2023 World Conference on Lung Cancer (Posters)-P1.06. Phenotype Mapping of Patient-Derived Small Cell Lung Cancer Organoids Illuminate Subtype-Specific Therapeutic Vulnerability

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Researchers presented their findings on the phenotype mapping of patient-derived small cell lung cancer (SCLC) organoids at the 2023 World Conference on Lung Cancer. SCLC is a highly aggressive cancer with a poor survival rate, and current targeted therapies have shown limited efficacy. Genomic studies have identified common genetic alterations in SCLC, but the association between specific subtypes and therapy remains unclear. Existing SCLC models, such as cell lines, genetically modified mouse models, and patient-derived xenografts, have limitations in accurately representing the disease.<br /><br />To address these challenges, the researchers used patient-derived organoids as an alternative preclinical SCLC model. Organoid models enable the analysis of genotype and phenotype assays and allow for prospective gene editing of normal lung tissues. The researchers aimed to establish a library of SCLC organoids representing all four transcription factor (4-TF) subtypes and evaluate their molecular and phenotype profiles.<br /><br />The results showed that the expression patterns of neuroendocrine markers were preserved in the SCLC organoids, confirming their relevance to the original tumors. Whole exome sequencing revealed genetic mutations and copy number losses in TP53 and RB1, consistent with SCLC genomics. Transcriptomic analysis classified the organoids into the 4-TF subtypes, which correlated with the accessibility of corresponding transcription factors. Gene ontology analysis revealed subtype-specific gene signatures, including an airway-like pattern in one subtype and enrichment of AP-1 motif in another.<br /><br />The researchers also investigated the response of the SCLC organoids to niche factor deprivation. They found that SCLC-YP organoids had a specific dependence on the PI3K/MAPK activating niche and were uniquely susceptible to IGF1R inhibition. The expression of IGF1R in patient-derived clinical tissues correlated with the subtype-specific vulnerability to IGF1R inhibition.<br /><br />In summary, the researchers successfully established a comprehensive library of patient-derived SCLC organoids representing the 4-TF subtypes. Through phenotype mapping, they identified subtype-specific niche factor dependency and demonstrated the biological vulnerability of SCLC-YP organoids to IGF1R inhibition. These findings contribute to a better understanding of SCLC subtypes and may inform the development of subtype-specific therapeutic strategies.

Asset Subtitle

Takahiro Fukushima

Meta Tag

Speaker Takahiro Fukushima

Topic Tumor Biology: Preclinical Biology - Tumor Immunity

Keywords

phenotype mapping

patient-derived organoids

small cell lung cancer

SCLC

genetic alterations

transcription factor subtypes

neuroendocrine markers

gene ontology analysis

niche factor deprivation

IGF1R inhibition