Targeting the Notch Signaling Pathway: A Novel Method to Inhibit Sarcomas with Constitutive Ras Activation
This grant examines the feasibility of targeting notch signaling in malignant peripheral nerve sheath tumors (MPNST’s), an aggressive sarcoma subtype with activation of ras signaling. We are studying notch because it is involved in ras transformation and MPNST’s express high levels of ras and notch. Notch may be disrupted by inhibiting its cleavage into an active form with gamma-secretase inhibitors (GSI’s), which have been developed by our collaborator Dr. Yueming Li. We hypothesize that notch disruption in MPNST’s with GSI’s will cause apoptosis, despite ras activation. Our preliminary data suggests notch can be disrupted by GSI’s in multiple cell lines, causing apoptosis that is p53-independent but through an unknown mechanism. Therefore, we will first characterize the notch receptors that are down-regulated by GSI’s in MPNST’s. We hypothesize that Notch1 is important, as it is implicated in ras signaling. Second, we will characterize the mechanisms of apoptosis by GSI’s. We hypothesize that notch disruption inactivates Akt, allowing BAD and NOXA to initiate apoptosis. Third, we will identify targets shared by notch and ras. We hypothesize that notch and ras share upstream signals (Ras or PI3K) and downstream targets (Akt). By studying GSI’s in MPNST’s, our goal is to define a new therapy for solid tumors with ras activation. We believe our partnership with Dr. Li and our record with preclinical discoveries will translate notch inhibitors into a Phase I clinical trial, a strategy that may define a new chemotherapy class for solid tumors.