TARCEVA LUNG CANCER AND EPIDERMAL GROWTH FACTOR INHIBITORS

 (keywords, Tarceva, lung cancer, epidermal growth factor receptor, Iressa, non-smoker's lung cancer, EGFR, EGF, Tarceva and lung cancer,  treatment for lung cancer, excerpted and updated from our book Lung Cancer and mesothelioma).  

15.0  THE EPIDERMAL GROWTH FACTOR PATHWAY   

  15.01   Cell Signaling  and a Basic Model of Cancer

The human body has a complex system of signaling between cells and duplication of genes is a normal part of this process.  Duplication of genes is necessary for growth, repair of damaged cells and other functions.    Proteins called growth factors signal other cells to initiate replication.  Malfunctions in these growth factors are a part of cancer, as growth factors prompt excessive duplication.  A separate type of gene called a tumor suppressor gene regulates and restricts growth, sending signals to stop duplication or initiate apoptosis, an orderly system of  cell death.    A basic model of cancer suggests it is is a product of abnormal growth factors prompting duplication of cells and the failure of tumor suppresor genes to properly regulate them.  

A sophisticated model suggests cancer represents a complex system of many growth factors, multiple tumor suppresor genes, and damage to other cellular regulators.   As we enter the 21st century we are learning that both models may be correct for different types of cancers- there are simple cancers with limited and identifiable growth factor abnormalities with complex ones like lung cancer have numerous contributing factors.  In the 60's and 70th, we learned that cancers acted differently depending upon their site; today we know that lung cancer involves multiples types cancers, some of which respond  differently to treatment than others.   We now look to one important growth factor, (EGF) and its treatments.  

     15.02  Epidermal Growth Factor                             

Epidermal Growth Factor (EGF) plays a role in normal human development helping to repair damaged tissue and develop lungs in fetuses.  Klein (49).   When glands associated with the epidermal growth factor were removed from pregnant mice, scientists found increased mortality and reduction of milk production.  Britannica (36).   EGF is expressed in many tumors.     To initiate cell reproduction, a growth factor links with an associated receptor, like a lock and key.  EGF links with EGFR, the epidermal growth factor receptor.   

    15.03 Epidermal Growth Factor Receptor

In recent months, the receptor rather than the growth factor itself has become the target of new drugs.  "The epidermal growth factor receptor (EGFR) signaling pathway is one of the most important pathways that regulate growth, survival, proliferation, and differentiation in mammalian cells."

“The epidermal growth factor receptor (EGFR) autocrine pathway contributes to a number of processes important to cancer development and progression, including cell proliferation, apoptosis, angiogenesis, and metastatic spread. The critical role the EGFR plays in cancer has led to an extensive search for selective inhibitors of the EGFR signaling pathway. .. The most promising strategies in clinical development include monoclonal antibodies to prevent ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity to inhibit autophosphorylation and downstream intracellular signaling."  Tartora, (2), See also FDA (1) .  See also (Baselga 24).   

 15.04 Structure of EGFR   

The receptor  has two basic parts.    The first part of the receptor is called the extracellular ligand-binding domain. There it receives a signal from the growth factor and a process called ligand binding occurs.  Once binding occurs, a signal is sent to the second part of the receptor called the tyrosine kinase domain.  There a process called autophosphorylation occurs.   A chemical change occurs and signals are sent to other cells.   In cancer, these signals are abnormal, and thus other cells are told to duplicate are perform other aberrant functions.  Cancer drugs can work in two basic ways, they can try to prevent binding at the ligand-binding domain,  or prevent autophosphorylation in the tyrosine kinase.  The fact that there are two separate functions means that drugs may later be combined.  Cells both give and receive signals.  A particular growth factor is involved both by receiving abnormal signals from other cells and giving them. 

    15.05 Expression of Epidermal Growth Factor and Lung Cancer

"The high level of expression of the EGFR on non small cell lung cancer (NSCLC) and the important role of EGFR in signal transudation make it potentially an excellent target for antibody directed therapy." Zhonghua (20).   One report found overexpression of EGF in 50% of lung adenocarcinomas, while another study found EGFR expression in 94 of 169 (56%) non small cell cases. Pass (3), Cox (4)  

15.1 RESULTS FROM IRESSA and TARCEVA CLINICAL TRIALS AND STUDIES

   15.11 Overview

Iressa and Tarceva are similar drugs.  Both inhibit the activity of the EGFR.  More specifically, each inhibits the action of the tyrosine kinase portion of the EGFR.  Tarceva is reputed to be stronger, and Iressa is no longer commercially available in the United States.

