A multinational research team led by scientists at
Duke-NUS Graduate Medical School has identified the reason why some patients fail to respond to some of the most successful cancer drugs.
Tyrosine kinase inhibitor drugs (TKI work effectively in most patients to fight certain blood cell cancers, such as chronic myelogenous leukemia (CML , and non-small-cell lung cancers (NSCLC with mutations in the EGFR gene.
These precisely targeted drugs shut down molecular pathways that keep these cancers flourishing and include TKIs for treating CML, and the form of NSCLC with EGFR genetic mutations.
Now the team at Duke-NUS Graduate Medical School in Singapore, working with the
Genome Institute of Singapore (GIS ,
Singapore General Hospital, and the
National Cancer Centre Singapore, has discovered that there is a common variation in the BIM gene in people of East Asian descent that contributes to some patients' failure to benefit from these tyrosine kinase inhibitor drugs.
"Because we could determine in cells how the BIM gene variant caused TKI resistance, we were able to devise a strategy to overcome it," said
S. Tiong Ong, MBBCh, senior author of the study and associate professor in the Cancer and Stem Cell Biology Signature Research Programme at Duke-NUS and Division of Medical Oncology, Department of Medicine, at Duke University Medical Center.
"A novel class of drugs called the BH3-mimetics provided the answer," Ong said. "When the BH3 drugs were added to the TKI therapy in experiments conducted on cancer cells with the BIM gene variant, we were able to overcome the resistance conferred by the gene. Our next step will be to bring this to clinical trials with patients."
Said Yijun Ruan, PhD, a co-senior author of this study and associate director for Genome Technology and Biology at GIS: "We used a genome-wide sequencing approach to specifically look for structural changes in the DNA of patient samples. This helped in the discovery of the East Asian BIM gene variant. What's more gratifying is that this collaboration validates the use of basic genomic technology to make clinically important discoveries."
The study was published online in
Nature Medicine on March 18.
If the drug combination does override TKI resistance in people, this will be good news for those with the BIM gene variant, which occurs in about 15 percent of the typical East Asian population. By contrast, no people of European or African ancestry were found to have this gene variant.
"While it's interesting to learn about this ethnic difference for the mutation, the greater significance of the finding is that the same principle may apply for other populations," said
Patrick Casey, PhD, senior vice dean for research at Duke-NUS and James B. Duke Professor of Pharmacology and Cancer Biology.
"There may well be other, yet to be discovered gene variations that account for drug resistance in different world populations. These findings underscore the importance of learning all we can about cancer pathways, mutations, and treatments that work for different types of individuals. This is how we can personalize cancer treatment and, ultimately, control cancer."
"We estimate that about 14,000 newly diagnosed East Asian CML and EGFR non-small-cell lung cancer patients per year will carry the gene variant," Ong said. "Notably, EGFR NSCLC is much more common in East Asia, and accounts for about 50 percent of all non-small-cell lung cancers in East Asia, compared to only 10 percent in the West."
The researchers found that drug resistance occurred because of impaired production of BH3-containing forms of the BIM protein. They confirmed that restoring BIM gene function with the BH3 drugs worked to overcome TKI resistance in both types of cancer.
"BH3-mimetic drugs are already being studied in clinical trials in combination with chemotherapy, and we are hopeful that BH3 drugs in combination with TKIs can actually overcome this form of TKI resistance in patients with CML and EGFR non-small-cell lung cancer," Ong said. "We are working closely with GIS and the commercialization arm of the Agency for Science, Technology & Research (A*STAR , to develop a clinical test for the BIM gene variant, so that we can take our discovery quickly to the patient."
The major contributors to the study include additional researchers and teams from the Duke-NUS Graduate Medical School, Genome Institute of Singapore (Dr. Yijun Ruan and Dr. Axel Hillmer , Singapore General Hospital (Dr. Charles Chuah , and National Cancer Centre Singapore (Dr. Darren Wan-Teck Lim .
In addition, the investigators also received important contributions from Akita University Graduate School of Medicine, Japan (Dr. Naoto Takahashi , the Cancer Science Institute of Singapore (Dr. Ross Soo , the National University Cancer Institute of Singapore (Drs. Liang Piu Koh and Tan Min Chin , the Yong Loo Lin School of Medicine, National University of Singapore (Dr. Seet Ju Ee , the University of Bonn, Germany (Dr. Markus Nothen , the University of Malaya (Dr. Veera Nadarajan , and the University of Tokyo, Japan (Dr. Hiroyuki Mano .
The study was supported by grants from the National Medical Research Council (NMRC of Singapore; Biomedical Research Council (BMRC of A*STAR, Singapore; Genome Institute of Singapore; Singapore General Hospital; and two NMRC Clinician Scientist Awards to Dr. Ong and Dr Chuah.
