Timothy G. Murray, MD
Professor of Ophthalmology
Treatment of Ocular Tumors

View published articles in the National Library of Medicine.

Research Summary

My research is dedicated to improving the treatment of children with intraocular retinoblastoma, the most common primary intraocular eye cancer in children. Although current treatments have contributed to a marked improvement in survival, they often leave the child without vision within the treated eye and have been associated with severe local and systemic complications. We believe that retinoblastoma treatment can be markedly improved by specifically targeting tumor cells for death with a combination of focally delivered blood vessel targeting therapy and conventional chemotherapy.

We are currently studying the mechanism of angiogenesis tumor development and the mechanism of tumor response to treatment using a transgenic mouse model for retinoblastoma. Our preliminary data in this area has served as the basis for an NEI grant, which received a priority score of 1.9 (funding pending). The animal model is unique and from a clinical standpoint is ideal to address the therapeutic strategies that will be translated to the treatment of children with retinoblastoma.

I recently completed my participation in an NEI-funded clinical trial, the Collaborative Ocular Melanoma Study (COMS). I am now working with others to develop a national clinical trial for treatment of retinoblastoma using some of the findings that have come out of my lab and the labs of others. We will be submitting this as an NIH grant application in the near future.

Angiogenesis during tumor progression: To effectively target vasculature in retinoblastoma, an understating of intratumural blood vessel development is needed. We believe that a specific pattern of gene expression of angiogenesis promoting factors is elicited during retinoblastoma tumor development and that these factors are disrupted in response to treatment. We are currently investigating factors that are susceptible to disruption, e.g. vascular endothelial growth factor (VEGF) and its receptors, by correlating protein production and in situ localization . We expect to see a time dependent increase of these factors as a function of tumor progression and expect to see their localization in areas of novel vasculature.

Tumor Cell Death in Response to Treatment : We are also investigating the mechanism by which focally delivered chemotherapy and blood vessel targeting therapy reduce tumor burden by the differential induction of tumor cell death ( i.e. apoptosis and necrosis). We have pilot data that suggests that a differential induction of apoptosis is elicited following various doses of chemotherapy. We expect that each treatment modality results in a unique induction of cell death over time, dependent on the agent used and treatment schedule. These studies will aid in the optimization of the delivery schedule of the combined treatment.

Blood Vessel Targeting Therapy : Using the transgenic murine model for retinoblastoma and two different vessel targeting agents, we have shown that tumor control can be achieved by focal treatment with angiostatic and anti-angiogenic agents. We have further shown that these therapies enhance focal conventional chemotherapy in achieving local tumor control. We are currently investigating optimal dose and delivery schedule to determine minimal effective doses. We believe that these combined treatments will help achieve greater retinoblastoma tumor control while decreasing toxicity and minimizing adverse side effects.