Abstract 2664: Identification of two small molecules with small cell lung cancer growth inhibition response profiles different from etoposide/topotecan
Authors: Allison A. Mootz, Michael Peyton, Paul Yenerall, Kimberley Avila, Kenneth Huffman, Tomohiro Haruki, Mahboubeh Papari-Zareei, Victor Stastny, Luc Girard, Elizabeth McMillan, Michael Roth, John MacMillan, Bruce Posner, Michael White, Gazdar Adi, John Minna
Journal: Cancer Research (2018)

Abstract Small Cell Lung Cancer (SCLC) is an aggressive, highly metastatic cancer with an overall 5-year survival rate of &amp;lt;5% whose treatment has not changed in the past 20 years and has been designated by the US Congress and the National Cancer Institute as a “recalcitrant cancer.” SCLCs are characterized by high initial response rates to chemotherapy (platin + etoposide) and radiation therapy but relapse is almost universal within 1 year. A NCI screen of 526 clinical or clinical investigational agents in 63 SCLC lines found large response phenotype differences (Polley, JNCI (2016) 108(10): djw122) but, in general, SCLC lines were either “sensitive” or “resistant” to all drugs tested and there was no correlation with tumor molecular biomarkers, or prior chemotherapy treatment. Thus, new drugs are needed (preferably with tumor associated molecular biomarkers) that have different profiles than available agents. As part of an NCI Cancer Treatment Discovery and Development Network (CTD2N) consortium we have screened large chemical libraries and identified chemical compounds that kill subsets of non-small cell lung cancers (NSCLCs) but not normal lung epithelial cells thus displaying a “therapeutic window” and tumor specificity. We first tested 116 of these compounds against 4 SCLC lines and found 30 that displayed dose dependent SCLC toxicity. We have so far tested 2 (SW034510, SW140154) compounds against a panel of 22 SCLC lines, which were also in the NCI screen, along with etoposide and topotecan as comparators, using 8-point dose response curves, for effect on SCLC growth inhibition. The SCLC lines (all with p53 and Rb mutations) were also phenotyped for expression of Myc family members (c-, N-, and L-), lineage transcription factors ASCL1 and NeuroD1 and neuroendocrine mRNAs. As found by Polley et al, etoposide and topotecan response phenotypes were correlated with each other (r2 = 0.7). By contrast, our two compounds, SW034510 and SW140154, response phenotypes did not correlate with etoposide/topotecan (r2 values of &amp;lt;0.08, and 0.1 respectively) and did not correlate with each other. Both agents cause cell death as assessed by the CellTox Green Assay suggesting efficacy across the ASCL1/NeuroD1, Myc family expression profiles. Cleaved caspase-3 western blot shows SW034510 causes caspase induced apoptosis. Cell cycle analysis suggests SW140154 causes a G1 cell cycle arrest. SARM1 gene expression anti-correlates with SW140154 IC50s. In conclusion, starting with chemical compounds that have selectivity for NSCLC, we have identified two new chemical compounds with specificity for subsets of NSCLC over normal lung epithelial cells, and which also inhibit the growth/kill subsets of SCLC in patterns different from the established therapy. Thus, these two new compounds provide potentially new therapeutic opportunities for SCLC patients resistant to current chemotherapies. Citation Format: Allison A. Mootz, Michael Peyton, Paul Yenerall, Kimberley Avila, Kenneth Huffman, Tomohiro Haruki, Mahboubeh Papari-Zareei, Victor Stastny, Luc Girard, Elizabeth McMillan, Michael Roth, John MacMillan, Bruce Posner, Michael White, Gazdar Adi, John Minna. Identification of two small molecules with small cell lung cancer growth inhibition response profiles different from etoposide/topotecan [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 2664.