Abstract 205: Patient-derived organoids from surgically treated, localized non-small cell lung cancer as high-throughput drug testing platforms for conventional and repurposed drugs

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.205-205
• Main Authors: Manjunath, Yariswamy, Nagaraj, Suvilesh Kanve, Nussbaum, Yulia I., Gadelkarim, Mohamed, Staveley-O’Carroll, Kevin F., Kimchi, Eric T., Li, Guangfu, Warren, Wesley, Shyu, Chi-Ren, Ciorba, Matthew, Mitchem, Jonathan B., Kaifi, Jussuf T.
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-205

Background: Non-metastatic NSCLC treated with curative surgery has a five-year survival of ~50%, mostly due to development of recurrences. Despite being considered as potential drug screening platforms, patient-derived xenograft (PDX) models are inefficient due to low tumor engraftment rates and complex animal care. Patient-derived organoid (PDO) models overcome these limitations as potential clinically applicable drug testing platforms. Our objective was to develop PDO models from non-metastatic NSCLC patients to study epithelial cell type heterogeneity and drug sensitivities for precision medicine. Hypothesis: PDO models reliably capitulate the patient primary tumor and serve as versatile platforms for high-throughput screening of standard-of-care and repurposed drugs. Methods: Single cell suspensions prepared from resected lung tumor tissues from ten NSCLC patients (both adenocarcinoma and squamous cell carcinoma) were mixed with Matrigel (growth factor-reduced) and cultured in organoid growth medium. Organoids and matched primary tumors were compared by histopathology [H&E staining and immunohistochemistry for cytokeratin (CK) 5/6, CK7, Napsin A, Thyroid transcription factor-1 (TTF-1) and p40] and by bulk RNA sequencing. Upon passaging, PDOs were seeded in triplicates, treated with carboplatin/paclitaxel doublet chemotherapy, and drug responses were determined using bright-field 3D imaging (z-stack method). Tumor growth (%) was determined on day 3 and 6 of treatments. RNA sequencing analyses identified a potential drug targets and repurposed drug (aldoketoreductase inhibitor Epalrestat) was tested to overcome chemoresistance in PDOs. Results: NSCLC PDO growth was established from 11/12 (91.7%) primary tumors with a median time of 11 days (range 4-18 days) to reach volume of 100 μm3. PDOs retained histopathological features and biomarker expression of the matched tumors. As determined by growth differences (p