Chemical Biology

Identification of Subtype-selective Vulnerabilities and Biomarkers in Non-small Cell Lung Cancer

Wednesday, February 7
3:00 PM - 3:30 PM
Location: 8

Lung cancer is the leading cause of cancer-related deaths with more than 1.3 MM people dying of this disease each year. Drs. John Minna and Adi Gazdar have collected over 100 non-small cell lung cancer (NSCLC) tumor samples and created corresponding cell lines that they have characterized by molecular and biological methods. From these studies and others, we postulated that lung cancer can be characterized as a collection of diseases, each distinguished by unique biomarkers and chemical vulnerabilities. Using a chemistry-first approach, we carried out high throughput, phenotypic screens of 12 representative lung cancer cell lines from our NSCLC panel against the UT Southwestern chemical library (~230,000 compounds). In follow up studies, we identified ~180 small molecule toxins representing over 30 chemical series that are toxic to subsets of the extended lung cancer cell panel (~105 cell lines) but not to immortalized human bronchial epithelial cells (HBEC’s). We have developed and used bioinformatics tools (machine learning and a novel variation of the Kolmogorov-Smirnov statistic) in conjunction with orthogonal molecular data sets (e.g. somatic mutations, gene expression, protein expression, metabolic flux, etc.) to identify biomarker hypotheses that have provided insights into mechanism of action and possible targets of these cancer subtype-selective compounds. Subsequent biochemical, cell based, and in vivo studies on selected compounds have identified several novel target/biomarker relationships that may have therapeutic impact.

Bruce Posner

Professor
UT Southwestern Medical Ctr

Dr. Posner received his Ph.D. in biochemistry with Professor Stephen Benkovic at Penn State University in 1994 and then carried out an NIH-sponsored post-doctoral fellowship with Professor Alfred G. Gilman at the University of Texas’ Southwestern Medical Center (UTSMC). Subsequently, he joined Pfizer, Inc as a Principal Scientist in the High Throughput Screening Center of Emphasis. During his 9 year tenure there, he led over 60 HTS campaigns and identified more than 20 hit-to-lead starts for early drug discovery programs. Two of these chemical series were submitted to first-in-human clinical trials. His efforts resulted in his recognition with Pfizer’s Discovery Recognition Award 2004 and subsequent promotion to Senior Principal Scientist. In 2009, he joined the biochemistry faculty at UTSMC as an associate professor and the director of the High Throughput Screening (HTS) Core. In this capacity, he leads the core facility efforts to aid in the discovery and the early stage, pre-clinical development of new small molecule therapeutics.

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