Medicine Development Center – Oncology
The formation of a tumour is a multistep process, manifested by an accumulation of serial genetic alterations as a normal cell transforms into a malignant cell. The challenge is to interfere with the complex molecular interactions that are the result of these genetic alterations such that a potential therapeutic benefit can be achieved. As our understanding of cellular regulation increases we can rationally identify therapeutic targets and hopefully deliver more effective cancer therapies. An ideal target needs two key attributes: unique expression (or activation) in the tumour and not in normal tissue; and a resulting selective growth advantage to the tumour cells.
The primary aim of targeted therapy is to halt tumour progression without adversely affecting normal cells. What follows is a brief overview of some of the molecular pathways involved in breast cancer development (ErbB network, Ras signalling and angiogenesis) and some of the agents that have been developed to target them.(1–3)
The ErbB network consists of four growth factor receptors (ErbB1–4). ErbB1 is often referred to as EGFR (epidermal growth factor receptor), while ErbB2 is often referred to as HER2/neu. Each receptor has three main domains: an extracellular ligand-binding domain, a transmembrane section and an intracellular tyrosine kinase domain. The receptors are inactive as monomers. Upon ligand binding, homo- and heterodimers are formed. Phosphorylation (activation) of the tyrosine kinase results from dimerisation, leading to activation of a complex and multilayered network of inter-related pathways important in apoptosis, migration, growth, adhesion and differentiation. Two important downstream pathways are the Ras/raf/mitogen-activated protein (MAP) kinase pathway and the phosphatidylinositol- 3-kinase (PI3K)/Akt pathway.
There is no known ErbB2 ligand; ErbB2 is the preferred dimerisation partner for the other receptors. ErbB2 heterodimers are highly stable, leading to prolonged and enhanced signalling. ErbB signalling is essential for normal cell growth; however, dysregulated ErbB signalling is associated with malignant transformation. There are a number of potential ways ErbB signalling can become dysregulated:
- Overexpression of a ligand.
- Overexpression of a normal receptor.
- Expression of a constitutively activated mutant ErbB receptor.
- Defective ErbB receptor internalisation, recycling or degradation.
Dysregulation of ErbB signalling is associated with a number of cancer types. For example, overexpression of ErbB2 (usually as a result of erbB2 gene amplification) is clinically important in approximately 20% of breast cancers.
Although ErbB receptors are not uniquely expressed on cancer cells, overexpression appears to be limited to cancer cells. The ErbB family of receptors is thus an important target for anticancer therapy.
There are two strategies to target ErbB receptors that have led to approved therapies: intracellular targeting via small-molecular-weight inhibitors of ErbB tyrosine kinases; and extracellular targeting via monoclonal antibodies.
There are several types of small-molecule ErbB inhibitors: specific, dual (ErbB1 and ErbB2) and pan-ErbB inhibitors. Inhibitors can also be reversible or irreversible (covalent binding) inhibitors. Two small-molecule ErbB1 inhibitors, gefitinib and erlotinib, are commercially available; both compounds are reversible inhibitors. Numerous other ErbB tyrosine kinase inhibitors are currently in development. Lapatinib, which is currently undergoing phase III trials, is a reversible dual ErbB1/2 inhibitor. EKB-569, an irreversible ErbB1 inhibitor, is also in development.
Trastuzumab (Herceptin) is a commercially available ErbB2-targeted monoclonal antibody. Approximately 20% of breast cancer tumours are ErbB2-positive (erbB2 gene amplified or overexpressed). This drug offers proof of principle for the efficacy and tolerability of antibody therapy if patients are properly selected (ErbB2-positive and normal cardiac function). Trastuzumab is an active drug in metastatic breast cancer. In this setting, in combination with chemotherapy, it prolongs overall survival. Recent studies have shown that, when administered in combination with and after adjuvant chemotherapy, it prolongs disease-free survival and thus, in all likelihood, it increases the cure rate of these therapies.
Cetuximab (Erbitux) is a commercially available monoclonal antibody against ErbB1 indicated, in combination with irinotecan, for the treatment of colorectal cancer. Numerous other antibodies directed against ErbB1 or ErbB2 are also in development.
Ras proteins are small guanine nucleotide-binding proteins that act as molecular switches. The Ras network is a key intermediary in proliferation, differentiation and apoptosis pathways. Post-translational modifications allow Ras to associate with the cell membrane, which must occur before Ras can be activated. The major modification is the addition of a farnesyl isoprenoid moiety, which is catalysed by the enzyme farnesyl transferase. The ras gene is mutated in about 30% of cancers, but not in normal cells; however, only 2% of breast cancers have ras mutations. Mutated ras is constitutively activated and is thus associated with uncontrolled cell proliferation. Even though ras is not commonly mutated in breast cancer, abnormal expression or signalling through Ras is common. Some inhibitors of farnesyl transferase, such as tipifarnib (R115777), are currently in development.
Angiogenesis (the development of new blood vessels) rarely occurs in nonreproductive healthy tissues but is important in the continued growth of a tumour and in the development of metastases. Tumours that are less than 0.5mm in size obtain oxygen and nutrients from diffusion. For tumours to grow larger, they need to develop new blood vessels. Tumour blood vessels are different from normal blood vessels in that they are irregularly shaped, dilated and tortuous. These tumour blood vessels are immature and rely on growth factors – primarily vascular endothelial growth factor (VEGF). In adults, VEGF is important in wound healing and follicular development. The cellular receptors for VEGF are almost exclusively on endothelial cells. Thus, although VEGF and VEGF receptors are not unique to cancer cells, cancer cells have a unique sensitivity to inhibition of VEGF signalling. Agents targeting the VEGF pathway have included monoclonal antibodies against VEGF (bevacuzimab), small molecules (tyrosine kinase inhibitors of VEGF receptors) and soluble VEGF receptors. Bevacuzimab, an antibody directed against VEGF, was recently shown to prolong survival in combination with chemotherapy in the first-line setting of ErbB2-negative metastatic breast cancer.
Rational target selection is upon us, and proof of principle exists in many settings, with use of these targeted agents already improving survival in certain types of breast cancer.
One can only hope that with the correct use of these agents in the right patients, greater strides will be made in cancer therapeutics.
- Johnson ML, Seidman AD. Emerging targeted therapies for breast cancer. Oncology 2005;19: 611-8.
- Kaklamani V, O’Regan RM. New targeted therapies in breast cancer. Semin Oncol 2004; 31 Suppl 4:20-5.
- Hortobagyi GN. Opportunities and challenges in the development of targeted therapies. Semin Oncol 2004; 31 Suppl:21-7.