CAST therapy

Cancer consists not only of tumor cells but also of tumor stroma. The latter has various components such as fibroblasts, mesenchymal cells, blood vessels or extracellular matrix proteins (e.g. collagen, fibronectin or fibrin). (See chapter by Tarin describing the pathogenesis of cancer and stromal changes during the process). Moreover, it also promotes tumor cell growth, survival, invasion and metastasis. It is thus increasingly important to understand the role of tumor stroma in tumorigenesis and tumor progression. In this chapter, stroma-mediated drug-resistance and methods to overcome it are described and evaluated. Most recently, antibody-drug conjugates (ADCs), consisting of an antibody and a cytotoxic drug connected via a specialized linker have become available as a next generation of antibody therapeutics, intended to enhance focused delivery of anti-cancer agents into the internal tumor environment. However, none of them has been proved to be effective in treating refractory cancers such as pancreatic cancer or scirrhous gastric cancer. These cancers are known to possess abundant stroma, which hinders the distribution of therapeutic antibodies and ADCs within the cancerous growth. This is the so-called tumor stromal barrier. To overcome this drawback, we have developed a unique type of ADC, namely, cancer stromal targeting (CAST) therapy, in which stroma targeting mAbs (anti-collagen 4 or anti-insoluble fibrin (IF) mAbs) were conjugated with anticancer agents. Our results confirmed that ADCs bound to collagen 4 or IF in the stroma, from which effective sustained release of the drugs occurred. The released drug subsequently diffused through the tumor tissue, causing marked arrest of tumor growth associated with damage to tumor blood vessels and death of cancer cells.