Abstract B188: Inhibition of Notch signaling for the treatment of cancer
2009
The Notch pathway is a highly conserved signaling system that plays an important role in development and tissue homeostasis. While Notch mutations are well characterized and implicated in hematological malignancies such as T‐cell acute lymphoblastic leukemia, in solid tumors ligand or receptor over‐expression may lead to enhanced/sustained Notch function, triggering increased tumor cell proliferation/survival, angiogenesis and tumor formation. In order to delineate an oncogenic role of activated Notch in tumors of epithelial origin, we carried out a series of in‐vitro and in‐vivo studies. We demonstrated that the activated Notch1 receptor (a ‐ secretase‐dependent Notch1 E with the transmembrane domain and a‐secretase‐independent constitutively activated Notch1 intracellular fragment) can transform normal rat cells, RK3E. These transformed cells formed colonies in soft agar, confirming their anchorage‐independent growth potential, and when implanted subcutaneously, formed tumors in athymic nude mice. Inhibition of Notch signaling through a small molecule inhibitor of ‐secretase, a key regulator of Notch processing, may provide an attractive targeted cancer therapeutic strategy. We have identified and characterized a novel small molecule that is an exquisitely potent inhibitor of Notch signaling in tumor cell lines and endothelial cells with an IC 50 ranging from 0.005 nM to 20 nM. The Notch inhibitor meets all pharmacokinetic criteria in pre‐clinical species. In a xenograft tumor model, the novel compound inhibited Notch cleavage in a dose‐dependent manner at 6 hours after a single oral dose. This inhibition of Notch cleavage resulted in the induction of apoptosis (as measured by activated caspase‐3 levels) that was statistically significant at 24 hours after a single oral dose of 3 mg/kg. Analysis of tumors from animals treated with the Notch inhibitor revealed inhibition of angiogenesis through formation of leaky vasculature which may also contribute to observed anti‐tumor activity. Furthermore, Notch inhibition produced tumor regression in the Notch‐dependent tumor models. Anti‐tumor activity was also observed in several human xenograft tumors of epithelial origin. To mitigate mucoid gasteroentropathy due to Notch inhibition, PK/PD data were incorporated in devising dosing strategies that identified an optimal intermittent dosing schedule without negatively impacting efficacy. Furthermore, the mucoid gastroentropathy was also mitigated by the prophylactic administration of dexamethasone without negatively impacting Notch inhibitor mediated efficacy. In summary, we have characterized an orally bio‐available small molecule Notch inhibitor that may provide therapeutic benefit to cancer patients. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B188.
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