Final Report Summary - AZNETAC (A zebrafish model of pancreatic neuroendocrine tumor to test resistance to antiangiogenic compounds)
Neuroendocrine tumours (NETs) consist of a range of malignant diseases that may arise from any (neuro)endocrine cell situated in any part of the human body. The NETs are considered rare; however, a significant increase in NET incidence over the past three decades has been shown in the western countries.
Recently, promising advances have been described in the management of these tumours when the surgical approach is not possible. Two small molecule inhibitors were approved by the European authorities for NETs: sunitinib, an antiantiogenesis compound, which shows activity in well-differentiated neuroendocrine tumours of the pancreas and the mTOR inhibitor everolimus in the same tumours. Not all patients with pancreatic neuroendocrine tumours (pNETs) will benefit from new drugs. For some patients, the cancer may not respond to treatment; they may even become more unwell because of the drug side-effects. We are looking for ways to select the right drug. In our project we aimed to generate a model that could allow us to investigate why these drugs stop working.
Our objectives were to generate a transgenic fish strain that would provide the opportunity to study the processes by which these rare tumours develop and spread. Moreover, we aimed to be able to test how resistance to anti-angiogenic compounds such as sunitinib develops.
After 3 different strategies used, we were able to generate one inducible transgenic fish strain that now seems to be stable. The initial 2 approaches failed compelling us to instigate the latter strategy that we now anticipate will allow us to commence experiments with different drugs in the near future.
Due to the problems we experienced in relation to the transgenic approach we developed in parallel a xenograft model consisting in injecting pancreatic neuroendocrine tumour derive human cell lines into 48 hours post fertilization embryos of a transparent fish strain expressing GFP in their vasculature named Casper kdrl:eGFP. Using this methodology we are able to study how the vasculature of the fish interacts with the human malignant cells (Figure 1) and interrogate this interaction using different drugs to study why they stop working and how we can overcome the resistance to them.
In summary, we are in a privileged position to generate hypothesis for new clinical trials using our zebrafish models as a testing platform for new strategies of treatment of these rare diseases.
In the future, we expect our work could be a cornerstone in selection of the right treatments for the right patients avoiding toxicity problems of non-active treatments.
Recently, promising advances have been described in the management of these tumours when the surgical approach is not possible. Two small molecule inhibitors were approved by the European authorities for NETs: sunitinib, an antiantiogenesis compound, which shows activity in well-differentiated neuroendocrine tumours of the pancreas and the mTOR inhibitor everolimus in the same tumours. Not all patients with pancreatic neuroendocrine tumours (pNETs) will benefit from new drugs. For some patients, the cancer may not respond to treatment; they may even become more unwell because of the drug side-effects. We are looking for ways to select the right drug. In our project we aimed to generate a model that could allow us to investigate why these drugs stop working.
Our objectives were to generate a transgenic fish strain that would provide the opportunity to study the processes by which these rare tumours develop and spread. Moreover, we aimed to be able to test how resistance to anti-angiogenic compounds such as sunitinib develops.
After 3 different strategies used, we were able to generate one inducible transgenic fish strain that now seems to be stable. The initial 2 approaches failed compelling us to instigate the latter strategy that we now anticipate will allow us to commence experiments with different drugs in the near future.
Due to the problems we experienced in relation to the transgenic approach we developed in parallel a xenograft model consisting in injecting pancreatic neuroendocrine tumour derive human cell lines into 48 hours post fertilization embryos of a transparent fish strain expressing GFP in their vasculature named Casper kdrl:eGFP. Using this methodology we are able to study how the vasculature of the fish interacts with the human malignant cells (Figure 1) and interrogate this interaction using different drugs to study why they stop working and how we can overcome the resistance to them.
In summary, we are in a privileged position to generate hypothesis for new clinical trials using our zebrafish models as a testing platform for new strategies of treatment of these rare diseases.
In the future, we expect our work could be a cornerstone in selection of the right treatments for the right patients avoiding toxicity problems of non-active treatments.