With funding from the National Pediatric Cancer Foundation, Dr. Dan Sullivan, Dr. Chris Cubitt, and the Translational Research Laboratory at Moffitt Cancer Center have been actively searching for better chemotherapeutics for use in childhood cancers. It is the goal of the Translational Research Laboratory to find drugs or drug combinations that can rapidly be moved into the Phase 1 protocol creation portion of the Sunshine Project.
For the past five years, we have focused our research on sarcoma drug therapies. Our labs routinely grow a panel of ten tumor cell lines originally isolated from common pediatric sarcomas. This panel includes cell lines derived from Ewing sarcomas, osteosarcomas, and rhabdomyosarcomas. For this research, we have developed a high-throughput automated plate system to test the anticancer effectiveness of newly discovered compounds and early pipeline drugs. The plates used in this system contain 384 separate test wells for the addition of cancer cells and different concentrations of test drugs. After adding drugs to the wells containing cancer cells, we can test whether a drug or compound kills or slows the growth of the sarcoma. Whether the cancer cells are killed by apoptotic or cytotoxic pathways can also be determined. In addition, our system allows us to rapidly look at the effects of multiple drug combinations. It is believed that multidrug combinations will be more effective against cancers when using recently developed targeted drugs. It is hoped that by combining two or more targeted agents or by combining a targeted agent with a more conventional cytotoxic, a greater or synergistic anticancer effect can be achieved at lower doses with the potential for less side effects. The order in which drugs should be added to a multidrug regimen can also be studied using our methods.
Using these techniques, we have discovered several novel drugs and drug combinations with promising results. Early findings led to a clinical trial using a HDAC inhibitor combined with a topoisomerase inhibitor. More recent findings have shown that the Src inhibitor Dasatinib when combined with an Akt inhibitor called Tricribine, results in a synergistic decrease in growth in 8 out of 10 sarcoma cell lines. This drug combination when tested in xenograft sarcoma mouse models indicated a significant increase in tumor cell death. To advance these findings toward a clinical trial, we have substituted Triciribine with a newer generation of Akt inhibitors called MK2206 that is currently being tested in early phase clinical trials. Our in vitro experiments show that MK2206 likewise demonstrates a highly synergistic activity in vitro, both in cancer growth inhibition and in cancer killing activity (apoptosis). These studies have led to a clinical trial proposal using MK2206 combinations, which we believe hold promise for the treatment of sarcomas and could also be applicable in the treatment of other cancers.
The overall goal of these studies performed on cell lines and models, is to identify promising drug combinations for the treatment of pediatric sarcomas. Most importantly, the molecular targets for our trials will have been identified prior to the trial initiation. Thus, the translation of the laboratory findings to the clinical setting will not be primarily empiric, but rather based on a molecular understanding of drug/target and drug/drug interactions.