Preclinical Profile of a Potent γ-Secretase Inhibitor Targeting Notch Signaling with In vivo Efficacy and Pharmacodynamic Properties

Abstract

Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of γ-secretase, producing inhibitory activity of Notch signaling in tumor cells. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch-related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way.

Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment

“…1A). In agreement with previous data 12,27 inhibition of Notch with RO4929097 in MM cells did not affect their viability as evaluated by MTT assay (Fig. 1B), and induced only minimal apoptosis in human MM cell line (Fig.…”

“…These results are in agreement with data reported by Luistro et al showing anti-angiogenic activity of this Notch inhibitor. 12 As expected, RO4929097 downregulated Notch target gene Hes1 expression and substantially decreased gene expression of all 3 VEGF receptors, but not VEGF ligand (Fig. 3D).…”

“…[8][9][10][11] RO4929097 is a potent g-secretase inhibitor (GSI) that also blocks Notch signaling and leads to reduced expression of the Notch transcriptional target gene Hes1. 12 This investigational drug has demonstrated evidence of antitumor activity in preclinical models of melanoma, colon, pancreatic and lung cancer 12,13 and had been tested in phase II clinical trials for solid tumors. [14][15][16][17] While RO4929097 has been well tolerated, it has insufficient anti-tumor activity as a single agent for solid tumors.…”

Application of Stem Cells in Targeted Therapy of Breast Cancer: A Systematic Review

“…This finding provides an opportunity for specifically targeting CSCs which are responsible for tumor initiation, progression, recurrence and metastasis (Curtin and Lorenzi, 2010). Significant progress has been made in developing therapeutics targeting Notch and Hh (Luistro et al, 2009;Robarge et al, 2009), whereas the Wnt pathway has been more challenging for targeted therapy (Curtin and Lorenzi, 2010).…”

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

“…Various preclinical trials show that GSIs have strong antitumor effects (73,74). When treated with MK-0752 in phase I studies, clinical benefits such as complete response (CR) and prolonged stable disease (SD) were observed (75)(76)(77)(78).…”