SBIR-STTR Award

The underlying hypothesis of this proposal is that inhibitors of ganglioside biosynthesis will prevent or slow the growth of neural crest-derived tumors (neuroblastoma, melanoma, astrocytoma). These tumor types produce an altered array of gangliosides that contribute to their growth and spread. Genetic and pharmacological experiments have proven that gangliosides are good targets for the treatment of neuroblastoma and melanoma. The current inhibitors of ganglioside biosynthesis have shown efficacy in mouse cancer models; however, these compounds act by inhibiting all glycosphingolipids (GSLs). Gangliosides are only a small subset of GSLs. The broad GSL inhibition mediated by the current inhibitors causes side effects; therefore, a ganglioside specific inhibitor should be superior. Here, we propose to develop a system to identify ganglioside specific inhibitors. These inhibitors should reduce the side effects of non-specific GSL inhibition while maintaining efficacy as anti-cancer agents. The goal of this proposal is to develop a system to discover drugs that block the production of gangliosides. Gangliosides are cell surface carbohydrates that are required for certain types of cancer such as melanoma and neuroblastoma. Using the system described here, new drugs can be discovered which will lead to new treatments for patients with melanoma or neuroblastoma

The underlying hypothesis of this proposal is that inhibitors of ganglioside biosynthesis will prevent or slow the growth of neural crest-derived tumors (neuroblastoma, melanoma, and astrocytoma). Clinical studies have shown that these tumor types consistently produce an altered array of gangliosides that can predict their clinical progression. Genetic and pharmacological experiments demonstrate that gangliosides are essential for the progression of these cancers. Together this validates gangliosides as a novel target for the treatment of neuroblastoma and melanoma. In our Phase I program, we not only developed the cell based high throughput discovery system that we proposed, but we also completed a screen of 74,000 drug-like compounds. In this Phase II application, we propose to develop the novel small molecule inhibitors of ganglioside biosynthesis that we discovered. We will characterize the hit compounds, test analogs to identify promising hit series, and test the most promising compounds in vivo. The in vivo studies will characterize the effects of the lead compounds on ganglioside biosynthesis in addition to anticancer efficacy in a melanoma model. Effective ganglioside inhibitors developed through these studies will have commercial potential as research tools and as lead compounds for novel anticancer therapies.

Public Health Relevance:
The goal of the proposed research is to develop novel anticancer drugs that work by inhibiting ganglioside biosynthesis. Gangliosides are lipid linked glycans that are required by melanoma and neuroblastoma for their rapid growth; however, there are no known agents that can specifically inactivate gangliosides. This Phase II SBIR application focuses on developing novel ganglioside inhibitors that we discovered in our Phase I SBIR research.

Public Health Relevance:
This Public Health Relevance is not available.

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