In collaboration with NIH and external academic researchers, we have performed drug repurposing screens for multiple projects across a range of therapeutic areas, including rare genetic disorders, bacterial and viral infectious diseases, and drug resistant cancer cells. DRUG RESISTANT CANCER: Cancer drug resistance is a severe clinical problem that often results in patient death. We performed drug repurposing screens for drug-resistant cell lines of ovarian cancer refractory to multiple standard care chemotherapies. Several approved drugs have been identified that either suppress the drug-resistant cancer cells directly or re-sensitize the resistant cells to the anticancer activities of the standard drugs. We also found that diverse mechanisms are involved in the drug resistance of ovarian cancer, indicating the importance of personalized treatment which can be obtained from personalized drug screens using patient-derived cancer samples. Using the cisplatin-resistant ovarian cancer cell line (IGROV1 CR), we identified LY2784544, a JAK2 inhibitor that overcomes cisplatin resistance in these cells. Further study found that the elevated reactive oxygen species (ROS) production in these drug resistant cells increases IL-11 expression and further activates JAK2STAT5 signal transduction pathway to endow the ovarian cancer cells with cisplatin resistance. Thus, LY2784544 could be applied with cisplatin to treat patients with this ROS-IL-11-JAK2 mediated drug resistance (Zhou et al, Oncogene 2018). Another repurposing screen using the cisplatin-resistant SKOV3 CR ovarian cancer cell line identified Chk1 inhibitors that re-sensitize cells to cisplatins apoptotic effects. Subsequent analyses using the identified Chk1 inhibitors found that elevated DUOXA1 increases ROS levels and activates the ATR-Chk1 pathway to cause the cisplatin resistance (Meng et al., Cancer Letter 2018). In a third drug repurposing screen using another multidrug resistant ovarian cancer cell line (A2780-cis), several compounds have been identified that restore cisplatin's apoptotic effect. One of the mechanisms for one group of active compounds involves reducing the elevated EGFR level in these cells. In addition to the compounds having synergistic effects with cisplatin, several other compounds have been found that suppress the drug-resistant cancer cells directly (Sima et al., Translational Oncology 2018). These compounds can be further studied for potential clinical applications. We also performed repurposing screens against liver cancer and other gynecologic cancers, including cervical and placental. A number of active compounds were identified, and we are currently in the process of hit confirmation and follow-up experiments. LYSOSOMAL STORAGE DISEASE: We have performed drug repurposing screens using patient-derived fibroblasts for Niemann-Pick disease type A with a new high throughput instrument, the Mirrorball fluorescent cytometer, to identify compounds that reduced sphingomyelin accumulation in the patient cells. A set of 19 primary hits was found. Of these hits, 10 were confirmed to have relatively potent activities. We also carried out repurposing screens for Niemann Pick disease type C and Mucopolysaccharidosis type I using neural stem cells derived from induced pluripotent stem (iPS) cells from patients. The primary hits are in the process of being validated and confirmed using secondary assays and biochemical methods. DRUG RESISTANT BACTERIA: Infections with multidrug-resistant (MDR) organisms have emerged as a significant worldwide public health crisis. The incidence is increasing, partially due to the selective pressure from widespread use of antibiotics in both humans and animals. We have performed high throughput screening to identify individual drugs as well as synergistic drug combinations active against drug-resistant Klebsiella pneumoniae and Acinetobacter baumannii, both isolated from patients. Several synergistic drug combinations have been identified and confirmed. These are currently being tested in animal models by our collaborators.
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