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

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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.