21 Molecular Targeted Therapies: Herceptin
In this chapter we will talk about Herceptin (Trade name Trastuzumab),which is a monoclonal antibody. Herceptin interferes with the HER2receptor. It’s main use is to treat a particular sub type of breastcancer.
21.1 Introduction to targeted therapies
Let us start with a definition of targeted therapies: >Targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumour growth, rather than by simply interfering with all rapidly dividing cells, e.g. with traditional cytotoxic chemotherapy.
Therefore, targeted cancer therapies are expected to be more effective than older forms of treatment and less harmful to normal cells. Targeted therapies have already been developed against a variety of cancers including breast, multiple myeloma, lymphoma, prostate cancer, melanoma and other cancers (Table 18.1).
Targeted therapies can either be small molecules, which target kinases, in particular tyrosine or serine/threonine kinases, monoclonal antibodies targeting specific receptors, or they can be antibody-drug conjugates, a combination of an antibody covalently linked to a small molecule.
In this chapter we will discuss Gleevec, which targets Bcr-Abl, as an example of a kinase inhibitor. We will talk about Herceptin as a monoclonal antibody, targeting the Her2 receptor, which is used against Her2-positve breast cancer. Later, we will discuss a antibody-drug conjugate, called Kadcyla, which is Herceptin linked to a MT inhibitor.
We would like to mention Avastin, which you probably know from the news. Avastin is an angiogenesis inhibitor targeting the VEGF-A (Vascular Endothelial Growth Factor A). It had been approved for breast cancer but the approval was later withdrawn, as clinical studies proved it was not effective.
|Tyrosine kinase||Serine/threonine kinase|
|Monoclonal antibodies||Antibody-drug conjugates (ADCs)|
In one of the previous chapters on the development of cancer, we have introduced the famous Hallmarks of Cancer (chapter 9), which we want to briefly mention here. Epidermal growthfactor (EGF) receptors are implicated in proliferative signalling and are validated targets for cancer chemotherapy (21.1). Inhibitors against this family of receptors have been developed and Herceptin belongs to the class of EGF receptor inhibitors. This is avery good example of how we can link cancer treatment with the Hallmarks of Cancer.
21.2 Herceptin: targeted therapy against Her2-positive breast cancer
We will now discuss Herceptin. Figure 18.2 represents different subtypes of breast cancer. Please remember that 20% to 25% of breastcancers are known to be Her2-positve. Her2-positive breast cancer hasthe 2nd poorest prognosis among breast cancer sub-types.
21.3 Introduction into the function of HER receptor family members
HER receptors are proteins that are embedded in the cell membrane and communicate signals from the outside the cell to the inside of cells and turn genes on and off (Figure 18.3).
The Her family comprises four members, which have different names in theliterature:
EGFR = ERBB1, Her1
HER2 = ERBB2, Her2/Neu
ERBB4 = Her4
HER proteins stimulate cell proliferation. In some cancers, notably breast cancer, HER2 is overexpressed and causes cancer cells to reproduce uncontrollably. For example, the HER2 gene is amplified in 20%- 25% of early-stage breast cancers. The HER2 pathway promotes cell growth and proliferation and hence tumour formation. Herceptin has amajor impact in the treatment of HER2-positive metastatic breast cancer.
Her2 is expressed at low levels on the surface of epithelial cells and is necessary for normal development of many tissues, including breast and ovary. In contrast, in breast cancer cells, immunohistochemical analyses revealed very high levels of Her2. It‘s overexpression triggers multiple downstream pathways required for the abnormal proliferation of cancer cells.
Signalling compounds such as EGF bind to the extracellular domain of the HER receptors to activate the pathway. Her2 is activated by the formation of homodimers or heterodimers with one of the other EGFR family members. Dimerisation leds to autophosphorylation or transphosphorylation of specific tyrosine residues which then leads to the activation of several pathways including
Signals on these pathways promote cell proliferation. Her2 activation leads to numerous effects including cell growth, proliferation and survival. The Her2/Her3 heterodimer is the most potent stimulator of downstream pathways, particularly the PI3K/AKT pathway, a master regulator of cell growth and survival. The first FDA-approved targeted therapy for breast cancer was Herceptin. Herceptin is a recombinant humanized monoclonal antibody and we will now discuss it‘s mechanism of action.
21.4 Mechanisms of action of Herceptin
The mechanism of action of Herceptin can be grouped into three major categories (Figure 18.5):
The most well known mechanism of Herceptin is the inhibition of the MAPK and PI3K/AKT pathways. Herceptin binds to domain IV of the extracellular segment of the HER2 receptor and disrupts receptor dimerisation, leading to an increase in cell cycle arrest, and the suppression of cell growthas well as proliferation and survival.
A second potential mechanism is the degradation of Her2 via ubiquitination (a post-translational modification, by which the small protein ubiquitin is attached to other proteins), but the exact mechanism of action is unknown.
A third mechanism is termed antibody-dependent cellular cytotoxicity (ADCC). In this mechanism the monoclonal antibody attracts immune cells to tumour sites that overexpress Her2.
Expert box: Therapeutic monoclonal antibodies (mAbs). Therapeutic monoclonal antibodies can be classified into different antibody types (Figure 18.6): murine, chimeric, humanised and human. An intact single immunoglobulin consists of a pair of light chains (in orange or red) and a pair of heavy chains (in yellow or pink). Humanised therapeutic monoclonal antibodies are predominantly derived from a human source, except for the complementarity-determining regions (CDRs), which are of murine origin.
21.5 Administration, clinical uses and side effects of Herceptin
Herceptin can be administered intravenously in the hospital or since 2013 subcutaneously at home. Treatment is generally for one year, based on the current clinical trial evidence. However, some countries fund only nine weeks of adjuvant therapy.
Herceptin is used either as monotherapy or in combination with other drugs to treat Her2 receptor-positive breast cancer. Herceptin is also used to treat metastatic stomach cancer in combination with Cisplatin and Capecitabine or 5-FU.
Some common side effects are flu-like symptoms, nausea and diarrhoea. A more serious complication is cardiomyopathy: Neuregulin-1, a member of the neuregulin family of proteins, is down-regulated. Neuregulin-1 is essential for the activation of cell survival pathways and the maintenance of cardiac function and Herceptin can therefore lead to cardiac dysfunction.
21.6 Trastuzumab Emtansine (Kadcyla), an example of a potent antibody-drug conjugate
Trastuzumab emtansin##e## is an antibody-drug conjugate, consisting of the antibody Herceptin linked to the cytotoxic agent Mertansine (Figure 18.7). Whereas Herceptin binds to the HER2 receptor, Mertansine targets tubulin/MTs. Because the mAB targets HER2, and HER2 is only over-expressed in cancer cells, the conjugate delivers the MT poison specifically to tumour cells.
In a clinical trial, named the Emilia trial, woman with Her2 positive breast cancer already resistant to Herceptin alone were treated with Kadcyla and compared to patients treated with Lapatinib and Capecitabine. Almost 1000 patients recruited in 213 centres in 26 countries were involved in this multinational and expensive clinical trial. Treatment with Kadcyla improved median overall survival by almost six months. Subsequently, this conjugate was approved by the FDA in 2013 for Her2-positive metastatic breast cancer. In the UK, treatment costs were £5900 per month and only after a confidential discount was approved with Roche, the Cancer Drug Fund decided to continue funding the drug conjugate.
References to be added