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Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in

Varun V Prabhu1, Amriti R Lulla2,3, Neel S Madhukar4

  • 1Oncoceutics, Inc., Philadelphia, Pennsylvania, United States of America.

Plos One
|August 3, 2017
PubMed

Insights

The drug ONC201 reduces cancer stem cell (CSC) self-renewal by altering gene expression in colorectal, prostate, and brain cancers. CSC gene expression may predict ONC201 treatment effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Cancer stem cells (CSCs) are linked to cancer recurrence, metastasis, and poor survival.
  • CSCs are validated therapeutic targets, with inhibitors showing promising clinical trial results.
  • ONC201 is an investigational small molecule imipridone targeting advanced cancers.

Purpose of the Study:

  • To investigate the anti-CSC effects of ONC201, focusing on early gene expression changes.
  • To determine if ONC201's mechanism involves modulation of stem cell-related pathways and genes.
  • To explore the potential of CSC-related gene expression as a predictive biomarker for ONC201 efficacy.

Main Methods:

  • Network analysis of gene expression profiles in colorectal cancer cells treated with ONC201.
  • Validation of gene expression changes at RNA and protein levels across colorectal, prostate, and glioblastoma models.
  • Assessment of ONC201's effect on CSC self-renewal and markers in various cancer cell lines and patient-derived cells.
  • Correlation analysis between basal CSC gene expression and ONC201 efficacy in over 1000 cancer cell lines.

Main Results:

  • ONC201 downregulates stem cell pathways (e.g., Wnt signaling) and key self-renewal genes (ID1, ID2, ID3, ALDH7A1) in cancer cells.
  • ONC201 inhibits self-renewal and CSC markers in prostate cancer and glioblastoma cells.
  • ONC201 resistance in colorectal cancer cells abrogated CSC depletion.
  • Basal expression of specific CSC genes (ID1, CD44, HES7, TCF3) strongly correlates with ONC201 efficacy.

Conclusions:

  • ONC201 exerts anti-CSC effects through early modulation of stem cell-related gene expression, preceding cell death.
  • CSC gene expression serves as a potential predictive and pharmacodynamic biomarker for ONC201 response.
  • Targeting CSCs with ONC201 offers a promising therapeutic strategy, with potential for personalized treatment based on biomarker expression.

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