Met-769 Met-769

FIGURE 9.9 Irreversible EGFR inhibitors.

Cetuximab (IMC-C225) is a chimeric monoclonal antibody* that has been approved for clinical use as a second-line treatment for EGF-expressing colorectal cancer. Despite not having demonstrated an improvement in survival it is being tested in combination therapies. Other antibodies directed to the same receptor that are under clinical evaluation are ABX-EGF, EMD-72000 (humanized), RH3, MDX-447, and panitumumab (fully human).2

3.2. Inhibitors of other receptors of the EGFR family: HER-2

As previously mentioned, HER-2 is a member of the EGFR family of receptors that has been identified as an important therapeutic target because it is overexpressed in around 20-30% of patients with aggressive breast cancer.

Besides the previously mentioned EGFR-HER-2 dual inhibitors such as lapa-tinib and canertinib, some monoclonal antibodies are directed at this receptor. The most important is trastuzumab, a humanized monoclonal antibody that targets the extra-cellular region of the HER-2 receptor, leading to its internalization and degradation. Interaction of trastuzumab with the human immune system via its human immunoglobulin G1 Fc domain may potentiate its antitumor activities. In vitro studies demonstrate that trastuzumab is very effective in mediating antibody-dependent cell-mediated cytotoxicity against HER-2-overexpressing tumor targets. In summary, the mechanism of action of trastuzumab includes antagonizing the constitutive growth-signalling properties of the HER-2 system, enlisting immune cells to attack and kill the tumor target, and augmenting chemotherapy-induced cytotoxicity.19

Trastuzumab has been approved for the treatment of metastatic breast cancer in women that have had at least two chemotherapy treatments for this type of cancer, in combination with paclitaxel. It is also being studied in combination with other chemotherapeutic agents. Other related antibodies that are under clinical evaluation are MCX-210 and 2C4.

* A chimeric protein can be defined as one that is encoded by a nucleotide sequence made by a splicing together of two or more complete or partial genes, which can even be from different species.

3.3. Inhibitors of insulin-like growth factor receptors: IGFR-1

The insulin-like growth factors (IGFs) are peptides with a high sequence homology with insulin. They are part of a complex system (often referred to as the IGF 'axis') that has a role in the promotion of cell proliferation and in the inhibition of apoptosis. The IGFR-1 is another membrane TK that is inhibited by several families of compounds. The most relevant one is AEW-541, an inhibitor of the receptor autophosphorylation, is being developed against musculoskeletal tumors and multiple myeloma.20

3.4. Inhibitors of TKs with pro-angiogenic activity: VEFGR and related kinases

Angiogenesis can be defined as the growth of new blood vessels from pre-existing microvasculature and will be discussed in more detail in Section 2 of Chapter 10. Since angiogenesis has a key role in tumor growth and metastasis because tumors cannot grow beyond a certain size unless they induce angiogenesis in order to establish a blood supply, it is an important source of anticancer drug targets. In adults, it is triggered only locally and transiently in processes such as wound healing, and changes in the equilibrium between pro- and anti-angiogenic factors are associated with a number of disease states. The receptors of some pro-angiogenic growth factors such as the vascular endothelial growth factor (VEGF) family, including VEGFR-1 (FLT-1), VEGFR-2 (KDR), and VEGFR-3 (FLT-4); the platelet-derived growth factor (PDGF); and the fibroblast growth factor (FGF) are TKs, and will be discussed here. The previously mentioned EGF also has activity as a pro-angiogenic growth factor. VEGFs bind to and activate the above-mentioned cell surface receptors (VEGFR).

VEGF signalling is critical for blood vessel formation and is involved in all stages of angiogenesis. Inhibition of VEGF signalling, therefore, is an attractive therapy target in a wide range of tumor types, and disruption of the VEGF has become one dominant strategy for the angiogenesis-related treatment of cancer.

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