Investigating and Targeting Replication Stress in Small Cell Lung Cancer

PROJECT SUMMARY/DESCRIPTION Small-cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate to chemotherapy and chemoimunotherapy, the majority of SCLC patients with extensive stage disease invariably relapse within one year. Although SCLC is currently managed as a single disease with platinum-based chemotherapy remaining the cornerstone of treatment, studies have identified that SCLC display both inter- and intra-tumoral heterogeneity with distinct transcriptome changes. However, the specific molecular determinants of response remains unclear, especially as the tumor evolves from a naïve chemo-responsive state to an acquired chemo-resistant state following chemotherapy. Effective therapeutic strategies are urgently needed to improve clinical outcomes. We will address this knowledge gap in overall Aim 1 by understanding how a critical determinant of chemosensitivity, Schlafen family member 11 (SLFN11), informs the degree of chemo-responsiveness in SCLC subtypes. In overall Aim 2, we will study how different replication stress response pathways and replication fork modulators work in concert to regulate chemo-sensitivity. Finally, in overall Aim 3 we will integrate insights gained from work performed in support of overall Aims 1 and 2 to develop strategies to target replication stress response pathways in combating acquired chemo-resistance in SCLC to yield deeper and more durable responses with improved tolerability. The research work will be highly coordinated within the Program Project framework with three Core facilities. The experiments, progress and direction of the science within each Project will be monitored with feedback via the Administrative Core A. Establishment of different SCLC cell lines, PDX, and GEM models will be supported by Core B. Advanced microscopy and computational approaches for each project will be supported by Core C. The Project/Core leaders have complementary expertise: John Poirier (functional genomics, Project 1, Core B), Tony Huang (molecular biology, Project 2, Core A), Eli Rothenberg (biophysics, Project 3, Core C), David Fenyo (computational biology, Core C), and Kwok-Kin Wong (cancer biology, Project 4, Core B). This ensemble of complementary expertise fosters cross-fertilization of ideas beneficial to the whole team, and makes work possible that can only be accomplished by a Program Project grant. This team also already has a long track record of productive collaboration. The results obtained by this Program Project will provide a fundamental advancement in the understanding of the molecular mechanisms underpinning DNA replication stress and SCLC therapeutics, and will pave the way for the design of novel cancer therapy targeting relapsed SCLC patients.