Targeting Notch Altered Patient Derived Xenografts (PDX) with AL101

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Presented by

Joel Kaye, PhD, VP Research & Nonclinical Development, Ayala Pharmaceuticals

About this talk

Notch pathway activation has been implicated in the development of cancer. Notch cleavage by γ-secretase frees the Notch intracellular domain (NICD), which promotes the expression of target genes involved in tumorigenesis. Tumors in which Notch has an oncogenic role often harbor activating alterations that promote ligand-independent Notch cleavage generating high levels of NICD, or alternatively alterations that result in sustained activity of NICD. Notch activating alterations have been found in several cancers including Adenoid Cystic Carcinoma (ACC) and Triple Negative Breast Cancer (TNBC).AL101 is an investigational small molecule pan-Notch γ-secretase inhibitor, previously testedin 3 Phase I trials as monotherapy or in combination regimens in > 200 solid/hematologic cancer patients. Here, we describe the preclinical work evaluating the effect of AL101 patient derived xenograft (PDX) tumor models with Notch activating genetic alterations. We demonstrate that PDX tumors bearing Notch activating genetic alterations are exquisitely sensitive to AL101 monotherapy. In both ACC & TNBC models, significant tumor growth inhibition (TGI) was seen only in Notch activated models. AL101 had nosignificant effect on tumors lacking Notch activating mutations. In addition, we also analyzed the effect of AL101 on Notch target genes using RNA-Seq and Western blot or Immunohistochemistry (IHC). These data support the clinical development of AL101 asa targeted therapy for tumors bearing Notch activating genetic alterations. Indeed, we are currently investigating AL101 in 2 Phase II open-label, single-arm, multicenter study in ACC patients (ACCURACY; NCT03691207) or TNBC (TENACITY; NCT04461600) harboring known Notch1-4 activating alterations

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