The discovery and development of new treatment agents for cancer that demonstrate enhanced selectivity for the tumor microenvironment continues to be an important and challenging goal in today's world. Vascular disrupting agents (VDAs) are compounds that are effective at selectively damaging the tumor vasculature while leaving the blood supply to healthy cells intact. These compounds effectively disrupt blood flow to tumors thus starving them of necessary nutrients and oxygen. This has the potential to ultimately lead to tumor death. While a number of VDAs are in human clinical trials, none have reached approval by the Food and Drug Administration (FDA), to date. Certain of these compounds function by inhibiting the assembly of tubulin into microtubules, thus causing morphology changes to the endothelial cells lining the tumor vasculature. This triggers a cascade of cell signaling events that results in catastrophic damage to the vessels feeding the tumor. The research presented in this proposal focuses on a highly collaborative, multidisciplinary approach to the synthesis and rapid biological evaluation of promising new VDAs. A combination of synthetic/medicinal chemistry to prepare newly designed compounds coupled with rapid biochemical and biological evaluation, including tumor imaging (BLI and MRI), will provide a strong platform for the discovery of new and improved VDAs. Importantly, this type of research may ultimately translate to the clinic providing additional chemotherapeutic agents that have enhanced selectivity towards the tumor microenvironment.
The discovery and development of new vascular disrupting agents (VDAs) is universally relevant to public health since compounds of this type have the potential to be significantly improved treatment agents for a variety of malignant tumor types. In addition to molecular design, chemical synthesis, and biochemical and biological assays (in vitro), the effective development of vascular disrupting agents for cancer therapy also requires in vivo assessment. Therefore, bioluminescence imaging (BLI) and magnetic resonance imaging (MRI) will be used in this project to evaluate new VDAs.
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