Response to stereotactic ablative radiotherapy in a novel orthotopic model of non-small cell lung cancer

Area of Science:

• Oncology
• Radiotherapy
• Molecular Biology

Background:

• Stereotactic ablative radiotherapy (SABR) is a primary treatment for inoperable early-stage non-small cell lung cancer (NSCLC).
• The biological factors influencing SABR response in NSCLC are not well understood.
• An orthotopic NSCLC animal model was created to investigate SABR's effects.

Purpose of the Study:

• To evaluate the biological response to clinically relevant doses of SABR in an NSCLC animal model.
• To identify molecular changes associated with SABR treatment and treatment failure.
• To explore the role of specific genes, such as IL8, in SABR-induced tumor behavior.

Main Methods:

• Developed an image-guided orthotopic NSCLC rat model.
• Administered a single 34 Gy fraction of SABR using clinical photon energies.
• Assessed tumors for differentiation, proliferation, and invasiveness post-treatment (10-60 days).
• Performed a 770-gene analysis on NSCLC cell lines from treated and untreated tumors.

Main Results:

• SABR achieved a complete response in 67% of animals, with 33% experiencing local failure.
• Distant failure occurred in 50% of animals with a complete response.
• Gene expression analysis revealed SABR significantly altered genes involved in adhesion, migration, and angiogenesis.
• Interleukin-8 (IL8), a key factor in tumor invasion, was highly secreted post-SABR.
• In vitro assays confirmed SABR induces NSCLC cell invasion and IL8 secretion.

Conclusions:

• SABR is effective but associated with local and distant failures in NSCLC.
• SABR modulates gene expression, potentially promoting tumor invasion via IL8.
• Targeted therapies are needed to counteract SABR-induced pro-invasive effects in NSCLC.