Markos Leggas Lab

The oncogenic transcription factor, EWS-FLI1, is recognized as the Achilles heel of Ewing sarcoma. However, efforts to develop treatments that interfere with its function have not succeeded. To close this gap between and identifying the molecular driver of disease and developing an effective treatment, we evaluate semi-synthetically modified mithramycin analogs, which have been shown to interfere with the oncogenic transcription factor responsible for Ewing sarcoma growth. Currently, several analogs are progressing through preclinical evaluation and, if successful, will transition to the NCI Experimental Therapeutics program to complete the preclinical evaluations required for entry into the clinic.

Our work also focuses on a randomized controlled clinical trial that evaluates the use of clonidine — an alpha-2 adrenoceptor agonist — in comparison to morphine for the treatment of neonates who are born physically dependent on opioids due to prenatal exposure. We are using population PK/PD to describe the exposure and response of each treatment in the neonates. We also attempt to understand the sources of variability in drug exposure and response through population covariate modeling that includes the pharmacogenetics of genes responsible for the transport, metabolism and pharmacological action of each drug. Our previous contributions to this area include the study of neonatal opioid exposure by analyzing the clinical utility of the Finnegan neonatal abstinence scoring tools and examining the biochemical and behavioral alterations that occur because of opioid exposure. These efforts contribute to early diagnosis and treatment of neonatal opioid withdrawal syndrome (NOWS).