Grant: Project Grant - Priority Announcement: Early Detection/Cancer Prevention

Cancer is a deadly disease that most often evolves in a step-wise manner. Initially, cells accumulate abnormally in a defined location in the body (benign tumor). Then it evolves into a frank malignant tumor as it grows and invades local tissue structure (malignant tumor). Finally, some cells can seed at distant sites and further grow (metastatic tumor). Almost universally, the sooner the diagnostic is done, the better the survival rate is. Over the past few years, we focused our attention on patients with a genetic predisposition to tumor formation. It turns out that some of these syndromes promote benign tumor formation but rarely manifest as a frank malignant tumor or metastatic tumor. When I will understand how these tumors are refractory to malignant progression, then I can foresee a new generation of anti-cancer therapeutics aiming at mimicking the mechanisms discovered in these hereditary benign tumor syndromes. One of these syndromes is Neurofibromatosis Type I. Our preliminary results using a mouse model recapitulating the typical tumor in neurofibromatosis suggests a novel mechanism impairing malignant progression: the release of certain proteins with tumor-suppressing properties by the normal cells surrounding tumoral cells. In this grant proposal, I will identify those factors and the cells producing them. I will make the demonstration using a mouse model that these factors indeed act as a gate, preventing malignant progression. Following this validation phase, medicinal chemists could begin to make drugs and systematically test them using our mouse model. This is a mandatory step in our quest to launch a novel generation of anti-cancer therapeutics, not only for Neurofibromatosis Type I patients but for the large population of cancer patients.