University of Texas Southwestern Medical Center: Lung Cancer Oncogenotype-selective Drug Target Discovery (Natural Products Focus)

The goal of this project is to use small molecules and RNAi to functionally define subtypes of non-small cell lung cancer (NSCLC) using a panel of cell lines prepared and molecularly annotated by Drs. John Minna and Adi Gazdar.

Experimental Approaches

Lung Cancer Natural Products Screening/Chemical Library Screening

Using biological and molecular characteristics, we divided a panel of 108 tumor samples representative of non-small cell lung cancer (NSCLC) into 7 distinct families, or clades. Based on preliminary data, we anticipated that the tumor membership of each clade will have shared genetic and chemical vulnerabilities, which can be exploited for target identification and drug discovery. To pursue this hypothesis, we selected representative cell lines from each NSCLC clade for chemical library screening. The UT Southwestern chemical library consists of ~230,000 compounds and includes ~25,000 natural products, 1,200 approved drugs, and 1,000 compounds prepared by UT Southwestern chemists. Screens were conducted using the Cell Titer Glo assay platform from Promega, Inc., which measures cell viability in terms of ATP levels. Data from primary screening and confirmation and dose-response studies were analyzed using GeneData’s ScreenerTM version 9.

Genome-Wide RNAi Screening

Using biological and molecular characteristics, we divided a panel of 108 tumor samples representative of non-small cell lung cancer (NSCLC) into 7 distinct families, or clades. Based on preliminary data, we anticipated that the tumor membership of each clade will have shared genetic and chemical vulnerabilities which can be exploited for target identification and drug discovery. To address genetic vulnerabilities, we selected representative cell lines from each NSCLC clade for genome-wide RNAi screening. Screens were conducted using the Cell Titer Glo assay platform from Promega, Inc., which measures cell viability in terms of ATP levels. Two genome-wide libraries were screened against each cell line (Dharmacon and Ambion libraries) in order to ensure complete coverage of genes and pathways. Data from primary screening and confirmation studies were analyzed using Gene Data’s ScreenerTM version 9.

Data

Access the Raw/Analyzed Data (DCC)
Access the Dashboard Submission(s)

For questions, please contact Bruce Posner.