Targeting the core program of metastasis with a novel drug combination

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Metastases exhibit a distinct gene expression profile activating tissue remodeling and vascularization, altering ion homeostasis, and inducing oxidative metabolism.
• This metastatic core program differentiates secondary tumors from primary tumors and host tissues, identifying key molecular targets.
• Gene products driving this metastatic program are potential targets for novel anti-metastasis drug development.

Purpose of the Study:

• To investigate the efficacy of targeting key components of the metastatic gene expression program.
• To evaluate a combination therapy involving inhibitors of tissue remodeling, oxidative metabolism, and ion homeostasis.
• To assess the therapeutic potential of repurposed drugs for treating established metastases.

Main Methods:

• Tested inhibitors targeting tissue remodeling, oxidative metabolism, and ion homeostasis in cancer cell lines.
• Evaluated pazopanib (VEGFR blocker), dimethyl sulfoxide/atovaquone (antioxidant), and bumetanide/tetrathiomolybdate (ionic modulators).
• Assessed drug efficacy individually and in combination in vitro and in two in vivo mouse cancer models.

Main Results:

• Individual agents showed inhibitory effects on cancer cell colony formation.
• Combination treatment demonstrated additive or synergistic effects, significantly inhibiting metastasis.
• Therapy applied early or late in metastasis development dramatically reduced disseminated tumor foci in mouse models.

Conclusions:

• Combining inhibitors of tissue remodeling, oxidative metabolism, and ion homeostasis shows significant promise for treating cancer metastasis.
• Repurposed drugs targeting these pathways offer a viable strategy for combination therapy.
• This multi-targeted approach holds potential for broad application across various metastatic cancers.