Sunday, December 8, 2024
12/8/2024
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine lung tumor responsible for > 30,000 deaths annually in the US. SCLC has a two-year survival rate of ~6% with no approved targeted therapies beyond recently-approved immunotherapy. SCLC is initially highly responsive to chemotherapy, but rapidly develops resistance leading to mortality in ~12 months. A major unmet need for SCLC treatment is the identification of new therapeutic targets and treatment strategies. SCLC has historically been treated as a single disease without patient stratification based on molecular information. We and others recently identified distinct SCLC molecular subtypes based on expression of lineage-related oncogenic transcription factors: ASCL1, NEUROD1, POU2F3 and more controversially, YAP1. MYCL oncogene is associated with the most common ASCL1 group (~70% of SCLC), while MYC is overexpressed in the NEUROD1/POU2F3/YAP1 subtypes (~30% of SCLC). Importantly, we and others found that MYC-driven SCLC has unique therapeutic vulnerabilities compared to MYCL-driven SCLC. MYC has the capacity to drive SCLC subtype plasticity, promoting ASCL1+ tumors to a NEUROD1+ and then a YAP1+ state. MYC-induced Notch pathway activation is critical for SCLC subtype plasticity. While ASCL1 has been frequently studied, much less is known about the 2nd-most common NEUROD1+-subtype. We hypothesize that NEUROD1 expression denotes a neuronal transcriptional state of SCLC, that NEUROD1- mediated repression of Notch signaling is critical for this tumor cell state, and that the NEUROD1+ state has unique therapeutic vulnerabilities. We further predict that NEUROD1 inhibition will shift tumors to developmentally predictable non-neuroendocrine cell fates. Our objective is to determine the function of NEUROD1 in the NEUROD1+ subtype of SCLC, to identify mechanisms that regulate subtype plasticity, and uncover the relationship between NEUROD1 and Notch signaling. Toward this end, we created the first mouse model of NEUROD1+ SCLC and generated mice with conditional Neurod1 loss to study its function in vivo. Preliminary data have identified highly conserved NEUROD1 target genes. Large-scale CRISPR-based genetic screens have identified predicted dependencies that have the potential for therapeutic targeting. Our hypotheses will be tested in two specific aims: 1) Determine the function of NEUROD1 in MYC-driven SCLC cell fate. 2) Determine the mechanistic relationship between NEUROD1 and Notch signaling in SCLC subtype plasticity. Our approach is innovative because we will employ novel immune-competent GEMMs of MYC-driven SCLC, ~17 new human PDX, and single cell data from primary human SCLC. We will use state-of-the-art technologies in single cell RNA-seq and lineage tracing in new organoid models coupled with our ChIP-seq data to comprehensively determine the role of NEUROD1 in SCLC. This research is significant because these findings will lead to a better understanding of SCLC molecular subtypes and ultimately facilitate tailored SCLC treatment.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
