Abstract P045: Preclinical transcriptome-based evaluation of the translatable potential of new treatments in Triple-Negative Breast Cancer
Authors: Salkini Ammar 
Published: January 2022

Objective: This study will evaluate the potential of four recently proposed TNBC treatments—which all successfully reduced tumor viability in vitro and/or in vivo—to inhibit genes involved in CSC survival, metastatic metabolomic signature, and tumor immunosuppression.

Methods: TNBC cell lines and/or patient-derived xenografts were treated with five different treatments: DCC-2036, 9Gy proton irradiation, miR302b+cisplatin combination, and DFX+doxorubicin combination. Genome-wide mRNA profiling (via either RNA-seq or microarray) was performed on control and treated groups. Data was obtained from NCBI GEO datasets. We assessed the differential expression of genes associated with CSC growth and metastatic metabolomic signature in TNBC tumors. Limma statistical analysis was performed. GSEA was also used to complement results from individual gene expression analysis.

Results: DCC-2036 treatment significantly induced the expression of CSC TNBC biomarkers—such as ALDH2, CD44, CCR5, and SNAI1—and genes associated with TNBC metastatic metabolomic signature—such as PPARGC1A. DCC-2036 showed inconsistent effects on the expression of immunosuppressive markers. Gene expression profiles of the remaining treatment groups are currently being analyzed. 9Gy proton irradiation has mixed effects on the expression of our candidate genes, yet mostly induced the expression of stemness, metastatic, and immunosuppressive markers. miR302b+cisplatin and DFX+doxorubicin both failed to inhibit the candidate genes, yet without significantly inducing their expression. GSEA analysis confirmed the results obtained for all four treatments.

Conclusions: Observing cancer rebound in TNBC patients after treatment with traditional cancer drugs is common and often happens when treatments fail to inhibit CSC growth, metabolic pathways associated with metastasis, and oncogenic immunosuppressive pathways. Our analysis shows that all four treatments failed to significantly impact the expression of protein pathways associated with increased metastasis and immunosuppression. It is worth noting that the researchers did report a decrease in tumor viability due to treatment of their experimental models with all four treatments. However, these findings correspond to the viability of the whole cell culture or tumor, not the viability of specifically the CSCs; in TNBC, CSCs make up only a small proportion of the total mass or the tumor, so the reported antiproliferative effects of the treatments do not necessarily suggest the treatment has effectively targeted the CSC population. Therefore, we hypothesize that these treatments will likely not show positive effects in clinical studies. Furthermore, none of the researchers performed any assays evaluating CSC growth—such as CSC-labelled flow cytometry—or metastasis—such as secondary tumor transplantation. Therefore, we encourage the researchers to perform more rigorous assays to evaluate the translatable potential of their treatments. Finally, the outline of this study provides a useful rationale for to evaluate emerging TNBC therapies.

Citation Format: Ammar Salkini. Preclinical transcriptome-based evaluation of the translatable potential of new treatments in Triple-Negative Breast Cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P045.