Event Title

Optimization of a Chemical Genetic Screen for Sensitization to Laromustine

Presenter Information

Kathryn Coe, Colby CollegeFollow

Location

Diamond 145

Start Date

1-5-2014 1:00 PM

End Date

1-5-2014 2:30 PM

Project Type

Presentation- Restricted to Campus Access

Description

Laromustine is an experimental chemotherapeutic prodrug that breaks down into two active components; a chloroethylating component that causes DNA interstrand crosslinks and a carbamoylating component whose biological activity is less understood. Laromustine has been used in clinical trials to treat acute myeloid leukemia and glioblastoma multiforme (GBM). Unfortunately, the GBM clinical trials have had limited success despite the ability of laromustine to cross the blood-brain barrier and its low non-specific toxicity. GBM is the most common type of malignant brain tumor, and patients currently have a mean survival time of only 13 months. As such, finding a way to increase the potency of laromustine against GBM cells would be invaluable. To learn more about the mechanism of laromustine and investigate potential partner compounds that will sensitize GBM cells to laromustine, a chemical genetic screen will be conducted. The screen will evaluate the ability of small molecules in a library of approximately 450 FDA-approved compounds to enhance the anti-proliferative effects of laromustine in U138 GBM cells. It will be conducted using a high-throughput proliferation assay with a fluorescent readout performed in 384-well plates. Optimization of the assay has included determining the proper cell seed density, drug concentration and incubation time, and fluorescent substrate concentration, among other variables. These optimization data will allow for the facile and accurate identification of partner candidates for laromustine when the screen is conducted.

Faculty Sponsor

Julie Millard

Sponsoring Department

Colby College. Chemistry Dept.

CLAS Field of Study

Natural Sciences

Event Website

http://www.colby.edu/clas

ID

447

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May 1st, 1:00 PM May 1st, 2:30 PM

Optimization of a Chemical Genetic Screen for Sensitization to Laromustine

Diamond 145

Laromustine is an experimental chemotherapeutic prodrug that breaks down into two active components; a chloroethylating component that causes DNA interstrand crosslinks and a carbamoylating component whose biological activity is less understood. Laromustine has been used in clinical trials to treat acute myeloid leukemia and glioblastoma multiforme (GBM). Unfortunately, the GBM clinical trials have had limited success despite the ability of laromustine to cross the blood-brain barrier and its low non-specific toxicity. GBM is the most common type of malignant brain tumor, and patients currently have a mean survival time of only 13 months. As such, finding a way to increase the potency of laromustine against GBM cells would be invaluable. To learn more about the mechanism of laromustine and investigate potential partner compounds that will sensitize GBM cells to laromustine, a chemical genetic screen will be conducted. The screen will evaluate the ability of small molecules in a library of approximately 450 FDA-approved compounds to enhance the anti-proliferative effects of laromustine in U138 GBM cells. It will be conducted using a high-throughput proliferation assay with a fluorescent readout performed in 384-well plates. Optimization of the assay has included determining the proper cell seed density, drug concentration and incubation time, and fluorescent substrate concentration, among other variables. These optimization data will allow for the facile and accurate identification of partner candidates for laromustine when the screen is conducted.

http://digitalcommons.colby.edu/clas/2014/program/217