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A novel drug, SM08502 (cirtuvivint), combined with PARP inhibitors (PARPi), shows promise in overcoming resistance to PARPi therapy in ovarian cancer models. This combination therapy reduces tumor progression and improves survival by targeting WNT signaling and remodeling the tumor immune microenvironment.

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Area of Science:

  • Oncology
  • Cancer Therapeutics
  • Molecular Biology

Background:

  • PARP inhibitors (PARPi) are effective in treating BRCA1/2-mutated high-grade serous carcinoma (HGSC).
  • PARPi resistance is a significant clinical challenge, limiting treatment options for patients with advanced ovarian cancer.
  • Elevated WNT signaling contributes to PARPi resistance, but direct targeting is difficult due to adverse events.

Purpose of the Study:

  • To evaluate SM08502 (cirtuvivint), an indirect WNT inhibitor, in combination with PARPi to overcome PARPi resistance in HGSC.
  • To investigate the mechanisms by which SM08502 affects WNT/TCF transcriptional activity, cell viability, and DNA damage in resistant models.
  • To assess the efficacy of SM08502 and olaparib combination therapy in preclinical models of PARPi-resistant ovarian cancer.

Main Methods:

  • Testing SM08502 in combination with PARPi in multiple PARPi-resistant HGSC models.
  • Assessing TCF transcriptional activity, differential gene expression, and splicing.
  • Utilizing multispectral immunohistochemistry (IHC) to analyze the tumor microenvironment in vivo.
  • Evaluating tumor progression, immune microenvironment remodeling, and survival in immune-compromised and immune-intact models.

Main Results:

  • SM08502 inhibited WNT/TCF transcriptional activity, reduced cell viability, and induced DNA damage in PARPi-resistant models.
  • The combination of SM08502 and olaparib significantly reduced disease progression in vivo.
  • Tumor immune microenvironment was remodeled, with decreased expression of PD-1 and PD-L1.
  • Combination therapy extended survival in preclinical models of PARPi-resistant HGSC.

Conclusions:

  • SM08502, as an indirect WNT inhibitor, demonstrates potential in overcoming PARPi resistance.
  • The combination of SM08502 with PARPi (olaparib) offers a promising strategy to treat PARPi-resistant ovarian cancers.
  • This approach warrants further clinical investigation for patients with resistant HGSC.