Abstract 6891: Establishment and characterization of a panel of naïve and pretreated small cell lung cancer (SCLC) XPDX models

Abstract

Abstract SCLC is an aggressive cancer of neuroendocrine origin, accounting for approximately 15% of all lung cancer cases. While the incidence of SCLC in the US has declined over past decades due to changes in smoking habits, this disease provides a poor prognosis and few effective treatment options for advanced disease. To better identify useful therapies for SCLC, we established and characterized a panel of 18 XPDX models representing primary and metastatic disease from either naïve or clinically treated patients and tested sensitivities towards chemotherapies and targeted agents. 18 models were established in immune-deficient mice including 8 from newly diagnosed patients (2 from lung primary), and 10 from recurrent disease (3 from lung primary). Models were IHC stained for Nectin-4, Trop2 protein and ERBB2 and profiled using WES and RNAseq. For in vivo studies, models were evaluated against several chemotherapies including cisplatin, etoposide, topotecan, and temozolomide, as well as ADC agents trastuzumab deruxtecan (T-DXd), enfortumab vedotin (EV), and sacituzumab govitecan (SG). Targeted therapies toward CDK4/6, KRASG12C, and PARP were evaluated in some models. Endpoints in all studies included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C<0%) versus Day 0 tumor volume was also reported. Less than 10% of models stained positive for Nectin-4, Trop-2 or ERBB2. Molecular characterization revealed RB1 frameshifts or deletions in most models, KRAS/NRAS point mutations in 3 models, and 2 gene fusions SEPTIN7P2-PSPH and TVP23C-CDRT4. In vivo studies reported differential responses to chemotherapies with the most sensitive models established from treatment-naïve patients. Temozolomide was active in several studies including tumor regressions in both naïve and pretreated models. ADCs also reported differential activity toward the tested panel. We have established and characterized a panel of SCLC XPDX models and benchmarked them against various cancer therapies. This panel can be utilized as a valuable tool in developing novel therapies for SCLC patients. Citation Format: Gabriela Huelgas Morales, Peter Forofontov, Johnnie Flores, Alyssa Simonson, Armando Diaz III, Jim Lund, Natalia Banos, Kyriakos Papadopoulos, Drew Rasco, Amita Patnaik, Ali Abedi, Napoleon Puente, Emiliano Calvo, Victor Moreno, Ronald Drengler, Lon Smith, Michael Wick. Establishment and characterization of a panel of naïve and pretreated small cell lung cancer (SCLC) XPDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6891.