KLIPP - a precision CRISPR approach to target structural variant junctions in cancer

Area of Science:

• Oncology
• Molecular Biology
• Gene Editing

Background:

• Conventional cancer therapies often cause dose-limiting normal tissue toxicity.
• There is a need for precision cancer treatments with high specificity for tumor cells.
• Targeting cancer-specific genetic alterations can improve therapeutic efficacy and reduce side effects.

Approach:

• We developed KLIPP (CRISPR/Cas9-mediated targeted endonuclease), a novel precision cancer therapy.
• KLIPP utilizes guide RNAs to target cancer-specific structural variant junctions, recruiting two parts of a Fok1 endonuclease for activation.
• Activated Fok1 induces DNA double-strand breaks (DSBs) specifically at targeted junctions, leading to cancer cell death.

Key Points:

• KLIPP demonstrated high specificity for tumor cells, independent of tumor-specific drivers.
• In orthotopic mouse models, activating Fok1 at two targeted junctions led to tumor cell disappearance in 7/11 mice.
• The approach induces targeted DNA double-strand breaks and subsequent cancer cell death.

Conclusions:

• KLIPP represents a promising precision cancer therapeutic strategy with high specificity and efficacy.
• This approach has the potential for individualized translation to patients, offering a transformative and simplified cancer treatment.
• Further development of KLIPP could lead to more consistent and effective cancer treatment decisions.