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Evaluation of Tumor Cell-Tumor Microenvironment Component Interactions as Potential Predictors of Patient Response to

An-Yun Chang1, Eric Hsu1, Jaimin Patel1

  • 1Boston Biomedical Inc., Cambridge, Massachusetts.

Molecular Cancer Research : MCR
|May 3, 2019
PubMed

Insights

Phosphorylated STAT3 (pSTAT3) may identify patients who benefit from napabucasin, an anticancer drug. This finding stems from research linking NQO1 expression to pSTAT3 levels and drug response in cancer cells and their microenvironment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Napabucasin is an NAD(P)H:quinone oxidoreductase 1 (NQO1)-bioactivatable small molecule.
  • NQO1 is hypothesized to affect multiple oncogenic pathways.
  • Previous studies suggest a link between NQO1 and pSTAT3 in cancer.

Purpose of the Study:

  • To investigate the relationship between NQO1 expression and pSTAT3 in cancer cells and the tumor microenvironment (TME).
  • To determine if pSTAT3 can serve as a predictive biomarker for napabucasin response.

Main Methods:

  • Retrospective analysis of the napabucasin phase III CO.23 study.
  • 3D spheroid coculture models of cancer cells and cancer-associated fibroblasts.
  • Measurement of cytokine levels (IL6, CXCL10, GM-CSF) and STAT3 phosphorylation.

Main Results:

  • Overall survival was longer with napabucasin versus placebo in patients with high pSTAT3.
  • Napabucasin's antitumor activity was dependent on NQO1 expression in coculture models.
  • NQO1-positive cocultures secreted higher levels of cytokines that promoted STAT3 phosphorylation.

Conclusions:

  • NQO1-expressing cancer cells can influence the TME to promote STAT3 phosphorylation.
  • pSTAT3 is a potential predictive biomarker for patient response to napabucasin.
  • Identifying patients with high pSTAT3 may optimize napabucasin treatment strategies.

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