Iressa and Tarceva have shown success in stabilizing disease, improving symptoms, and achieving reduction of disease in selected patients.  Since Iressa only targets a specific growth factor receptor, it impacts only a limited number of cells.  Thus it can cause fewer side effects and disruption in the body.

   15.12 Use with Non-Smokers and Light Former Smokers

Initial studies with Iressa showed a small number of patients had responses to the drug.   See  FDA (47).   AT Harvard, Lynch was able to identify who responded, finding that 8 of 9 patients had specific identifiable damage to the tyrosine kinase portion of the EGFR.   Lynch (55).  All the patients who responded had never smoked or were light former smokers.  The damage to the tyrosine portion of the EGFR meant that this was driving their cancer and that stopping this signalling could provide dramatic help to the patient.  Lynch's findings have been duplicated in a number of subsequent studies. 

"EGFR mutations in exons 19 or 21 are correlated with clinical factors predictive of response to gefitinib and erlotinib. Those with EGFR exon 19 deletion mutations had a longer median survival than patients with EGFR L858R point mutation. These observations warrant confirmation in a prospective study and exploration of the biological mechanisms of the differences between the two major EGFR mutations. " "Presence of EGFR mutations was the only independent predictor for disease control."   Chou (58).

       15.13 Adenocarcinoma and Subtypes

The patients who responded in Lynch's studies all had adenocarcinoma or BAC subtype.  Lynch (55) See also (52) and Garbiter (53).
Other studies have also found adenocarcinoma and BAC formed of patients with the EGFR mutation who responded.  However, a small percentage in some studies were outside this group.   Sasaki found 12.5% of patients who responders were outside the adenocarcinoma target group.  Sasaki (69).

       15.14 Other Patterns of Response

Less easy to explain, women and Japanese have higher rates of response.  FDA (62).   Additionally, while we can predict who is likely to have the mutation, there remains some uncertainty.  One study found  "EGFR mutations were present in 35 patients (36.8%). These mutation statuses were significantly correlated with gender (women 73.3% vs. men 20%, p < 0.0001), smoking status (never smoker 69.4% vs. smoker 16.9%, p < 0.0001), pathologic subtypes (adenocarcinoma 45.1% vs. nonadenocarcinoma 12.5%, p = 0.0089) and differentiation status of the lung cancers (well 51% vs. moderately or poorly 18.4%, p = 0.0021). "  Sasaki (69).  The abstract does not indicate the extent of smoking or the characteristics of non-adenocarcinoma patients.

         15.15 EGFR Testing

Since we can identify those likely to respond based upon the area of genetic damage, it makes sense to test patients to identify this.  A press release for testing performed at the Harvard Medical School explains:

"The Harvard Medical School - Partners HealthCare Center for Genetics and Genomics (HPCGG) has begun to offer a test that gives doctors a valuable new tool to guide the treatment of certain lung cancers.  The test – known as EGFR Kinase Domain Sequencing – was developed in cooperation with the pathology laboratories of Brigham and Women’s Hospital and Massachusetts General Hospital, and detects mutations in a critical part of the gene called epidermal growth factor receptor (EGFR). The gene mutation is present in a subset of non-small cell lung cancers, most commonly adenocarcinomas and bronchoalveolar carcinomas arising in nonsmokers. When the mutation is present, it is associated with a response to the anti-cancer drug Iressa (gefitinib). Iressa works by blocking the function of the mutant EGFR protein that these cancer cells need to survive and proliferate."

Similar testing is being performed in Japan.

Non-smokers or those with limited smoking histories will want to promptly consider Tarceva. 

15.16 Tarceva for Smokers  

The studies have found those who responded (tumor reduction of 50% or more) were non-smokers.  It did find a smaller number of light    former smokers.

Sasaki's (69)found that while most of the patients with the EGFR mutation are non-smokers, a few smokers had it.  (The extent of smoking history was not stated in the abstract).   Prior research suggests those are likely to be former smokers with limited smoking histories.  Hsieh likewise found a small percentage of smokers with the mutation who responded to Tarceva.  Hsieh (70).  Those with greater smoking histories are unlikely to have responses to Tarceva.

Thus smokers who quit or who have limited histories might want to obtain the EGFR test. If the test is positive, the drug is likely to be beneficial.

Whether Tarceva can help stabilize the disease of those who do not have the mutation is controversial.  Many believe response is associated with an EGFR driven cancer suppressed by Tarceva.  Some believe that EGFR is not so easily measured and that drugs like Tarceva may help stabilize disease (few responses are seen in those without the mutation). 

