Abstract
Purpose :
The primary goals of intraocular retinoblastoma (RB) therapy are cure and ocular salvage; however, nonselective systemic chemotherapy remains the standard of care, and enucleation is a frequent outcome for advanced disease. The eye provides a unique opportunity for local, concentrated delivery of therapeutic agents targeting specific mechanisms of RB pathogenesis to minimize systemic exposure and side effects while maximizing efficacy. Previous studies have implicated the MDMX protein in suppressing the p53 pathway in RB and shown that Nutlin-3a, an MDM2 inhibitor with moderate MDMX antagonism, has promising activity in mouse models of RB by intravitreal (iV) dosing but was not feasible for clinical use due to solubility. ALRN-6924 is a soluble, cell-permeating, stabilized alpha-helical peptide with equipotent affinity to MDMX and MDM2 in clinical development in adult and pediatric cancer patients. We evaluated ALRN-6924 in preclinical models of RB.
Methods :
Isotonic, pH-neutral solutions of ALRN-6924 were used with sterile saline as diluent; no other additive was required. Proliferation of Weri and Y79 RB cell lines was measured by Cell-Titer-Glo, with gene expression measured by using total stranded RNA-sequencing.
Results :
ALRN-6924 inhibited Weri1 and Y79 RB cell proliferation with an EC50 of 7 nM and 12 nM, respectively, vs. Nutlin-3a with EC50 of 40 nM and 70 nM. CDKN1A, MDM2, GADD45A and BTG2 gene expression was upregulated, consistent with on-mechanism p53 activation
Conclusions :
ALRN-6924 is highly soluble, compatible with intraocular injection, and shows potent, on-mechanism anti-proliferative activity in RB cell lines. Based on these results and more favorable comparison with Nutlin-3a, a phase I trial with intraocular injection of ALRN-6924 in RB patients with recurrent/refractory vitreous seeding is planned.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.