Development of Transporter Targeted Platinum Drugs for Glioblastoma - ¿
DESCRIPTION (provided by applicant): The blood brain barrier (BBB), the restrictive endothelium of the vasculature in the brain, represents a major challenge for the development of drugs to treat disorders of the Central Nervous System, CNS. In particular, many drugs cannot enter the brain because they are not able to cross the BBB. However, influx transporters in the BBB, which facilitate the entry of essential nutrients and various endogenous molecules, can be harnessed to deliver drugs to the brain. Using knowledge of the transporters in the BBB, we designed influx transporter targeted anti-cancer drugs to treat an important and aggressive human cancer, glioblastoma (GB). GB is the most malignant form of brain cancer that involves glial cells. Overall, the incidence is rare with 14,000 people diagnosed in the US each year. Platinum drugs are highly effective anti- cancer drugs; however, have had limited use in cancers of the brain because of their inability to cross the BBB. Preliminary studies suggest that our lead
transporter-targeted compound, AT- 69, is highly potent in GB cell lines. The major goal of this SBIR Phase I research is to establish proof of concept that the analogs form DNA adducts, are dependent on transporters to enter the brain and the tumor, and are efficacious in GB xenograft mouse models. Two aims are proposed. In studies under the first aim, we will determine the potency of AT-69 and a back-up analog, AT-70, and measure the DNA adduct formation in ten GB cell lines with low- and high- grades of aggressiveness. In the second aim, we will establish efficacy in xenograft models of GB and determine the identity of the transporters that mediate the delivery of the compounds across the BBB. The proposed studies will confer high commercialization potential for the two lead compounds since both analogs will be poised for critical Investigational New Drug (IND) enabling studies.
