association of Nuclear Medicine (EANM).    
The leading part within the newly developed PET imaging concept is played by the so-called fibroblast activation protein (FAP). This enzyme is found abundantly on the membrane of Cancer-associated fibroblasts (CAFs). These cells are present in more than 90 percent of epithelial carcinomas, including for example pancreatic, colon and breast cancer. High occurence of FAP indicates a poor prognosis. However, although CAFs are involved in the growth and spreading of the tumor they are no cancer cells themselves. Since they are genetically more stable than cancer cells they are less likely to develop therapy resistance. “All these characteristics make FAP a promising target for nuclear medical diagnostic as well as therapeutic approaches,” says EANM expert Prof. Uwe Haberkorn who developed the new imaging method together with his team in Heidelberg. 
Outperforming the standard methods
PET imaging always requires that the patient be injected with a small amount of a radioactively labeled substance, a so-called tracer, by which biological processes such as the metabolism of tumor cells can be targeted and made visible through the imaging system.  So far, the most commonly used tracer has been 18F-fluorodeoxyglucose (FDG), a radioactively-marked sugar, taken up by cells with high-energy consumptions such as cancer
 or the brain. However, as Prof. Haberkorn points out, the results achieved with FDG with regard to tumor uptake and image contrast are not always satisfactory. 
Against this backdrop his team developed a novel tracer based on an FAP-specific enzyme inhibitor (FAPI), a small molecule that binds to the FAP by blocking its chemical reaction. The FAPI-tracer which is labeled with the radionuclide gallium-68 shows high uptake by the tumors but fast clearance by the healthy parts of the body. This results in high-contrast images due to very low binding to the surrounding healthy tissue in tumor patients, thus clearly outperforming FDG in important regions of metastatic disease such as the liver and the brain. The positive outcome has been repeatedly demonstrated by a number of preclinical and clinical studies.
Intertwining diagnosis and therapy
“Radiolabeled FAPIs allow for fast imaging with very high contrast in all tumors that contain a high amount of connective tissue cells,” says Prof. Haberkorn. But there is even more to it: “FAPIs, as opposed to FDG, can also be employed for treatment purposes. This is due to chemical properties allowing labeling not only with gallium-68, but also with radionuclides such as rhenium-188 (188Re), lead-212 (212Pb) or yttrium-90 (90Y) that can be used to destroy the tumor. That means, a theranostic approach – a tight intertwining of diagnosis and therapy taylored to the individual patient’s needs – seems feasible.”  FAPI-imaging is not even restriced to cancer since it can be applied to all processes that involve the remodelling of tissue. This makes it very likely that the technique will soon be used for diagnosing and treating non-cancerous conditions too, such as cardiovascular and rheumatic diseases as well as fibroses of the lung, the liver and the kidney.
So far, the new tracer has been successfully applied to several hundreds of patients in a number of hospitals in Germany, and is currently being used for preclinical studies in the US and Japan. “FAPI-imaging has opened up a promising avenue for the detection and treatment of many malignant tumors and offers additional potential with respect to several other diseases,“ says Prof. Haberkorn.   
https://www.facebook.com/officialEANM.
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Press contact   impressum health & science communication   Frank von Spee E-Mail: vonspee@impressum.de  
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Chemical modification of the FAPI framework enabled enhanced FAP-binding and improved pharmacokinetics in the majority of the derivatives, resulting in high contrast images. Moreover, higher doses of radioactivity can be delivered while minimizing damage of healthy tissue, which may improve therapeutic outcome.

2019 Mar 8. pii: jnumed.118.224469. doi: 10.2967/jnumed.118.224469. [Epub ahead of print]

Development of novel FAP-targeted radiotracers with improved tumor retention.

Abstract

Purpose: Cancer associated fibroblasts constitute a vital subpopulation of the tumor stroma and are present in more than 90% of epithelial carcinomas. The overexpression of the serine protease fibroblast activation protein (FAP) allows a selective targeting of a variety of tumors by inhibitor-based radiopharmaceuticals (FAPIs). Of these compounds, FAPI-04 has been recently introduced as theranostic radiotracer and demonstrated high uptake into different FAP-positive tumors in cancer patients. To enable the delivery of higher doses, thereby improving the outcome of a therapeutic application, several FAPI variants were designed to further increase tumor uptake and retention of these tracers. Methods: Novel quinoline-based radiotracers were synthesized by organic chemistry and evaluated in radioligand binding assays using FAP-expressing HT-1080 cells. Depending on their in vitro performance, small animal PET imaging and biodistribution studies were performed in HT-1080-FAP tumor bearing mice. The most promising compounds were used for clinical PET imaging in a total of 8 cancer patients. Results: Compared to FAPI-04, 11 out of 15 FAPI derivatives showed improved FAP binding in vitro. Of these, 7 compounds demonstrated increased tumor uptake in tumor bearing mice. Moreover, tumor-to-normal organ ratios were improved for a majority of the compounds, resulting in images with higher contrast. Notably two of the novel radiotracers, FAPI-21 and -46, displayed substantially improved ratios of tumor to blood, liver, muscle, and intestinal uptake. A first diagnostic application in cancer patients revealed high intratumoral uptake of both radiotracers already ten minutes after administration, but a higher uptake in oral mucosa, salivary glands and thyroid for FAPI-21. Conclusion: Chemical modification of the FAPI framework enabled enhanced FAP-binding and improved pharmacokinetics in the majority of the derivatives, resulting in high contrast images. Moreover, higher doses of radioactivity can be delivered while minimizing damage of healthy tissue, which may improve therapeutic outcome.

KEYWORDS:

FAP inhibitor; Fibroblast activation protein; Oncology: General; PET/CT; Radiopharmaceuticals; theranostics; tracer development

PMID:
30850501
DOI:
10.2967/jnumed.118.224469

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