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BETACURE Report Summary

Project ID: 602812
Funded under: FP7-HEALTH
Country: Netherlands

Periodic Report Summary 2 - BETACURE (Personalized diagnosis and treatment of hyperinsulinemic hypoglycaemia caused by beta-cell pathology)

Project Context and Objectives:
Hyperinsulinaemic hypoglycaemia is a potentially lethal disease caused by overproduction of insulin by the beta cells of the pancreatic islets of Langerhans. Lethal hypoglycaemia and brain damage is a problem especially in infants born with the disease. The major challenge of current therapeutic approaches (partial/near total pancreatectomy combined with medical treatment) are the frequently observed severe side effects/morbidity (diabetes, exocrine pancreas insufficiency etc.) considered acceptable in relation to the lethal outcome of the disease itself although they massively reduce quality of life as well as life expectancy.
In order to significantly reduce the side effects of current therapeutic approaches and to increase quality of life and life expectancy, we develop an integrated simultaneous imaging/therapeutic (“theranostic”) platform that will allow targeted image guided surgical, photodynamic and radiopeptide therapy to selectively resect or destroy diseased beta cells.

Congenital hyperinsulinism
Congenital hyperinsulinism (CHI) is a rare disease of infants characterized by presence of functionally defective nonneoplastic beta-cells with inappropriate (over-) secretion of insulin, leading to life-threatning hypoglycaemia. CHI is a major cause of hypoglycaemic brain injury with mental retardation, epilepsy and cerebral palsy. CHI has an incidence of 1 in 50 000 live births and can be divided into two major subforms, a focal (40%-50%) and a diffuse one (50%-60%). While for the focal form cure is possible by surgical resection (if the focus can be identified), diffuse CHI is more difficult to treat as a consequence of the distribution of diseased beta cells throughout the pancreas.
If certain gene mutations are detected, the disease usually responds to diazoxide treatment. However, cases not responsive to medical treatment may require surgical intervention with near-total pancreatectomy (up to 98%) resulting in lifelong diabetes mellitus and pancreatic exocrine insufficiency.
Positron Emission Tomography (PET) with 18F-DOPA (8F-L-3,4-dihydroxyphenylalanine) is used to identify foci of hyperplastic beta cells, surgical resection is then performed by enucleation or partial pancreatectomy. Surgical treatment of CHI is accompanied by considerable morbidity (up to > 40%); however, in many cases surgery only helps to reduce hypoglycemia without achieving complete cure. This condition requires continued medical treatment which also has considerable side effects so that to date, cure without side effects or morbidity cannot be achieved for many if not most patients.

Adult organic hyperinsulinaemic hypoglycemia
Insulinomas derive from pancreatic beta-cells and are the most common form of functional neuroendocrine tumors of the pancreas with an incidence of 1-4 newly diagnosed cases per 1 million per year. Most are benign and have a diameter of less than 2 cm. Resection is the therapy of choice and in many cases, the localization can be determined preoperatively (18F-DOPA PET, MRI (magnetic resonance imaging), endoscopic ultrasound). Ultrasonography in combination with palpation is used to identify the lesion intraoperatively. Another cause of adult hyperinsulinemic hypoglycemia is nesidioblastosis and it appears that in approximately 5% of the cases of adult hyperinsulinemic hypoglycaemia (AHH) nesidioblastosis may be the underlying pathology while insulinoma is responsible for the majority of cases.

Objectives of BetaCure
BetaCure aims at overcoming the key challenges so far preventing optimized individual patient-tailored treatment of CHI and AHH, aiming to reduce side effects while achieving high cure rate with low morbidity, improved quality of life and survival. We will develop a theranostic platform utilizing tracer molecules as (intraoperative) biomarkers specifically targeting the beta-cells that will allow
• preoperative non-invasive localization of foci in CHI and AHH with higher sensitivity and specificity than currently available imaging tracers (see attached figure1)
• pre-operative calculation of the exact volume of beta cells to be destroyed in order to achieve cure in diffuse CHI/AHH
• intraoperative visualization of diseased beta cells for individualized image guided surgery allowing to reduce morbidity
• laparoscopic highly specific and quantitative treatment of diseased beta cells without requiring resection of large quantities of pancreatic tissue with potential for repeated treatment until cure is achieved
• non-invasive systemic treatment of diseased beta cells in selected patients
Project Results:
The consortium has achieved the following:
• Development and clinical testing of an innovative highly sensitive open air fluorescence camera for real time imaging in image guided surgery
• Extension of optical path through a coherent fibre bundle and imaging of cancer lesions in an endoscopic setting and successful imaging experiments ex vivo through a laparoscope
• Inclusion of the coherent fibre bundle into a system suitable for delivery of endoscopic targeted photodynamic therapy, which is currently under optimization
• Different Exendin compounds for imaging were evaluated and show promising results, including detection of insulin producing tumors in patients suffering from hypoglycaemias for several years
• In vitro and in vivo experiments with Exendin labeled with fluorescent dyes and photosensitizers show highly promising tPDT and IGS properties
• An innovative F-18 labeled compound has been developed for optimized imaging of beta cell pathology and clinical trials are under preparation
• The kit labeling technology of Ga-68-Exendin-4 for clinical trials is established and has been successfully implemented in several centers, including adaptation to local requirements – this achievement forms the basis for future market implementation
• Concepts for kidney uptake reduction of radiolabeled Exendin have successfully been tested in humans
• Production of tracers (radiotracers and optical tracers) according to full GMP standards has been achieved or is ongoing
• In vitro and in vivo evaluation of photodynamic therapy of beta cells has been optimized and now shows highly promising results
• Training activities have covered GMP production and GMP product handling, data management, ethics, PET standardization, etc. and are still ongoing according to requirements
• Dissemination activities on international and national scientific and patient/family conferences
• Design and programming of the project website ( and intranet.
• Seven project meetings successfully organized and minuted.
Potential Impact:
The innovative theranostic technological platform under development in BetaCure is expected to have a high impact on patient management in beta cell-derived diseases. This technology will allow to individually tailor therapy concepts and will help to massively reduce the side effects of treatment (especially in infants with CHI) that are currently accepted in order to avoid life threatening hypoglycaemias and early death. Specifically, the consequences of diabetes resulting from therapeutic intervention will be avoided; this will help to increase the quality of life and improve life expectancy especially in CHI patients.
BetaCure is developing standards for quantitative imaging and IGS/tPDT expected to have a massive influence on international guide lines and subsequently patient treatment. The theranostic platform developed in BetaCure will become available on an international level so that the implementation of these innovative technological standards can comparatively easily be achieved in clinical practice.
The data base together with the electronic data management system and the quality control system for scanners implemented in BetaCure will serve as a basis for further optimization of IGS and tPDT after the runtime of the project and will be open for other projects, thereby helping to enhance quality and competitiveness of European research in molecular imaging and therapy.
The technologies developed in this consortium are innovative European technologies. The results obtained in BetaCure can easily be translated to other diseases, boosting innovation capacity in IGS and tPDT, and will help to increase international competitiveness of the European industry. We expect that BetaCure partners will profit from additional patents resulting from technical development achieved through BetaCure research. SMEs with R&D capacities have a leading role in this project; this will help to further enhance European research capacities, and the expected outcomes will be of clear interest and potential benefit to the SMEs participating in the project.
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