15.2 Omitted

15.3 TARCEVA AND CHEMOTHERAPY AND RADIATION

15.31 Human Clinical Trials Using Iressa and Chemotherapy

Two large scale clinical trials found Iressa did not improve the effects of chemotherapy.  (50).  The well-publicized clinical trial compared patients who took chemotherapy and Iressa with those who took chemotherapy alone.   Surprisingly the group taking the combination did no better than the group using chemotherapy alone.  Rates of survival, partial response, and complete response were similar between the two experimental groups using 250mg and 500 mg Iressa + chemotherapy, versus the control group taking chemotherapy alone with placebo.   
 

15.4 SIDE EFFECTS OF TARCEVA  

    15.41 Rash

The most prevalent side effect is a localized rash.  Patients have reported it but it appears to be localized and not unusually serious.  , Some studies have found the existence of a rash indicates Iressa is working with patients with rashes having  longer survival rates.  A limited number of other studies have questioned the correlation.  (53)    "Patients who developed any degree of skin rash had prolonged time to disease progression with median of 6 months (95% CI: 2.56, 15.5) versus patients without skin rash median 3 months."  Dudek (66).

        15.411 Treatment of the Rash. 

Some suggest a moisturizing product is helpful in addressing the rash.  At a non-small cell lung cancer newsgroup, patients and care-givers discuss dealing with drug side effects and offer suggestions.
See www.acor.org

    15.42 Diarrhea

Diarrhea though not particularly severe has also been reported.   

    15.43 Pneumonitis

One serious side effect associated with Iressa wasn an unusual form of pneumonia. Pneumonia is associated with lung cancer and chemotherapy generally. However, there have been a series of pneumonitis deaths linked to Iressa initially reported in Japan:
“We assessed four patients who had non-small cell lung cancer causing severe acute interstitial pneumonia in association with gefitinib. Although two patients recovered after treatment with steroids, the other two died from progressive respiratory dysfunction. On the basis of autopsies and bilateral distribution of diffuse ground-glass opacities in chest CTs, we diagnosed diffuse alveolar damage, which was consistent with acute interstitial pneumonia. Patients with interstitial pneumonia also had other pulmonary disorders such as previous thoracic irradiation and poor performance status. Physicians should be aware of the alveolar damage induced by gefitinib, especially for patients with these characteristic features.” Inoue (22)


FDA describes the onset this way, “patients often present with the acute onset of dypnea (difficulty breathing), sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization.” FDA (1).
Careful monitoring for this side effect has been recommended. Patients on Iressa should monitor temperature rises, fevers, and immediately report problems to their oncologist. FDA suggests that “persons with concurrent pulmonary fibrosis have a higher mortality rate. This would presumably includes people with silicosis, asbestosis and similar fibrotic disease.

Tal benefit in its clinical trial.  Patients using Tarceva survived an average of 6.7 months compared to those under placebo only."  

15.5 RESISTANCE AND DEVELOPMENT OF A SECOND MUTATION AFTER TREATMENT

       15.51 The Problem of  Drug Resistance 

Patients with EGFR damages will frequently initially respond but the tumor recurs.  Scientists have found that a second EGFR pathway develops following initially successful therapy with Tarceva or Iressa. 

"Although these targeted therapies are initially effective in this subset of patients, the drugs eventually stop working, and the tumors begin to grow again. We call this acquired or secondary resistance," said Vincent A. Miller, MD, a thoracic oncologist at MSKCC and one of the study's two lead authors. "This is different from primary resistance, which means that the drugs never work at all," Dr. Miller said. The study involved six patients who had received treatment with gefitinib or erlotinib and who later developed acquired resistance. Researchers studied samples taken from the patients' tumors at different times before and during treatment. All of the tumors had the kinds of mutations in the EGFR gene that were previously associated with responsiveness to these drugs. But, in three of the six patients, they found that tumors that grew despite continued therapy had an additional mutation in the EGFR gene, strongly implying that the second mutation was the cause of drug resistance. Further biochemical studies showed that this second EGFR mutation, which was the same in all three tumors, could confer resistance to the EGFR mutants normally sensitive to these drugs. "It is especially interesting that the mutation we found is strictly analogous to a mutation that makes other kinds of tumors resistant to another targeted therapy, imatinib mesylate (Gleevec®)," said Harold Varmus, President of MSKCC and senior author of the study. "Acquired resistance to Gleevec is a well-known problem, and understanding its molecular causes has led to the design of other drugs that overcome that resistance,"  Why Some Cancers Stop Responding (62) .

