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Senior Member
Join Date: Nov 2005
Posts: 943
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nice summary of various targeted therapies for her2 bc...
Target Breast Cancer Target Breast Cancer - Contents====================CONTENTSINTRODUCTIONTH E STRUCTURE AND FUNCTION OF THE HUMAN BREASTBREAST CANCER - Some Questions and Answers- What is breast cancer?- Can benign lumps give rise to true breast cancer- How can you tell the differnence between a benign lump and breast cancer?- How are breast cancers classified and described?- What is meant by being breast aware?- Who can have a routine breast screen?- Is the exposure to X-rays in mammography dangerous?- Has the breast screening programme had any impact on survival?- Can breast cancer occur at any age?- How common is breast cancer compared to other cancers?- Are there different types of breast cancer?- How does breast cancer spread?- Are there any known risk factors for breast cancer?- What can be done to detect breast cancer if occurs?- To what extent is breast cancer determined by our genes?- Can men get breast cancer?- What types of treatment are currently available for breast cancer?- What is meant by neoadjuvent, adjuvent and palliative therapy?- What role does surgery have in treating breast cancer?- What role does radiotherapy have in treating breast cancer?- What types of medicine are used in treating breast cancer?- What help is available for people with breast cancer?- THE DIAGNOSES OF BREAST CANCER?BREAST CANCER AND THE PHARMECUITCAL INDUSTRY?- The history of the treatment of breast cancer- MEDICINES FOR THE TREATMENT OF BREAST CANCER AND HOW THEY WORK-- Cell division and the cell cycle-- Medicines that act on cell division and how they work-- Hormone therapy - compounds that modify hormone action and how they work-- Sex hormones and breast cancer-- Cell receptors and internal signalling systems-- Supportive and palliative treatmentsNEW DEVELOPMENTS AND FUTURE DIRECTIONSCONCLUSIONSSUMMARY TABLESOME USEFULL ADDRESSES BREAST CANCER AND THE PHARMACEUTICAL INDUSTRY
MEDICINES FOR THE TREATMENT OF BREAST CANCER AND HOW THEY WORK
Cell receptors and internal signalling systems
So far this booklet has considered cytotoxic medicines that act on DNA to stop cell division, and hormonal therapies that deprive cancer cells of steroidal growth substances. But there are many other receptor types, as well as networks of messenger molecules inside cells. All provide targets for new medicines design and have come to the forefront in the past 10-15 years.
A simple analogy may help to understand these complex events. If a visitor approaches your house and rings the door bell, he could be envisaged as the medicine and the door bell the receptor. He interacts with the door bell and in so doing triggers a whole series of internal events. He has caused electric current to flow in the wires, has activated the bell, has alerted you to his presence, and possibly even set the dog barking! In consequence, you move to and open the front door. The door knocker could be regarded as a different receptor which would produce the same result by different mechanisms. Much the same thing happens in living cells. Many receptors span membranes and have an external and an internal part called a domain. Of particular importance in breast cancer are receptors whose inner domain has what is called tyrosine kinase activity that is switched on when the receptor is activated. But it must be remembered that there is not just one doorbell (receptor) but dozens of different ones depending on the cell type and its metabolic status.
The receptors and pathways involved in breast cancer are complex and can only be described in simple outline here. Not only are there multiple receptors and pathways, but many may cooperate to bring about cell responses. Also, the receptors present in any one patient may differ from those of another patient. That is one reason why there are responders and non-responders in many clinical trials and why a range of medicines will be needed. What is suitable for one person may not help another. Several kinds of receptor which have proved important in breast and some other cancers are listed in Table 5 and many of them span the cell membrane. Their activation then triggers an internal biochemical reaction which initiates a range of cellular responses such as gene activation, cell multiplication, and protein synthesis.
Receptor name Abbreviations or synonyms Medicines acting on them Functions Vascular
Endothelial Growth
Factor VEGF ZD6474
Bevacizumab A substance made by cells that stimulates new blood vessel formation Epidermal Growth
Factor Receptor 1 EGFR or
ErbB1 or
HER-1 Ertolinib
Gefitinib
Lapatinib
ZD6474
Pertuzumab Both EGFR-1 & EGFR-2 activate
enzymes called tyrosine kinases (TK) involved in cell division, metabolism and cell death (apoptosis) Epidermal Growth
Factor Receptor 2 ErbB2 also known
as HER2 or
HER2/neu Lapatinib
Trastuzumab
Pertuzumab Farnesyl
transferase FT Tipifarnib Modifies Ras protein to render it functional Mitogen-activated
Protein-erk kinase MEK ARRY-142886 Internal signalling and gene activation mTOR temsirolimus
RAD001 These have many functions including control of protein synthesis Table 5: Some receptors, signalling pathways and medicines in breast cancer
Three compounds, known as monoclonal antibodies, work by preventing the interaction between certain naturally occurring cell receptor stimulators and the receptors themselves. In this way they mask cell activation. These are large Yshaped proteins made by genetic engineering. One, trastuzumab (Roche) binds specifically to the HER2 receptor, while pertuzumab (Chugai) stops receptors of the HER-family cooperating with each other. Pertuzumab is the first of a new class called HER-dimerisation inhibitors (HDIs). A third, bevacizumab (Roche-Genentech), binds to the VEGF itself, thus preventing it from activating the VEGF receptor.
