Evaluation of Tumor/Tumor Microenvironment Interactions for Potential Predictors of Patient Response to Napabucasin


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Harry Rogoff1,An-Yun Chang1,Eric Hsu1,Jaimin Patel1,Minjie Zhang1,Haruhisa Iguchi1
1Boston Biomedical, Inc.

Abstract

Background

The tumor mass resides in close proximity to multiple other cell types in the tumor microenvironment (TME). The dynamic interactions between tumor cells and the surrounding non-tumor cells can facilitate tumor progression and influence the response to therapeutic intervention. Understanding the complex signals within the TME may help us to predict what tumors may respond to specific treatments. Exploratory observations from the napabucasin Phase III CO.23 study suggest that patients show a better response to napabucasin if they have pSTAT3 in the TME and tumor cells.

Method

A549 and FaDu cancer cells, or cells deleted for NQO1 using CRISPR (NQO1CR), were cultured in 2D monolayer cultures or in 3D sphere cultures alone or in combination with normal or cancer-associated fibroblasts. Cytokine profiler arrays and ELISA were used to identify differentially secreted factors. FLOW cytometry and immunofluorescence was used to identify phosphorylated STAT3 (pSTAT3) positive populations in human PBMC and tumor/fibroblast co-cultures.

Results

Using a 3D cancer cell/fibroblast co-culture model, we found that NQO1 positive cancer cells are highly sensitive, while NQO1 negative cancer cells are resistant, to napabucasin. NQO1 positive cancer cells co-cultured with fibroblasts are found to secrete different levels of factors than NQO1 negative cancer cell co-cultures. Some of these factors include IL-6, GM-CSF, and CXCL10. These factors are found to increase pSTAT3 levels in cell types found in the TME, including fibroblasts, lymphocytes, and monocytes. Direct 3D co-culture of tumor cells with fibroblasts demonstrates that NQO1 positive cancer cells promote greater STAT3 phosphorylation in both the cancer cells and cells of the TME than NQO1 negative cancer cells. 

Conclusion

pSTAT3 in the cells of the TME may serve as an indication of the sensitivity of the tumor to napabucasin, and therefore has potential to be used to identify patients that would likely benefit from napabucasin treatment.