Cancer gene therapy with iCaspase-9 transcriptionally targeted to tumor endothelial cells

Area of Science:

• Oncology
• Gene Therapy
• Cancer Biology

Background:

• Tumor growth relies on unique angiogenic factors, leading to varied responses to antiangiogenic therapies.
• Tumors can develop resistance by activating alternative angiogenic pathways when targeted.

Purpose of the Study:

• To test if a caspase-based artificial death switch in tumor-associated endothelial cells can disrupt tumor vasculature and slow progression.
• To evaluate this strategy's efficacy across different tumor types, irrespective of their specific angiogenic profiles.

Main Methods:

• Adenoviral vectors (Ad-hVEGFR2-iCaspase-9) were engineered to express inducible Caspase-9 (iCaspase-9) under the VEGFR2 promoter.
• The vector induced apoptosis in proliferating human dermal microvascular endothelial cells (HDMECs) but not in various human tumor cell lines.
• Apoptosis was dependent on the dimerizer drug AP20187 for iCaspase-9 activation.

Main Results:

• Local delivery of Ad-hVEGFR2-iCaspase-9 followed by AP20187 administration ablated tumor microvessels.
• Tumor growth was significantly inhibited in xenograft models of diverse cancer types (head and neck, liver, prostate, Kaposi's sarcoma, breast).
• The approach demonstrated selective targeting of endothelial cells without affecting tumor cells directly.

Conclusions:

• A gene therapy strategy using transcriptionally targeted viral vectors with inducible caspases enables selective microvessel ablation.
• This method offers a promising approach for controlling tumor progression in histopathologically diverse cancers.
• The inducible death switch provides a controlled mechanism for disrupting tumor vasculature, overcoming resistance pathways.