Durability of cell line xenograft resection models to interrogate tumor micro-environment targeting agents

Area of Science:

• Oncology
• Cancer Biology
• Translational Research

Background:

• Angiogenesis is crucial for tumor growth and metastasis within the tumor microenvironment (TME).
• Classical subcutaneous xenograft models show limited predictive value for anti-angiogenic therapies compared to clinical trial results.
• There is a need for more predictive preclinical models to guide the development of targeted cancer therapies.

Purpose of the Study:

• To establish and validate orthotopic surgical resection models for breast cancer.
• To assess the efficacy of bevacizumab in combination with chemotherapy and trastuzumab in a clinically relevant setting.
• To demonstrate the predictive potential of these models for tumor microenvironment targeting agents.

Main Methods:

• Orthotopic implantation of bioluminescent Her2+ breast cancer cell lines (MDA-MB-231, HCC1954) in SCID mice.
• Surgical resection of established orthotopic tumors followed by adjuvant treatment regimens.
• Treatment groups included chemotherapy (paclitaxel) plus trastuzumab, with or without bevacizumab, monitored for metastasis via imaging.

Main Results:

• The addition of bevacizumab to trastuzumab and chemotherapy did not improve outcomes or reduce metastasis.
• The orthotopic resection model accurately recapitulated the findings of the BETH adjuvant trial (NCT00625898).
• Subcutaneous xenograft models failed to predict the lack of benefit from bevacizumab in this context.

Conclusions:

• Orthotopic breast cancer resection models are superior to subcutaneous models for predicting clinical outcomes of anti-angiogenic therapies.
• Bevacizumab does not provide additional benefit when combined with adjuvant trastuzumab and chemotherapy in this model.
• These validated resection models offer a powerful tool for evaluating TME-targeting agents and improving clinical trial design.