Development and Delivery of Candidate Retinoblastoma Therapeutics

Abstract

Purpose: While mortality is low with aggressive multimodal therapy, partial or full loss of vision occurs in approximately 50% of patients with advanced bilateral retinoblastoma. There is an urgent need to develop targeted therapies that preserve vision and reduce late effects of current treatment modalities, which include facial malformations and increased incidence of secondary malignancies. Candidate therapeutics should ideally (1) completely clear disease to prevent progression and metastasis, (2) be well tolerated locally to preserve vision, and (3) act quickly to overcome rapid clearance from the eye. Phase I and II clinical trials for retinoblastoma are difficult due to the young age of the patient population and relative rarity of the disease. Therefore robust preclinical testing of new therapies is critical.

Methods: To meet this need, we conducted library screening of approximately 300 compounds using focused libraries from St. Jude Children’s Research Hospital (SJCRH) chemical collection to determine in vitro potency in retinoblastoma cell lines (RB355, Weri, and Y79) and a normal human fibroblast control cell line (BJ). Further in vitro testing was conducted to prioritize “hits” (compounds active in retinoblastoma cells, but not BJ cells). For lead compounds, we determined speed of effect with washout studies and cidality with outgrowth studies. Synergy testing was performed to eliminate candidates with antagonistic interactions with current standard of care retinoblastoma drugs and prioritize any with strong agonism. We characterized pharmacokinetics (PK) to compare intraocular exposure for different routes of delivery (local and systemic) for high priority candidates.

Results: Screening identified several candidates to advance to the preclinical testing phase, including histone deacetylase (HDAC) inhibitors and FDA-approved oncology drugs that might be repurposed for ocular use with local delivery methods. Consistent with treatment goals and the unique constraints of reaching an intraocular target, we prioritized HDAC inhibitors with rapid, cidal, potent and selective effects on retinoblastoma cells in vitro.

Conclusions: In vitro and PK testing suggest local delivery of HDAC inhibitors represents a promising potential targeted therapy for retinoblastoma. Next steps will include toxicity and efficacy testing in preclinical animal models of retinoblastoma.