Matthew Oser

Small cell lung cancer (SCLC) is a highly aggressive and treatment-resistant malignancy with limited therapeutic options. This challenge stems in part from the near-universal loss-of-function (LOF) mutations in key tumor suppressor genes such as RB1 and TP53, as well as the absence of mutations in druggable oncogenes. SCLC comprises distinct molecular subtypes, each defined and driven by specific lineage transcription factors (TFs), including ASCL1, NEUROD1, and POU2F3. Notably, SCLC exhibits significant lineage plasticity, allowing tumor cells to transition between subtypes. Similarly, non-small cell lung cancer (NSCLC) can undergo lineage reprogramming, with histological transformation into SCLC serving as a mechanism of resistance to targeted therapies.

My laboratory leverages functional genomic tools, particularly CRISPR/Cas9 screening, to investigate the regulation of these lineage-defining transcription factors in SCLC. Our aim is to uncover actionable mechanisms capable of disrupting the activity and function of these transcription factors. In addition, we employ in vivo CRISPR-based somatic gene editing to develop novel mouse models of lung cancer. These models enable us to identify epigenetic regulators that drive both SCLC subtype plasticity and the histological transformation from NSCLC to SCLC. We are also focused on studying novel therapeutics being developed for SCLC to uncover the mechanisms underlying their efficacy and resistance, with the goal of identifying biomarkers and developing combination strategies to enhance the effectiveness of these emerging treatments. This includes both targeted therapies and new immunotherapeutic approaches for SCLC, such as DLL3 bispecific T cell engagers.

Ultimately, our goal is to elucidate the mechanisms that govern SCLC subtype identity and plasticity and to uncover new therapeutic strategies that target transcription factor dependencies, subtype transitions, and tumor immunogenicity. Through this work, we aim to advance the development of precision therapies for patients with SCLC and other high-grade neuroendocrine tumors.