Targeting cancer stem cells expressing an embryonic signature with anti-proteases to decrease their tumor potential

Area of Science:

• Oncology
• Stem Cell Biology
• Pharmacology

Background:

• Cancer stem cells (CSCs) drive tumor growth and recurrence.
• CSCs with an embryonic stemness signature (Oct-4, Nanog, Sox2) are linked to poor prognosis in high-grade solid tumors.
• Targeting CSCs is crucial for effective cancer treatment.

Purpose of the Study:

• To identify molecules selectively toxic to CSCs expressing an embryonic stemness signature.
• To evaluate the efficacy of human immunodeficiency virus (HIV)-protease inhibitors (HIV-PIs) against these specific CSCs.
• To explore therapeutic opportunities for solid tumors with poor prognosis.

Main Methods:

• Isolation of pure CSC populations from solid tumors.
• Screening of molecules for selective toxicity against CSCs.
• Dose-dependent proliferation and cell death assays.
• In vivo allograft formation studies.
• Identification of key pharmacophores in effective compounds.

Main Results:

• HIV-protease inhibitors (HIV-PIs) specifically target and reduce proliferation of CSCs with an embryonic signature.
• HIV-PIs demonstrated higher specificity for CSCs compared to total cancer cells or healthy stem cells.
• Lopinavir (LPV) was the most effective HIV-PI, reducing CSC self-renewal and inducing apoptosis.
• LPV impaired in vivo CSC-induced tumor formation, with identified pharmacophores responsible for targeting and activity.

Conclusions:

• HIV-PIs, particularly Lopinavir, show significant potential as targeted therapies for CSCs with an embryonic stemness signature.
• These findings open promising therapeutic avenues for patients with poor-prognosis solid tumors.
• The study identifies specific molecular features responsible for CSC targeting and anti-tumor activity.