These findings have been duplicated in several recent studies.  Pao (68). Yokoyama (65).

    15.52 Location of  Second Mutation at  T790M

Pao (68) writes, "We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. "

This appears to be a mutation the tumor develops in response to the administration of Tarceva or Iressa.  The mutation is not found in other lung tissue or the patient's tissue before the use of Tarceva or Iressa. 

    15.53 Reserved

    15.54 Addressing The Second Mutation 

The development of the second mutation allows EGFR signalling and cell duplication.    The doctor should theoretically have an easier task with a patient who initially responded to Tarceva but has now developed the second mutation.   First, testing to confirm the mutation makes sense.  Secondly knowing which growth factor is prompting the developement and spread of the tumor, our choice of drugs may be easier.  Other anti-EGFR drugs may be tried.  Additionally pan-inhibitors can be considered for this subgroup.

    15.55 

Pan inhibitors permanently and irreversibly stop certain functioning of EGFR.   While this may not be a valid alternative for many patients, it may make sense for patients whose cancers have been shown to be associated with EGFR. 


 

15.7 OTHER EPIDERMAL GROWTH FACTOR AND COMBINED THERAPIES

 15.71 Erbitux

"Erbitux  is a new drug from Imclone, previously called Cetxumad or IMC-C225.   It "is believed to interfere with the growth of cancer cells by binding to EGFR so that the normal (natural) epidermal growth factors cannot bind and stimulate the cells to grow."  FDQ.gov.  It was originally approved for treatment of colon cancer, but many believe it will also assist in the treatment of lung tumors.

15.711 Difference between Erbitux and Iressa and Tarceva

As I understand it, Erbitux attempts to prevent the initial binding while Iressa and Tarceva try to prevent phosphylation after binding.  Basically Erbitux binds to the EGFR before EFR can.

15.72 Herceptin

Herceptin (Trastuzumab) has been FDA approved for metastatic breast cancer. The drug targets Erb2 which is a “molecular marker of ductal breast cancer although it is overexpressed in other adenocarcinomas as well (e.g. endometrial, colorectal and lung cancers).” While drug effectiveness is organ specific, lung, colon, and breast are categorized as solid tumors and have some common characteristics. For example, the chemotherapy drug Taxol is used for both breast and lung cancer.
 

 CONCLUSION 

Non-smokers and light former smokers frequently have the EGFR damage that predicts response.  For this group, Tarceva is an important treatment which frequently achieves a partial response.  Outside this group, the use of Tarceva is controversial; some may argue that the prevalence of EGFR signalling in many lung tumors and limited side effects, mean that Tarceva can be a helpful drug, particularly with chemotherapy.  Others argue studies show that response is associated with the EGFR damage  and that the perception of stabilized disease may be unrelated and that other treatments make more sense.  Tarceva's side effects are limited particularly when contrasted with chemotherapy drugs which impact many types of dividing cells causing more substantial changes.  EGFR testing makes sense to confirm that the patient has the type of disease which is likely to respond to Tarceva.

Unfortunately, many who respond to Tarceva develop second areas of genetic damage allowing signalling at EGFR.  The possibility of this should be closely monitored with consideration given to cell samples to monitor EGFR.  Where a second area of EGFR damage is identified. the patient can consider pan-inhibitors which permanently suppress EGFR functioning.  He may also wish to consider the use of other drugs to inhibit EGFR signalling. 

 

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 (portions of this article wereexcerpted from the book Lung Cancer and Mesothelioma,  with added material based on recent research).  
for questions about this article, email howian@aol.com.  This article is not intended to provide medical advice or treatment. keywords  Tarceva, lung cancer, epidermal growth factor receptor, Iressa, non-smoker's lung cancer,  EGFR, EGF, Tarceva and lung cancer,  treatments for lung cancer).  

Dictionary of Terms and Science

ATP  The high-energy medium in the cell.  ATP has " high-energy phosphate bonds and is used to transport energy to cells for biochemical processes, including muscle contraction and enzymatic metabolism."   The term is short for Adenosine triphosphate,

Epidermal Growth Factor Receptor EGFR is a member of the ErbB family receptors, a subfamily of four closely related receptor tyrosine kinases:  Its activation has been associated with various carcinogenic processes. EGFR activated by binding of its ligands by EGF or other growth factors. 

