Metastasis is the major factor responsible for the death of cancer patients. Lung and breast cancer are highly aggressive tumors and clinical evidence demonstrates that brain and liver are tumor-supporting microenvironments for successful metastatic colonization of these cancers. The microenvironment provides molecules/nutrients which may act inducing the invasion of the parenchyma and sustain the cell's metabolic demand in the novel site. Brain microenvironment is rich in serine and glycine, glutamine, glutamate since these aminoacids are not only nutrients but also important neurotransmitters.
For this project we will set a model in vitro to study the interaction between endothelial cells of BBB and breast or lung cancer cells to understand if this interaction trigger the invasive process. In more detail we want to clarify the influence that cancer cells have on the process of amino acids release by the brain through the process called "brain to blood efflux" and the influence that these aminoacids have in the invasive process of the cerebral parenchyma by lung and breast cancer cells.
Epidemiological studies demonstrate that 19-40% of patients with lung cancer and 5-20% of patients with breast cancer will develop brain metastasis. Regardless of the origin of the primary tumor, patients with cerebral metastasis have a poor prognosis with a median survival between 2 and 12 months.
At the moment the efficiency of the therapies available are absolutely unsatisfactory, the 3-year survival rate of these patients is only 4.8%.
We want to use an in vitro model to study the interaction between tumor cells and BBB cells and in particular to test the use of inhibitors of amino acids uptake to block the ability of lung and breast cancer cells to invade the brain parenchyma. In particular, we propose the use of well-known molecules such as sarcosine, 4LFPG and DL-TBOA already used in the treatment of pathologies of the CNS.
We believe that the data produced through this project will be fundamental to demonstrate that our new approach, based on the prevention of the development of metastases using previously known (and considered safe) molecules, is a ground-breaking idea that may lead to a paradigm-shift in the way this issue is addressed.