WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• The WNT pathway is crucial for cell fate regulation during development and is often dysregulated in cancers.
• Targeting the WNT pathway is a key strategy for developing novel anticancer therapies.
• Vantictumab (anti-FZD) and ipafricept (FZD8-Fc) are WNT antagonists advanced for clinical development.

Purpose of the Study:

• To evaluate the antitumor efficacy of WNT antagonists in combination with various chemotherapies.
• To investigate the synergistic effects and mechanisms of WNT blockade combined with taxanes.
• To determine the optimal sequential dosing strategy for WNT antagonists and taxanes.

Main Methods:

• Utilized patient-derived xenograft (PDX) models to test combination therapies.
• Administered WNT antagonists (vantictumab, ipafricept) with different chemotherapeutic agents.
• Analyzed the impact of WNT blockade on taxane-induced mitotic blockade and cell death.
• Investigated the effect of sequential dosing on WNT-active, chemotherapy-resistant cancer stem cells.

Main Results:

• WNT blockade demonstrated profound synergy with taxanes (e.g., paclitaxel) in responsive PDX models.
• Taxane monotherapy selected for WNT-active, chemotherapy-resistant tumor cells.
• Sequential administration of WNT antagonists followed by taxanes prevented this resistance selection.
• WNT antagonists enhanced paclitaxel's mitotic blockade, leading to increased mitotic cell death and sensitization of cancer stem cells.

Conclusions:

• Combining WNT antagonists with taxanes, particularly using a sequential dosing regimen, offers a promising strategy for enhancing cancer treatment efficacy.
• This approach effectively overcomes chemotherapy resistance by targeting WNT-active cancer stem cells.
• The combination strategy and sequential dosing regimen are currently under clinical investigation for vantictumab and ipafricept.