Investigator: Jie Shen, University of Rhode Island

Mentor: Edith Mathiowitz, Brown University

Abstract:

Uveal melanoma (UM) is rare yet the most common and malignant primary intraocular tumor in adults. Due to the lack of effective treatment, the mortality rate of UM has remained high over the past few decades. In order to improve the prognosis and survival of UM patients, it is critical to inhibit tumor progression and metastasis  as  early  as  possible  after  the  initial  presentation/diagnosis   of  the  disease.  This  proposed research broadly aims to explore novel therapeutic strategies against UM through the development of a bioinspired  in  situ  gelling  drug  delivery  platform  that  is  capable  of  sustained  delivering  a  variety  of therapeutics (including small molecule and gene) at the site of administration  to inhibit tumor progression and metastasis. The long-term objectives of this line of research are to: i) improve prognosis and survival of cancer patients; and ii) treat other human diseases and disorders (such as central nervous system diseases) using the in situ gelling drug delivery platform that will be developed. In the present proposed research, both small molecule and genetic therapeutics that target hypoxia inducible factor-1α (HIF-1α) pathway, one of the key pathways govern UM tumor progression and metastasis, will be utilized as model therapeutics. Aim One of the proposed work will be to design/optimize a bioinspired in situ gelling drug delivery platform to achieve sustained drug delivery and improved in vitro and in vivo anti-UM efficacy. Curcumin will be used as the small molecule model therapeutic to optimize the in situ gelling hydrogel system, and to obtain proof of concept. The safety of the developed drug delivery platform in the posterior segment of the eye will also be evaluated. Aim Two of the proposed work will be to expand the application of the developed in situ gelling drug delivery platform to deliver gene therapeutics. Anti-HIF-1α siRNA will be used as the model gene therapeutic,  and  the  in  situ  gelling  system  will  be  fine-tuned  (if  necessary)  to  ensure  sustained  siRNA delivery and improved in vitro anti-UM efficacy. The proposed research will expand our understanding of how long-term suppression of HIF-1α pathway affect UM tumor progression and metastasis. Moreover, the in situ gelling drug delivery platform built upon biocomponents, can be easily modified/applied for the treatment of various human diseases and disorders.