The early promise and hope for antiangiogenic therapy (AAT) in cancer has matured to a more realistic understanding that changes in the tumor microenvironment (TME) result in confounding effects that complicate outcome of combination therapy that includes an ATT component. Because of earlier detection, death rates from breast cancer have decreased over the last decade, but many patients still recur with metastatic disease with poor prognosis. A combination of paclitaxel and antiangiogenic agents is an attractive novel strategy in therapy of aggressive breast cancer. In a study of HER2-negative metastatic breast cancer a combination of paclitaxel with an anti-VEGF humanized antibody, bevacizumab, showed a doubling in progression free survival from 6 to 12 months. However, despite an initial clinical benefit, most patients ultimately develop disease progression. Potential mechanisms of tumor resistance to this form of therapy may include activation of alternative signaling pathways, and interference of AAT with the vascular supply that can result in reduced drug delivery. Another reason is possible induction of tumor hypoxia by AAT that further increases tumor aggressiveness and invasiveness. Small molecule inhibitors of tyrosine- kinase receptors represent a more potent approach as they inhibit functions of multiple cytokine receptors and have better delivery properties compared to monoclonal antibodies (mAb). A new multikinase inhibitor, pazopanib, is one of the promising AAT drugs and has been recently approved for advanced renal cell carcinoma and is currently in clinical trials for combination therapy of multiple tumor types. Pazopanib has low systemic toxicity and is available as oral formulation. In this study we will develop imaging methods for guidance of combination therapy in preclinical orthotopic breast cancer models using pazopanib and novel image-guided targeted paclitaxel nanocarriers. This drug delivery platform will enable noninvasive MRI monitoring of the delivery and release of the encapsulated components at the target site and will also enhance distribution of paclitaxel in the tumor thus improving treatment response and minimizing toxicity. A combination of advanced molecular and functional imaging will be used to characterized changes in tumor vasculature and TME induced by the therapy and to identify mechanisms that can contribute to treatment response or subsequent cancer progression.
In this project we will develop a novel platform for targeted image-guided delivery of a cytotoxic component of combination antiangiogenic therapy. Novel technology will provide optimized delivery of the drug to the tumor and noninvasive detection of the response early in the treatment. Implementation of the novel image-guided drug delivery system can have significant impact for public health by improving the treatment outcome and minimizing systemic toxicity of the combination chemo- and antiangiogenic therapy.
