Molecular and immunological heterogeneity of Small Cell Lung Cancer (SCLC) and its impact on relapse and therapeutic response

PROJECT SUMMARY
Small cell lung cancer (SCLC) is an aggressive malignancy for which there is a critical need for improved
therapeutic strategies. While targeted and immune-based therapies have demonstrated encouraging results
recently, they have shown benefit in only a subset of patients and, thus, have yielded little to no impact on the
survival of unselected populations and even these benefits are limited by the rapid onset of resistance. There
are currently no standard markers for selecting treatment or evaluating therapeutic resistance, issues made more
challenging by the dearth of available tissue for molecular assessment in SCLC. Recent evidence from our group
and others suggests that SCLC is a molecularly diverse disease and can be divided into four subtypes largely
defined by the differential expression of three transcription factors [ASCL1 (SCLC-A), NEUROD1 (SCLC-N), and
POU2F3 (SCLC-P)], and a fourth subtype with high expression of inflammatory and mesenchymal markers
[Inflamed, (SCLC-I)]. Each subtype is characterized, in vitro, by distinct therapeutic vulnerabilities. Moreover, we
showed that genomic and immune intra-tumoral heterogeneity (ITH) portends poorer survival, while increasing
transcriptional ITH may be associated with therapeutic resistance in SCLC. The overarching goal of this proposal
is to systematically investigate heterogeneity in SCLC and its association with therapeutic response, and develop
tools to evaluate these features in the clinic. More specifically, we hypothesize (1) That SCLC is heterogeneous
and can be divided into major subgroups with distinct therapeutic vulnerabilities; and (2) That greater ITH-
assessed either at the genomic, immune, or transcriptional level- is associated with therapeutic resistance in
SCLC and can be assessed dynamically during treatment in a non-invasive manner using blood-based
biomarkers. To address these hypotheses, in Aim 1, we will assess whether these four molecular subtypes can
serve as predictive biomarkers in co-clinical trials in vivo and in retrospective patient tissue analyses, while also
developing blood-based strategies to identify the subtypes. In Aim 2, we will assess ITH at multiple molecular
levels, including genomic, transcriptomic, methylomic, and immunologic, to characterize how baseline ITH
influences patient survival. Lastly, in Aim 3, we will assess dynamic changes in transcriptional ITH following
treatment, using paired samples from in vivo models and patient samples, to determine if increasing ITH of
molecular subtype drives resistance and whether epigenetic modification may prevent or reverse it. The overall
hypothesis tested here is that careful initial molecular subtyping of SCLC tumors, paired with strategies aimed
at assessing, then limiting/reversing ITH, may better optimize the rate and duration of response to therapy. The
studies will be facilitated by a comprehensive library of patient-derived murine models and extensive clinical data
sets and executed by a multidisciplinary team of clinical/laboratory investigators, pathologists, computational
biologists, and others with a strong track record of innovation in SCLC and translating laboratory findings into
the clinic.

Grant Number: 5U01CA256780-05
NIH Institute/Center: NIH
Principal Investigator: Lauren Byers