Abstract P3-09-06: Targeting tumor subpopulations based on single-cell transcriptomics

Abstract

Abstract Breast cancers that are hormone receptor negative, such that they do not express the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2), are known as triple-negative breast cancer (TNBC), and are predominantly of the basal-like subtype. These tumors aggressively metastasize, have limited effective therapeutic options, and are prevalent in patients of African descent. In these studies, we utilized a racially diverse set of 21 breast cancer patient-derived xenografts (PDXs) and 6 cell lines to identify new therapeutic combinations that may exhibit increased efficacy for patients based on ancestral heritage. Tumor subpopulation abundance was measured by single-cell RNA-sequencing (scRNAseq) a set of 13 PDXs, including some that had been subjected to long term carboplatin treatment or endocrine therapy in vivo. We identified two to four major cell types per PDX and sought to integrate this information with cytotoxic high throughput screens (HTS) of 516 clinically actionable agents. Among several interesting and overlapping findings from these multiscale models, BIRC5 (Survivin) was identified as a readily actionable target in the proliferative component of all TNBC models assayed. Analysis of public datasets found that BIRC5 expression in TNBC patient tumors was significantly correlated with reduced metastasis-free survival. In vitro and in vivo studies from our group and others found that YM155, which targets Survivin, was highly cytotoxic towards breast cancer cells. YM155 has been previously safely administered in Phase I/II clinical trials. To uncover putative dependency pathways that may be exploited to prevent acquired resistance to BIRC5 (Survivin) inhibition, we performed synergistic HTS assays whereby the efficacy of our 516 therapeutic library was assessed in the presence versus absence of YM155. Those drugs which were found to be more highly effective when given in combination with YM155 were then selected for ongoing in vitro and in vivo applications. Grant ID: 1R01CA246182-01A1 (NIH/NCI), CCR19608826 (Susan G. Komen Foundation), VCU School of Medicine VETAR, the Jeffress Trust, UL1TR002649 (CTSA/NCATS) Citation Format: Jacqueline M Grible, Tess Leftwich, Amy L Olex, Alex K Duong, Nicole Hairr, Narmeen S Rashid, Timothy M Smith, Lia Signaevskaia, David C Boyd, Mikhail G Dozmorov, Joshua C Harrell. Targeting tumor subpopulations based on single-cell transcriptomics [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-06.