AstraZeneca has awarded Duke Anesthesiology’s Madan Kwatra, PhD, a $97,109 grant for his project titled, “Efficacy of AZD9291 against EGFRvIII-positive glioblastoma.”
Glioblastoma (GBM) is a deadly brain cancer, and according to Dr. Kwatra, all attempts to control it have failed so far. GBMs exhibit significant inter- and intratumoral heterogeneity, and to control this type of tumor, he believes a personalized approach is required.
According to the research statement, one target, whose gene is amplified and mutated in a large number of GBMs, is the epidermal growth factor receptor (EGFR). But, all attempts to target it have been unsuccessful. Dr. Kwatra attributes this failure to the extreme molecular heterogeneity of EGFR, as well as to the poor brain penetration of previously tested EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs). Recently, a third generation EGFR-TKI, known as AZD9291, was reported to have good brain penetration. AZD9291 also blocks EGFRvIII, a mutant EGFR present in 20 percent of GBM tumors, with high affinity. Dr. Kwatra’s preliminary studies (conducted under a collaborative agreement among his laboratory, NIH, and AstraZeneca) indicate AZD9291 is active against EGFRvIII-positive GBMs intracranially transplanted in nude mice.
This study will test if AZD9291’s efficacy against EGFRvIII-positive GBMs can be improved by giving 25mg/kg AZD9291 twice a day. Finally, before conducting studies in GBM patients, Dr. Kwatra will examine whether EGFRvIII-positive GBMs differ in their response to AZD9291. This way the compound is tested only in those GBM patients expressing the sensitive form of EGFRvIII (precision medicine approach).
Dr. Kwatra is an associate professor in anesthesiology and the director of the Molecular Pharmacology Laboratory where researchers focus to understand the role of G protein-coupled receptors in human diseases.