Grant: Project Grant

Normal functioning of the body requires that all the cells accomplish their function according to a precise and detailed plan. When normal growth or modulatory signals are altered this results in an imbalance of signals that together promote growth, suppress death, and enhance the invasive capacity of cells contributing to cancer growth and progression. One of the important signals involves a regulator of growth and invasion called the Met receptor. Met controls normal tissue organization during development and wound healing, but when Met signals are aberrantly activated in human solid cancers, such as lung, gastric, kidney, head and neck and hard to treat breast cancers Met contributes to tumour cell invasion, resistance to therapies and progression to metastases. We now know that a particular alteration in the Met receptor, involving a new and poorly understood variant called delta exon 14, occurs as a mechanism of resistance to precision therapies currently in the clinic for many of these cancers. Increasing evidence supports the use of Met-targeting therapies in cancers that harbor molecular alterations in Met but we also need to identify patients who will respond to such therapies as well as those who will develop alterations in Met as a mechanism of resistance to other therapies currently in the clinic. By building a multidisciplinary team of surgeons, clinician scientists as well as fundamental researchers with innovative technologies and leadership in Met, we propose to acquire new mechanistic understanding on how Met promotes aggressive and therapy resistant cancers, as well as develop biomarkers to predict Met dependent mechanisms of resistance to precision therapies in the clinic and elaborate novel strategies to improve patient selection, response to current therapies with a goal to delay and overcome drug resistance and metastasis.