Targeting aberrant replication and DNA repair events for treating breast cancers

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Conventional DNA-targeting chemotherapy drugs face significant limitations including severe toxicity, acquired resistance, and secondary cancer development.
• Cancer cells exhibit unique dependencies on specific DNA-related processes for survival, such as uncontrolled replication and aberrant DNA repair.

Purpose of the Study:

• To investigate the therapeutic potential of a novel small molecule, Carbazole Blue (CB), as a targeted cancer therapy.
• To evaluate CB's efficacy in inhibiting cancer growth and metastasis while assessing its safety profile.

Main Methods:

• CB was evaluated for its DNA-binding properties and its effect on pro-tumorigenic gene expression.
• Pre-clinical studies in mouse models assessed the systemic delivery of CB for suppressing breast cancer growth and metastasis.
• CB's efficacy was further tested using patient-derived xenografts (PDX) and ex vivo explants from various breast cancer subtypes.

Main Results:

• CB effectively inhibits the expression of genes driving unchecked cell replication and aberrant DNA repair in cancer cells.
• Systemic administration of CB suppressed breast cancer growth and metastasis in mouse models without inducing toxicity.
• CB demonstrated efficacy against both therapy-sensitive and therapy-resistant breast cancers, including ER-positive, ER-mutant, and triple-negative breast cancer (TNBC) subtypes, without harming normal breast tissue.

Conclusions:

• Carbazole Blue (CB) represents a promising therapeutic agent that targets cancer-specific DNA processes, offering a potentially safer and more effective treatment strategy.
• CB's ability to inhibit growth and metastasis across diverse and resistant breast cancer types warrants its further development as a viable therapeutic option.