PET imaging with zirconium-89 labeled antibodies to guid cancer therapy

Abstract

Currently, chemotherapeutic drugs aiming directly or indirectly at DNA damage still most often form the cornerstone of systemic cancer treatment. Meanwhile, molecular targeted drugs of a new generation are increasingly used alone or combined with chemotherapy. Tumor biology research continues to identify new molecular targets involved in uncontrolled tumor growth, invasion and metastasis. For many tumor types, multiple molecular phenotypes have been identified and the next step is translating this rapidly expanding knowledge in tumor biology into new targeted systemic treatments. Tumor growth often depends on a few dysregulated growth signaling pathways and identifdng this 'tumor Achilles heel' might reveal the most relevant target for systemic therapy. Among the numerous drugs that target relevant pathways are drugs targeting human epidermal growth factor receptor-2 (HER2), the pro-angiogenic vascular endothelial growth factor (VEGF), the molecular chaperone heat shock protein-90 (HSP90) and the pro-metastatic transforming growth factor f3 (TGF-r3). It is of interest to identify the best drug candidate(s) in an earlly phase of development, to identify the patient (sub)populations most likely to benefit and to early predict response. Therefore the development of predictive biomarkers of antitumor efficacy is of releyance. In addition, there is a need for techniques that can rapidly and precisely elucidate the pharmacokinetic and pharmacodynamic profile of new agents, Molecular imaging can potentially fulfill all these tasks and is therefore explored for its use in translating cancer science, and in the discovery, development, evaluation and implementation of targeted anticancer agents. Molecular imaging can be performed in c1 whole body and repetitive setting, providing information about (changes in) all organs and tumor lesions, Techniques used for molecular imaging include radionuclide imaging with positron emission tomography (PET) or single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI) and optical imaging. Of these techniques, PET currently is the most suitable for whole body imaging and has the best quantification properties. This thesis aimed at evaluating the role of molecular imaging with zirconium-89 ("'Zr) labeled antibodies in the guidance of targeted anticancer agents, with a focus on breast cancer.