Lung Cancer Support Group
Lung cancer is a cancer of the lungs characterized by the presence of malignant tumours. Most commonly it is bronchogenic carcinoma (about 90%). Lung cancer is one of the most lethal of cancers worldwide, causing up to 3 million deaths annually. Although lung cancer was previously an illness that affected predominately men, the lung cancer rate for women has been...
I post on Tarceva resistance because I believe this is one area where research and knowledge can improve the outcome.
1. Initial response
EGFR positive patients have an impressive initial response rate of about 60% to Tarceva. EGFR positive patients are primarily non-smokers with adenocarcinoma or subtypes like BAC. Testing makes sense since some non-smokers are negative while former smokers, particularly light ones can be EGFR positive. While Tarceva is frequently very effective with this EGFR positive group, resistance can later develop. Cancer can be as creative in circumventing treatments as scientists are in creating them.
2. Sources of resistance
With the target (EGFR) known, scientists have identified one source for resistance, T790M. Google provides over 40,000 responses to a query for the term T790M. Technically it is a substitution in a long line of DNA of threonine 790 with methionine (T790M). That seems to be sufficient to frustrate Tarceva and restore the abnormal and repetitive cell signaling that characterizes cancer.
3. Comprehensive Cancer Centers
25 years ago, one could argue the choice of hospital did not matter since the same chemotherapy drug would probably be given at a local hospital or major research facility. Today, sophisticated testing and access to clinical trials and research development may make a difference in providing testing and determining treatment. While a local oncologist may deal with over 100 different types and subtypes of cancer, a doctor at Sloan-Kettering can specialize in lung cancers, and have an easier time addressing developments in his specialty or sub-specialty. Comprehensive Cancer Center is a designation give to major hospitals which meet certain standards of research and specialization. You can select a doctor by selecting one who is conducting important research as indicated by medical journals.
4. Erbitux and new approaches to EGFR
Tarceva is a tyrosine kinase inhibitor; it attempts to stop the phosphylation at the kinase that facilitates abnormal signaling. In contrast, Erbitux, another anti-EGFR FDA approved drug, works at the external domain level. The two drugs are arguably complimentary with different mechanisms of action. Erbitux is FDA approved for another type of cancer but is showing promise in preventing T790M resistance, in combination with new drugs called pan-inhibitors.
5. Pan-inhibitors
There is a group of drugs called permanent pan-inhibitors, and a number are being tested to address T790M resistance including HKI 272, PF00299804. Some similar drugs have been FDA approved such as Lapatanib (Tykerb), a dual inhibitor FDA approved for another type of cancer.
EGFR or Erb 1, is a part of the Erb family of tyrosine kinases involves with cell signaling, with the others Erb2-4. One theory for resistance is that these other tyrosine kinases such as Erb-2 help restore abnormal signaling and provide signals among the Erb family, called cross-talk. Erb-2 is a target of other cancers, and the well-known drug Herceptin targets Erb-2. Newer studies indicate a combination of Erbitux and a pan-inhibitor can frustrate T790M. (1) (2). These promising cell studies need to be replicated in human clinical trials.
6. Cell studies
Cell studies are important, and a drug which shows promise should be considered. First look to the scope of the study, a study dealing with many forms of cancer made not apply to your own. T790M studies are impressive because they provide results relating to the specific type of tumor.
Cell studies do not automatically convert to an effective drug in humans and a cell study cannot evaluate potential side effects. Delivery is a problem, the cell study allows the new drug to directly interact with cells, while in the complex of the human body, that interaction can be more difficult.
The converse is easier to say. If the drug is not effective in cell studies, how can it do better in humans. Where a patient has Tarceva resistance and a treatment is proposed, the obvious question is whether at least cell studies have shown the new drug can overcome that resistance at least in cell studies. In determining what to do, the question is not whether the dual inhibitor combination has been proven, but what provides the best promise for the EGFR positive patient with resistance.
7. Testing
Testing to determine the cause of resistance makes the most sense to me. Another mutation called MET may be responsible for Tarceva resistance, and there are other possibilities. Some T790M testing is advertised and it should be available at a sophisticated research facility, but probably not at most local hospitals.
8. Other approaches to Resistance HSP90
Just this month, a study carried the ambitious title, Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer.
Mol. Cancer Ther., December 1, 2009; 8(12): 3296 - 3306. Chemotherapy can carry significant side effects because it impacts a number of cells. Drugs like Tarceva carry comparatively less side effects because they more narrowly target a particular cell such as EGFR. Thus the possibility exists to combine various types of drugs.
9. Group Role
In the ideal situation, patients and family members could spend 2-3 hours or more to really discuss and understand treatment with their doctor. That generally cannot be done, and the patient has to prepare for a meeting and limit areas of inquiry for consultations that will typically be less than an hour and as little as 10-15 minutes. The idea is not to replace the doctor but prepare so your questions are targeted and the doctor can spend more time on the specifics of treatment and less on general explanation. The discussion does need to be diplomatic if not deferential.
10. Approach
While it is tempting to suggest various combinations, and use of drugs off-label, many physicians will be conservative. First do no harm is part of the physicianss creed, and one may worry about legal liability using a new and untested combination. Many physicians will usually want to see some recognized literature recommending a particular combinations, or enter the patient in a recognized clinical trial which disclosure of potential risk is part of the entrance.
11. Conclusion
Science holds out the possibility of addressing Tarceva resistance. I am not a doctor and have not reviewed any individual records in the preparation of this and the foregoing represents my personal opinions.