Epidermal growth factor receptor is "A protein found on the surface of cells to which epidermal growth factor (EGF) binds. When EGF attaches to EGFR, it activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply. EGFR is found at abnormally high levels on the surface of many types of cancer cells, which may divide excessively in the presence of EGF.  The drug Iressa attaches to EGFR and thereby inhibits the attachment of EGF and stops cell division. The gene for EGFR is on chromosome 7p12.3-p12.1. The EGFR molecule has 3 regions -- one projects outside the cell and contains the site for binding EGF; the second is embedded in the cell membrane; and the third projects into the cytoplasm of the cell's interior. EGFR is a kinase that attaches phosphate groups to tyrosine residues in proteins. EGFR is also known confusingly as ErbB1, ErbB, oncogene ErbB, and HER1." www.medterms.com

"The binding of the ligand stimulates the intrinsic protein-tyrosine kinase activity of EGFR which initiates a signal transduction cascade, principally involving the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation. The kinase activity can also result in autophosphorylation of five tyrosine residues in the C-terminal domain of EGFR. Autophosphorylation elicits downstream activation and signaling events of other proteins that are often distinct from those activated by the kinase domain of EGFR."   Answers.com -epidermal growth factor receptor

Erbitux Erbitux is a monoclonal antibody and its mode of action has been distinguished from Tarceva and Iressa. "Two classes of anti-EGFR agents are currently approved for the treatment of patients with cancer: cetuximab, a monoclonal antibody directed at the extracellular domain of the receptor, and gefitinib and erlotinib, oral, low-molecular-weight (MW), adenosine triphosphate (ATP)-competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR monoclonal antibodies have demonstrated activity in the therapy of advanced colorectal carcinoma and in a variety of epithelial tumor types, including head and neck cancer and non-small cell lung cancer (NSCLC). "  Mendelsohn,Epidermal growth factor receptor targeting in cancer Semin Oncol. 2006 Aug;33(4):369-85.

 

Monoclonal Antibody

Phosphyation  The chemical process in which a phosphate group is added to an organic molecule. In eukaryotic cells,  "protein phosphorylation is probably the most important regulatory event.  Many enzymes and receptors are switched "on" or "off" by phosphorylation and dephosphorylation. Phosphorylation is catalyzed by various specific protein kinases,"    Within a protein, phosphorylation can occur on several amino acids. Phosphorylation on serine is the most common, followed by threonine.  Answers.com Phosphylation.

Tarceva (Erlonitib) Tarceva "is one of a new group of drugs that target tiny flaws in the cell's communication system. Many cells have receptors on their surfaces for epidural growth factor (EGF), which is a protein produced by the body which induces growth and multiplication of cells. This protein causes an enzyme called tyrosine kinase to become active within the cells. Erlotinib blocks the cancer cell from getting the message that tells the cell to grow and divide, and the cells stop growing."  Answers.com Erlonitib.

Tarceva competitively binds to EGFR  and therefore prevents ligand-binding which can initiate cancerous signalling.  Studies indicate it is most effective on non-smokers and light smokers whose tumors have a specific EGFR tyrosine kinase mutation.  Lynch, Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib, Volume 350:2129-2139, May 20, 2004

Tarceva comes in pill form and is taken orally with water before eating. 

Tyrosine Kinase  "A protein kinase is an enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). This usually results in a functional change of the target protein (substrate), by changing enzyme activity, cellular location or association with other proteins. Up to 30% of all proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction, the transmission of signals within the cell. The human genome contains about 500 protein kinase genes; they constitute about 2% of all eukaryotic genes."  Wikipedia, protein kinase

There are two types of tyrosine kinases, cytoplasmic kinases  and receptor tyrosine kinases.  EGFR is a receptor tyrosine kinas.   Receptors lie on the surface of these cells, hence the term, cell-surface receptor, and connect with various growth factors. . 

Its structure is
1) an extracellular domain domains which is involved in recognizing and binding the ligands that are able to activate the receptor,
2)membrame,
3) the intracellular domain where the enzymatic activity of the tyrosine kinase that is able to phosphorylate tyrosine residues occurs.

A reaction is initiated by binding at the ligand-binding level, which leads to phosphylation chemical changes in the kinase region resulting in signaling to other cells.     "Binding of a ligand to this type of receptor stimulates the receptor's intrinsic protein-tyrosine kinase activity, which subsequently stimulates a signal-transduction cascade."  Lodish,Mollecular Cell Biology  872 (4th ed. 1999).    " A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein."  Tyrosine Kinase, Wikipedia.