Abstract 5864: Novel anti-BMI-1 therapy in non-small cell lung cancer

Abstract

Abstract Lung cancer represents one of the most significant and lethal diseases worldwide. Advances in treatment protocols, the development of targeted agents, and our comprehensive understanding of the genetics and mechanisms driving this disease, have helped identify novel agents with therapeutic promise, yet mortality remains high. Thus, there is a real need to identify new therapeutic options that can target this disease to improve patient outcome. BMI-1 (B cell-specific Moloney murine leukemia virus integration site 1), a key component of the epigenetic Polycomb Repressive Complex 1, plays a substantial role in many solid tumors, including NSCLC. It represents a compelling therapeutic target for NSCLC cancer patients as the majority of NSCLCs (~75%) display positive BMI-1 protein expression. Several compounds that reduce levels of the oncogene BMI-1 protein have been discovered by PTC Therapeutics i.e., PTC596 and a related analog PTC-028. PTC596 completed Ph1 trials and is currently being further tested in Ph1b trials. By using xenografts and established murine models of NSCLC, we are investigating BMI-1 as a novel therapeutic target in lung cancer, the mechanisms through which BMI-1 confers tumorigenicity, and determine the efficacy of BMI-1 inhibition in in vivo models of lung cancer at the single cell level. One critical aspect of cancer development lies in the 3-dimensional network of interactions that occurs between cells within their microenvironment. Therefore, by means of droplet-based molecular barcoding techniques we are analyzing single cell transcripts and identifying the population clusters within the heterogeneous tumor cellular milieu, to determine which cellular populations exist within tumors and how they respond to anti-BMI-1 treatment. Our data show that mutant EGFR and K-Ras driven lung cancer transgenic mice, as well as xenograft mice, express high levels of BMI-1 protein. In addition, we show that tumor growth of both models is affected by PTC596 treatment, with a more rapid response than that of currently available therapeutics. Tumor growth was measured at different time-points by magnetic resonance imaging. Transcriptional deconvolution of single cell sequencing data has enabled us to identify tumor-associated pulmonary subpopulations displaying epithelial, immune, fibroblast, and endothelial features. Importantly, tumor associated epithelial cells display a positive BMI-1 signature, which we also identified in primary NSCLC samples, underscoring the beneficial effects of anti-BMI-1 therapy in NSCLC patients. Citation Format: Indira Krishnan, Giorgia Maroni, Sean Clohessy, Virginia Savova, Mahmoud Bassal, Rapolas Zilionis, Eva Csizmadia, Clara M. Kerwin, Sun Choi, Claire V. Meyerovitz, Nicole Pandell, Chee W. Fhu, Junyan Zhang, Daniela S. Basseres, Cristina M. Magli, Julian Goggi, Robert S. Welner, Allon M. Klein, Marla Weetall, Art Branstrom, Raphael Bueno, Azhar Ali, Daniel G. Tenen, Elena Levantini. Novel anti-BMI-1 therapy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5864.