References
1. Regales, Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer, J Clin Invest. 2009 October 1; 119(10): 30003010.
2. Tang, Dual METEGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer, Br J Cancer. 2008 September 16; 99(6).
3. Bao, Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer, Mol. Cancer Ther., December 1, 2009
1. Initial response
EGFR positive patients have an impressive initial response rate of about 60% to Tarceva. EGFR positive patients are primarily non-smokers with adenocarcinoma or subtypes like BAC. Testing makes sense since some non-smokers are negative while former smokers, particularly light ones can be EGFR positive. While Tarceva is frequently very effective with this EGFR positive group, resistance can later develop. Cancer can be as creative in circumventing treatments as scientists are in creating them.
2. Sources of resistance
With the target (EGFR) known, scientists have identified one source for resistance, T790M. Google provides over 40,000 responses to a query for the term T790M. Technically it is a substitution in a long line of DNA of threonine 790 with methionine (T790M). That seems to be sufficient to frustrate Tarceva and restore the abnormal and repetitive cell signaling that characterizes cancer.
3. Comprehensive Cancer Centers
25 years ago, one could argue the choice of hospital did not matter since the same chemotherapy drug would probably be given at a local hospital or major research facility. Today, sophisticated testing and access to clinical trials and research development may make a difference in providing testing and determining treatment. While a local oncologist may deal with over 100 different types and subtypes of cancer, a doctor at Sloan-Kettering can specialize in lung cancers, and have an easier time addressing developments in his specialty or sub-specialty. Comprehensive Cancer Center is a designation give to major hospitals which meet certain standards of research and specialization. You can select a doctor by selecting one who is conducting important research as indicated by medical journals.
4. Erbitux and new approaches to EGFR
Tarceva is a tyrosine kinase inhibitor; it attempts to stop the phosphylation at the kinase that facilitates abnormal signaling. In contrast, Erbitux, another anti-EGFR FDA approved drug, works at the external domain level. The two drugs are arguably complimentary with different mechanisms of action. Erbitux is FDA approved for another type of cancer but is showing promise in preventing T790M resistance, in combination with new drugs called pan-inhibitors.
5. Pan-inhibitors
There is a group of drugs called permanent pan-inhibitors, and a number are being tested to address T790M resistance including HKI 272, PF00299804. Some similar drugs have been FDA approved such as Lapatanib (Tykerb), a dual inhibitor FDA approved for another type of cancer.
EGFR or Erb 1, is a part of the Erb family of tyrosine kinases involves with cell signaling, with the others Erb2-4. One theory for resistance is that these other tyrosine kinases such as Erb-2 help restore abnormal signaling and provide signals among the Erb family, called cross-talk. Erb-2 is a target of other cancers, and the well-known drug Herceptin targets Erb-2. Newer studies indicate a combination of Erbitux and a pan-inhibitor can frustrate T790M. (1) (2). These promising cell studies need to be replicated in human clinical trials.
6. Cell studies
Cell studies are important, and a drug which shows promise should be considered. First look to the scope of the study, a study dealing with many forms of cancer made not apply to your own. T790M studies are impressive because they provide results relating to the specific type of tumor.
Cell studies do not automatically convert to an effective drug in humans and a cell study cannot evaluate potential side effects. Delivery is a problem, the cell study allows the new drug to directly interact with cells, while in the complex of the human body, that interaction can be more difficult.
The converse is easier to say. If the drug is not effective in cell studies, how can it do better in humans. Where a patient has Tarceva resistance and a treatment is proposed, the obvious question is whether at least cell studies have shown the new drug can overcome that resistance at least in cell studies. In determining what to do, the question is not whether the dual inhibitor combination has been proven, but what provides the best promise for the EGFR positive patient with resistance.
7. Testing
Testing to determine the cause of resistance makes the most sense to me. Another mutation called MET may be responsible for Tarceva resistance, and there are other possibilities. Some T790M testing is advertised and it should be available at a sophisticated research facility, but probably not at most local hospitals.
8. Other approaches to Resistance HSP90
Just this month, a study carried the ambitious title, Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer.
Mol. Cancer Ther., December 1, 2009; 8(12): 3296 - 3306. Chemotherapy can carry significant side effects because it impacts a number of cells. Drugs like Tarceva carry comparatively less side effects because they more narrowly target a particular cell such as EGFR. Thus the possibility exists to combine various types of drugs.
9. Group Role
In the ideal situation, patients and family members could spend 2-3 hours or more to really discuss and understand treatment with their doctor. That generally cannot be done, and the patient has to prepare for a meeting and limit areas of inquiry for consultations that will typically be less than an hour and as little as 10-15 minutes. The idea is not to replace the doctor but prepare so your questions are targeted and the doctor can spend more time on the specifics of treatment and less on general explanation. The discussion does need to be diplomatic if not deferential.
10. Approach
While it is tempting to suggest various combinations, and use of drugs off-label, many physicians will be conservative. First do no harm is part of the physicianss creed, and one may worry about legal liability using a new and untested combination. Many physicians will usually want to see some recognized literature recommending a particular combinations, or enter the patient in a recognized clinical trial which disclosure of potential risk is part of the entrance.
11. Conclusion
Science holds out the possibility of addressing Tarceva resistance. I am not a doctor and have not reviewed any individual records in the preparation of this and the foregoing represents my personal opinions.
References
1. Regales, Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer, J Clin Invest. 2009 October 1; 119(10): 30003010.
2. Tang, Dual METEGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer, Br J Cancer. 2008 September 16; 99(6).
3. Bao, Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer, Mol. Cancer Ther., December 1, 2009
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