New molecular imaging in oncology : a focus on angiogenesis

Abstract

Chemotherapeutic agents are the mainstay in systemic anti-cancer treatment. Therefore patients that die of metastatic disease do so because they do not respond or develop resistance towards these anti-cancer drugs. The occurrence of tumor resistance to several structurally unrelated classes of natural products, including anthracyclines, taxanes and epipodophyllotoxines, is often referred to as multidrug resistance (MDR). MDR can be caused by several mechanisms including increased expression of the ATP-binding cassete transporters (ABC-transporters) and drug efflux pumps like P-glycoprotein (P-gp) and multidrug resistance protein (MRP 1). It was initially thought, that overcoming MDR would resolve the problem of intrinsic or acquired resistance for these drugs. This was aimed for by inhibiting drug efflux pumps like P-gp. However, randomized clinical studies in different groups of cancer patients evaluating the effect of P-gp modulators when added to chemotherapeutic drugs, have not shown any benefit in outcome. These and other findings led to the idea that the ceiling was reached with classical chemotherapeutic drugs. The abundance of knowledge from the preclinical research on dysregulated cellular pathways in tumor cells has resulted in new targeted agents. Therefore the use of the so-called new targeted agents, with or without chemotherapy, might be superior to circumvent MDR and enhance anti-tumor effects. Over the last decade numerous new targeted anticancer agents, specific for intra- and extra cellular tumor targets and antigens located in the extracellular matrix or at the blood vessels of tumors have been developed. There is increasing evidence that several of these agents (combined with chemotherapy) can increase antitumor efficacy. A subgroup of these agents targets the so-called "process of angiogenesis". This process: of new blood vessel formation is not only important for normal tissue development, but is also one of the hallmarks in carcinogenesis. Already 30 years ago it was recognized that tumors need blood vessels to allow tumor cells to execute their critical growth by supplying the tumor with nutrients and oxygen, enabling disposal of metabolic waste products and it provides a route for metastatic spreading. An important factor involved in angiogenesis is vascular endothelial growth factor A (hereafter referred as VEGF). It is released by tumor cells and it induces tumor neovascularization. Overexpression of VEGF occurs in many human tumor types which made VEGF a rational target for anti-angiogenic therapy. This has led to interest in blocking the signaling of VEGF in human tumors. Antibodies binding to VEGF and its receptors, as well as chemical molecules which can block the tyrosine kinase function of VEGF-receptors, and drugs inhibiting cellular tumor signaling pathways) affecting angiogenesis have been developed. Although anti-angiogenic treatment, either as single agent or combined with chemotherapy has improved disease outcome for several tumor types, such as renal cell cancer and colorectal cancer, benefit has been modest and often only transient. Therefore it would be extremely helpful when a predictive marker would exist to select patients upfront. An option to achieve this might be the non-invasie use of molecular imaging. This thesis aimed to circumvent drug resistance and develop new imaging modalities to evaluate targeted anti-cancer drugs, with a focus on the use of anti-angiongenic agents and the development and evaluation of VEGF PET tracers.