Chicago - 4:00 PM - 5:00 PM
Please join the Department of Pharmacology for a Works-in-Progress presentation by Tracy Gertler and Ratika Kunder.
Tracy Gertler, M.D., Ph.D. - Child Neurology Fellow in Dr. Alfred George's Laboratory
"Functional Analysis of KCNT1 Pathogenesis in Epileptic Encephalopathies"
Epileptic encephalopathies (EEs) are severe, infantile-onset epilepsies characterized by drug-resistant,
pleomorphic seizures and early developmental arrest. Malignant migrating partial epilepsy of infancy (MMPEI) is
a type of EE. Gain-of-function missense mutations in KCNT1, the gene encoding a sodium-activated potassium channel called Slack, have been identified in up to 40% of MMPEI patients. There are no approved treatments for MMPEI, but quinidine, a known Slack channel modulator, exerts anticonvulsant effects in MMPEI, whereas conventional anticonvulsants routinely fail. These findings suggest that targeting hyperactive Slack channels has therapeutic potential. While the anatomical location and neuronal identity in which KCNT1 is expressed is unknown, we hypothesize that MMPEI is an interneuron-driven disease phenotype. Thus, if the target ion channel complement and pathophysiologic neuronal activity in MMPEI can be more precisely ascertained, there is an opportunity for therapeutic targeting of Slack.
Ratika Kunder, Ph.D. - Post Doctoral Fellow in Dr. Dai Horiuchi's Laboratory
"Identifying Clinically Viable Targeted Therapy to Treat Triple Negative Breast Cancer"
Triple-negative breast cancer (TNBC), which lacks functional expression of the estrogen, progesterone, and HER2 receptors, represents the breast cancer subtype with the poorest clinical outcome. No clinically viable targeted therapy is currently available against this subtype due to lack of validated molecular targets. Therefore, we seek to take advantage of the unique molecular features found in this tumor type to identify potent and effective treatment strategies. Previously, we discovered that pathways mediated by the MYC oncoprotein were disproportionally elevated in triple-negative (TN) tumors compared to receptor-positive (RP) tumors. However, clinical development of rationally designed small molecule inhibitors that can directly and specifically inhibit oncogenic MYC activity has remained challenging. An alternative approach to selectively kill MYC-driven tumors is to inhibit proteins that are indispensable for the viability of such tumors but are not essential in non-tumorigenic cells. This form of indirect treatment strategy has become known as the synthetic lethal approach. Our efforts to identify such novel targets has identified PIM1, a non-essential kinase. PIM1 expression is significantly elevated in TN tumors and is associated with poor clinical outcomes specifically in patients with hormone receptor-negative tumors. In our recently completed preclinical efficacy studies, small molecule PIM kinase inhibitors showed activity in a panel of patient-derived tumor xenograft (PDX) mouse models of TNBC. My presentation will describe our ongoing efforts, which combine genomics and functional drug screening, aimed at bringing our laboratory findings to early stage clinical testing here at Northwestern.