Abstract 1789P
Background
ACC & TNBC are tumors associated with Notch signaling pathway dysregulation. Ayala is targeting Notch activated tumors with investigational small molecule pan-Notch γ-secretase inhibitors AL101 & AL102. AL101 is currently being investigated in 2 phase II open-label, single-arm, multicenter studies in ACC (ACCURACY; NCT03691207) and TNBC (TENACITY; NCT04461600) in patients harboring known Notch1-4 activating alterations. Notch interacts via crosstalk with other signaling pathways, and here we describe testing for their identity to provide guidance for future combination studies with AL101.
Methods
Beyond known dysregulated pathways in ACC, we investigated additional pathways using a bioinformatic approach. We calculated differential gene expression in tumors versus normal tissue regardless of Notch activation status, then focused on significantly upregulated genes common in all studies to identify enriched pathways (FDR<0.05) using MetacoreTM (Compare Experiments workflow) Our strategy for compound selection focused on pathways that are targetable with approved oncology drugs. To test whether combinations provided added benefit, we compared each drug alone or in combination using PDX models.
Results
In ACC, the most significantly dysregulated pathway in tumor vs normal was Notch, although the mutational status of the tumors was unknown. Following AL101 treatment in ACC PDX tumors, Notch pathway genes are downregulated regardless of their mutational status. This suggests combining AL101 with other drugs can be beneficial in both Notch activated and wild type ACC. Indeed, combination of AL101 with inhibitors of the identified pathways, Bcl2, HDAC, FGFR & CDK4/6 demonstrated significant tumor growth inhibition compared to each drug alone. This confirms dual targeting of Notch and other dysregulated pathways provides significant benefit. We are using a similar approach to test combinations in other tumor types including TNBC.
Conclusions
These data support a strategy of combination therapy with AL101 in ACC tumors, regardless of mutational status. It also provides a promising approach for expansion to other cancer indications in which the Notch pathway is dysregulated.
Clinical trial identification
NCT03691207; NCT04461600.
Editorial acknowledgement
Legal entity responsible for the study
Ayala Pharmaceuticals.
Funding
Ayala Pharmaceuticals.
Disclosure
R. Ferrarotto: Financial Interests, Institutional, Principal Investigator: Ayala Pharma. R. Rauch, T. Leibovich: Financial Interests, Institutional, Full or part-time Employment: Ayala Pharma. A. Shitrit, E. Herz, R.M. Walker: Financial Interests, Personal and Institutional, Full or part-time Employment: Ayala Pharma. O. Solomon: Financial Interests, Personal and Institutional, Stocks/Shares: Ayala Pharma. A.L. Ho: Financial Interests, Institutional, Advisory Role: Ayala Pharma. J. Kaye: Financial Interests, Personal, Full or part-time Employment: Ayala Pharma.