Project description:SCLC is molecularly and immunologically heterogenous. Here, using transcriptional and epigenomic profiling of plastic SCLC states in human and mouse cell lines, and patient samples, we define the phenotype of a SCLC population marked by increased MHC Class I antigen presentation.
Project description:Purpose: SCLC is an aggressive high-grade neuroendocrine carcinoma (hgNEC) known for its dismal prognosis, with only half of patients with ES-SCLC surviving even one year after diagnosis. Platinum-based doublet chemotherapy continues to be the mainstay of standard of care (SOC), with the addition of immune checkpoint blockade (ICB) improving overall survival by only two months. Few studies have analyzed patient specimens from relapsed SCLC. Experimental design: To better define the biology of relapsed SCLC, we analyzed core needle biopsies and surgical resections from SCLC patients by single-cell (sc)RNAseq. The objectives of this study were to identify unique cell populations present in relapsed disease, including those expressing YAP1 and AXL.
Project description:Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inhibitor of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. DNA methylation profiling was performed using Infinium 450K methylation arrays on SCLC cell lines, patient derived xenografts, and patient samples. Data was processed and normalized using GenomeStudio V2011.1
Project description:SCLC is molecularly and immunologically heterogenous. Here, using transcriptional and epigenomic profiling of plastic SCLC states in human and mouse cell lines, and patient samples, we define the phenotype of a SCLC population marked by increased MHC Class I antigen presentation.
Project description:SCLC is molecularly and immunologically heterogenous. Here, using transcriptional and epigenomic profiling of plastic SCLC states in human and mouse cell lines, and patient samples, we define the phenotype of a SCLC population marked by increased MHC Class I antigen presentation.