Abstract
Abstract Small cell lung cancer (SCLC) is a highly malignant form of lung cancer that accounts for 15% of lung cancer cases. The tumor has a tendency to disseminate early resulting in ~ 85% patients being diagnosed with extensive stage disease (ES-SCLC). Chemotherapy has been the mainstay of treatment for many decades, until recently when immunotherapeutic agents have been approved as first-line agents. However, resistance to anti-cancer drugs represents the main cause of cancer-related deaths. Thus, new therapeutic approach to suppress chemotherapy-resistant ES-SCLC constitutes a significant unmet medical need. We have generated novel biodegradable QUATRAMERTM polymeric nanoparticles comprised of a polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG- polylactic acid (PLA)-tetra-block copolymer for the intracellular delivery of salinomycin (HSB-1216). Here we studied the HSB-1216 activity in a resistant SCLC cell line (NCI-H69AR). Compared to cisplatin and irinotecan, a second-line agent often used in ES-SCLC, HSB-1216 exhibited a ~7-fold and ~2-fold decrease in IC50in the aggressive and resistant variant of NCI-H69AR cell line and ~30-fold and ~18-fold decrease in a non-resistant NCI-H69 SCLC line. The tumorsphere formation assay has become an essential tool for quantifying cancer stem cells (CSC) and testing of anti-cancer agents. We used this assay to estimate an effect of HSB-1216 on NCI-H69AR tumorspheres .Our results demonstrated significant dose-dependent inhibition of tumorosphere formation in response to HSB-1216. In addition, exposure to HSB-1216 resulted in substantial decrease in number of CD44+/CD24- cells in comparison to untreated control. Furthermore, significant reduction in the expression of CSC markers such as ALDH1 and Oct3/Oct4 was seen when chemotherapy-resistant NCI-H69AR cells were treated with HSB-1216.Taken together, based on these findings, HSB-1216 is being developed as a novel agent in the treatment of second-line ES-SCLC in chemo-resistant tumors, where a gap exists in current standards of care. Further work of this novel agent is planned to outline its effect when combined with targeted and non-targeted therapies in both first- and third-line SCLC. Citation Format: Anees Mohammad, Sachchidanand Tiwari, Neha Mehrotra, Bozena Korczak, Steve Laumas, Sireesh Appajosyula, Harpal Singh, Surender M. Kharbanda. HSB-1216, A Novel Agent for the Treatment of Chemotherapy-Resistant ES-SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3107.
Published Version
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