The HER2 receptor on breast cancer cells may be activated by the human epidermal growth factor (EGF), a naturally occurring substance in the body. When this happens, the cells begin to divide and the tumour grows. Trastuzumab works by binding to the HER2 receptor, thus preventing the EGF from reaching it. The medicine only works in women (about 20 per cent) who have high levels of HER2 on their tumour cells. In some cases, it can shrink the tumour, while in others it just stops it growing. It is mainly used in advanced or recurrent breast cancer. Tests which measure HER2 are now used in about one-third of UK cancer centres as they can help guide the use of trastuzumab in the adjuvant setting. Trastuzumab may be used alone or combined with a taxane.
Bevacizumab, another monoclonal antibody, binds to Vascular Endothelial Growth Factor (VEGF), blocking its ability to stimulate the VEGF receptor. This factor is involved with the formation of new blood vessels. In a growing tumour, a whole network of new blood vessels develops to supply it with oxygen and nutrients, a process called angiogenesis. Bevacizumab blocks this process so that the tumour is starved and shrinks. The compound is approved in the UK and USA for metastatic colorectal cancer. It is now in Phase 3 trials in advanced breast cancer.
SU11248 (Pfizer) is currently in Phase 2 trials in advanced breast cancer. It has multiple targets in cells, including the VEGF receptor and the platelet-derived growth factor receptor (PDGFR), among others which give it a dual mode of action – i.e. both anti-angiogenesis and a direct anti-tumour effect.
Pertuzumab is at an earlier stage of development, but differs in that it prevents the HER2 receptor cooperating with other members of the HERreceptor family, including EGFR-1, in a process called dimerisation. This blocks internal signalling and may ultimately cause cells to stop growing and die. It is in Phase 2 trials in HER2-negative breast cancer (i.e. where HER2 is not overexpressed).
The EGFR-1 receptor stretches across the cell membrane. The receptor itself is on the outside, while the inner part is an enzyme called tyrosine kinase (TK). Activation of the receptor switches on TK and starts the internal signalling sequence. Three compounds have been developed that enter the cell and block the internal TK activity, namely gefitinib (AstraZeneca), ertlotinib (Genentech) and lapatinib (GlaxoSmithKline). Gefitinib has activity on several solid tumours, including breast cancer, where it has shown activity in ER-positive and ER-negative women. It has the unusual property of being able to restore the sensitivity of cancer cells to tamoxifen after they have developed resistance. This opens up the possibility that gefitinib may be useful when given in combination with tamoxifen – a prospect that is under clinical investigation. Erlotinib (Genentech/Roche) works in a similar way. Early trials looked promising, but a Phase 2 study was disappointing and its current status is unclear.
GSK’s lapatinib differs from gefitinib and erlotinib in that it is a dual inhibitor of both HER2 and EGFR-1 tyrosine kinase activity. It has been found that inhibiting both pathways produces a stronger biological effect on cancer cell internal signalling than inhibiting one or the other. The compound has shown promising activity even against some trastuzumab-resistant cancers. Like gefitinib, it also overcomes tamoxifen resistance, thus providing a strong rationale for combinations of hormone therapy with growth factor receptor-TK inhibitors. It has entered Phase 2/3 trials in advanced breast cancer given alone and in combination with other medicines such as the aromatase inhibitor, letrozole.
Another dual inhibitor is ZD6474 (AstraZeneca), but in this instance, it blocks the EGFR-1 receptor and the VEGF receptor. As with bevacizumab above, blocking the VEGF receptor would be expected to slow or prevent angiogenesis, while action on EGFR-1 would modify cell division and growth, with possible synergistic effects. The compound showed activity against breast cancer cells in the laboratory and has now entered Phase 2 clinical trials.
Another pathway involved in cell growth regulation is called Ras-Raf-MEK. Sometimes the Ras gene mutates in cancer cells, but its mutated product has to be activated by an enzyme called farnesyl transferase (FT). Because of the prominent role of Ras in many cancers, the FT enzyme has been a focus for the design of inhibitors. Tipifarnib (Johnson & Johnson) is described as a ‘biological agent’ that has the ability to inhibit the activation of Ras protein, and thus stop cell division. Used alone in early trials, tipifarnib showed promising activity in advanced breast cancer in a small number of patients. Combination trials of this medicine with others are continuing.
Further down the Ras pathway are the key regulators of cell signalling, MEK1 and MEK2, which are at the hub of several pathways. MEK1 and MEK2 are able to activate further proteins called ERK1 and ERK2 that are able, among other actions, to initiate cell division and activate some genes associated with tumours. Over-activation of MEK occurs in several forms of cancer, including breast cancer. Array Biopharma, in collaboration with AstraZeneca, is developing a potent and specific inhibitor of MEK called ARRY-142886 (also known as AZD6244) and Phase 1 trials began early in 2004.
Last in this complicated warren of cell signalling pathways is a protein called mTOR, also associated with a kinase activity. Its functions are numerous, but among them is the initiation of protein synthesis and turnover, cell survival, and angiogenesis. It can be activated by stimulation via the Akt pathway from the EGFR-1 or the VEGF receptor. Because mTOR is a sort of bottleneck in cancer cell signalling, an inhibitor of mTOR kinase would be expected to suppress many cell functions and to arrest cell division
Temsirolimus (Wyeth) is an inhibitor of this kind and results were promising in a Phase 2 trial in locally advanced metastatic breast cancer in heavily pre-treated patients. Further Phase 3 studies of temsirolimus in combination with the aromatase inhibitor letrozole are continuing. A second mTOR inhibitor is RAD001 (Novartis) which had strong anticancer activity against tumour cell lines and in animal models and displayed anti-angiogenic activity. It is now in Phase 2 clinical studies against several tumour types, including breast cancer.
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Robin
2002- dx her2 positive DCIS/bc TX Mast, herceptin chemo
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