Notch Program

The Notch gene family encodes four receptors (Notch 1-4) on the surface of cells, whose activity has been shown to play important roles in normal stem cell function and in multiple aspects of tumor biology. Notch signaling is believed to be important in various aspects of tumorigenesis, including angiogenesis, and for the maintenance of cancer stem cells. These stem cells are thought to represent a distinct cell population in tumors and may cause tumor metastasis and relapse by regenerating the tumor tissue. Dysregulated Notch expression has been linked to many human cancers, including breast cancer, lung cancer, skin cancer, brain cancer, T-ALL, B-CLL, and thyroid cancer. Genetic screens conducted in AVEO’s HRP have demonstrated that activation of the Notch signaling pathway is a potent driver of tumor growth and confirmed its important role in tumor formation.

 

The goal of AVEO’s Notch drug discovery efforts is to identify specific inhibitory antibodies to Notch1, Notch2 and Notch3 that prevent ligand binding and activation of the receptors. AVEO has generated functional inhibitory antibodies against the Notch1 and Notch3 receptors. AVEO’s most advanced Notch antibody, targeting Notch1, specifically inhibits activation of this receptor and downstream signaling by Notch ligands. AVEO has demonstrated in vivo proof of concept with its lead Notch1 antibody in preclinical models, where it inhibits thymocyte development, alters T-cell fate specification, inhibits functional angiogenesis, and induces loss of hair pigmentation through inhibition of melanocyte stem cells, all well described effects of Notch1 inhibition. Importantly, in these preclinical models, AVEO’s lead Notch1 antibody shows no evidence of the gastrointestinal toxicity that has limited the clinical development of other Notch inhibitors. Further preclinical testing is ongoing, and humanization of the lead murine Notch1 antibody is in progress.

 

AVEO is utilizing its HRP to investigate the context in which Notch inhibition, either alone or in combination with AVEO’s investigational triple vascular endothelial growth factor (VEGF) receptor inhibitor, tivozanib, would have the greatest efficacy. Because the blockade of Notch1 signaling results in a potent inhibition of angiogenesis by a mechanism that differs from VEGF inhibition, AVEO believes that the blockade of both pathways simultaneously offers the potential to increase the efficacy of anti-angiogenesis therapy. Notch1 inhibitors may also work in tumor contexts that are resistant to VEGF inhibitors.

 

AVEO is also exploring preclinical models to determine which tumors might be uniquely dependent on Notch1 function for survival as another mechanism of action for tivozanib. Company scientists have identified the HeyL protein as a biomarker that identifies a significant subset of tumors driven by the mutant Ras oncogene that may depend on Notch function. Specifically, high levels of HeyL in colon and pancreatic cell lines that carry a mutated form of Ras correlate with the sensitivity of these tumors to Notch pathway inhibitors. In June 2009, AVEO was granted a U.S. patent on a method of identifying cancer tissue likely to be sensitive or resistant to treatment with an inhibitor of Notch receptor activation.

 

In addition to a long list of potentially attractive opportunities in cancer, a growing body of literature suggests that the inhibition of Notch signaling may also have interesting clinical and commercial opportunities in other indications, including immune diseases and cardiovascular applications for Notch1 and Notch3 antibodies, respectively.