Retinoblastoma (RB) is the most common intraocular malignancy in children. The recent introduction of intra- arterial chemotherapy (IAC) and intravitreal injections, both using melphalan-based regimens, has improved globe survival for eyes with advanced RB, while avoiding the systemic toxicities of intravenous chemotherapy. However, melphalan is toxic to the retina and retinal vasculature, and both treatments are associated with many ocular side effects, potentially resulting in life-long loss of vision. The goal of this research is to identify alternative drugs that are less toxic to the ocular structures but remain effective against intraocular RB, for use via IAC and intravitreal injection. In rabbits, we have developed the only small animal model of IAC, and have demonstrated excellent ocular penetration and reproducible pharmacokinetics (PK) for melphalan. We have also developed a rabbit model of RB that develops both retinal tumors and vitreous seeds grown from human RB cell lines, recapitulating features found in patients with advanced RB. Using these novel models, we plan to determine the PK, retinal/retinal vascular toxicity profiles, and efficacy of a selected group of chemotherapeutic agents that already have FDA-approval. Focusing on FDA-approved drugs will allow rapid translation of our findings into clinical practice. Both vitreous and intra-retinal drug concentrations and PK curves will be calculated for each drug following both IAC or intravitreal injection, using traditional mass spectrometry and a novel in situ imaging mass spectrometry technique that was developed at Vanderbilt. Once the PK curves have been calculated, the maximum tolerable dose (MTD) for each drug will be calculated for both IAC and for repeated intravitreal injections. Functional and structural ocular toxicity will be measured using a comprehensive panel of techniques. A robust Bayesian Continual Reassessment Method clinical study design will be employed. The MTD will then be used in studies of the efficacy of each drug, given by either IAC or intravitreal injection, for the treatment of RB in the above rabbit models. Following identification of safe and effective target doses in vivo in our rabbit model, we will confirm the absence of retinal toxicity using a cutting edge technology that allows drug toxicity to be monitored over time in ex vivo human retinal tissues that can be kept alive in a supportive perfusate for functional evaluation. This ensures that these drugs are safe for human eyes (not just rabbits). Dr. Daniels brings experience with ocular tumor biology and genetics, as well as clinical expertise with IAC for RB. The long-term goal of his research is to develop safer, pathway-targeted agents for the treatment of RB. This Mentored Clinical Scientist Research Career Development (K08) Award will allow Dr. Daniels to be mentored by a world-class team of mentors, who have extensive expertise in retinal biology, tumor biology and therapeutics, and in the preclinical assessment of antineoplastic agents and intraocular drugs. Through a combination of hands-on experimentation and didactics, Dr. Daniels will develop necessary skills in the use of animal models for preclinical studies, in vivo assessment of retinal toxicity and efficacy, and biostatistics, while developing a comprehensive drug-testing platform that can be used to assess novel compounds in the future.
Retinoblastoma is the most common eye cancer in children, with a devastating and long-lasting influence on quality of life. While new treatments allow clinicians to save most eyes affected by this cancer, the treatments themselves are often damaging to the eye and can lead to lifelong vision loss. To address this pressing problem, our proposal leverages new experimental models that will enable us to test more thoroughly the effectiveness, safety and long-term effect of novel treatments, thus allowing us to identify new drugs that are safer to use in the eyes of children fighting retinoblastoma.
|Daniels, Anthony B; Froehler, Michael T; Pierce, Janene M et al. (2018) Pharmacokinetics, Tissue Localization, Toxicity, and Treatment Efficacy in the First Small Animal (Rabbit) Model of Intra-Arterial Chemotherapy for Retinoblastoma. Invest Ophthalmol Vis Sci 59:446-454|
|Lu, Jonathan E; Francis, Jasmine H; Dunkel, Ira J et al. (2018) Metastases and death rates after primary enucleation of unilateral retinoblastoma in the USA 2007-2017. Br J Ophthalmol :|