“Human resistance to antibiotics could bring ‘the end of modern medicine as we know it’,” according to The Daily Telegraph. The newspaper says that we are facing an antibiotic crisis that could make routine operations impossible and a scratched knee potentially fatal. Similarly, the Daily Mail’s headline stated that a sore throat could soon become fatal.
The alarming headlines follow a new report by the World Health Organization (WHO , which set out ways to fight the growing problem of antimicrobial resistance (AMR . AMR occurs when infectious organisms, such as bacteria and viruses, adapt to treatments and become resistant to them. The publication specifically addressed the long-known problem of antibiotic resistance, where increasing use of antibiotics can lead to the formation of “superbugs” that resist many of the antibiotic types we currently have. It outlined a variety of measures that are vital for ensuring we can still fight infections in the future and described how other major infectious diseases, such as tuberculosis, HIV, malaria and influenza, could one day become resistant to today’s treatment options.
However, despite the future danger posed by antimicrobial resistance, the situation is not irretrievable. As Dr Margaret Chan, director general of WHO, said: “much can be done. This includes prescribing antibiotics appropriately and only when needed, following treatment correctly, restricting the use of antibiotics in food production to therapeutic purposes and tackling the problem of substandard and counterfeit medicines.” The report also highlighted successful cases where antimicrobial resistance has been tackled, demonstrating that we can safeguard the effectiveness of important antimicrobial medicines with dedicated, rational efforts.
Where has the news come from?
WHO has just published a new report (“The evolving threat of antimicrobial resistance - Options for action” that sets out a global strategy for fighting antibiotic resistance. It explores how over past decades, bacteria that cause common infections have gradually developed resistance to each new antibiotic developed, and how AMR has evolved to become a worldwide health threat. In particular, the report highlights that there is currently a lack of new antibiotics in development and outlines some of the measures needed to prevent a potential global crisis in healthcare.
This is not the first time WHO has set out such a strategy. In the 2001, WHO published its “Global strategy for containment of antimicrobial resistance”, which laid out a comprehensive list of recommendations for combating AMR. The current report looks at the experiences over the past decade of implementing some of these recommendations, the progress made, and what else should be done to tackle AMR.
What is antimicrobial resistance?
Antimicrobial resistance (AMR occurs when microorganisms, such as bacteria, viruses, fungi or other microbes, develop resistance to the drug that is being used to treat them. This means that the treatment no longer effectively kills or inactivates the microorganism. The term “antimicrobial” is used to describe all drugs that treat infections caused by microorganisms. Antibiotics are effective against bacteria only, antivirals against viruses, and antifungals against fungi.
The case of penicillin illustrates the AMR phenomenon well. When penicillin was first introduced in the 1940s, it revolutionised medicine and was effective against a wide range of staphylococcal and streptococcal bacteria. It was also able to treat infections that had previously been fatal for many people, including throat infections, pneumonia and wound infections. However, with increasing use of antibiotics over the decades, bacteria began to adapt and develop changes in their DNA that meant they were resistant to the actions of the once powerful antibiotic. These bacteria would survive and proliferate, which meant their protective genes would then be passed on to other strains of bacteria. As a result, new and stronger antibiotics had to be created to combat the resistant bacteria.
AMR is driven by many factors, including overuse of antimicrobials for human and animal health and in food production, which can allow microbes to adapt to antimicrobials they are exposed to. Poor infection-control measures, which fail to prevent the spread of infections, also contribute. In particular, the WHO publication reports what it describes as the five most important areas for the control of AMR, as recognised in its 2001 strategy:
- surveillance of antimicrobial use
- rational use in humans
- rational use in animals
- infection prevention and control
- innovations in practice and new antimicrobials
How big is the problem?
As the report describes, AMR makes it difficult and more expensive to treat many common infections, causing delays in effective treatment or, in the worst cases, an inability to provide effective treatment at all. Many patients around the world suffer harm because infections from bacteria, viruses, fungi or other organisms can no longer be treated with the common medicines that would once have treated them effectively.
The report presents some startling facts on major infectious diseases worldwide:
- Malaria: malaria is caused by parasites that are transmitted into the bloodstream by a bite from an infected mosquito. Resistance to antimalarial medicines has been documented for all classes of the drug, which presents a major threat to malaria control. The report describes that a change in national antimalarial treatment policy is recommended when the overall treatment failure rate exceeds 10%. Changes in policy have been necessary in many countries due to the emergence of chloroquine resistance. This means that alternative forms of combination therapy have to be used as first-line treatment.
- Tuberculosis: in 2010, an estimated 290,000 new multidrug-resistant tuberculosis (TB cases were detected among the TB cases notified worldwide, and about one-third of these patients may die annually. Inaccuracies in diagnosis also impede appropriate treatment.
- HIV: resistance rates to anti-HIV drug regimens ranging from 10% to 20% have been reported in Europe and the USA. Second-line treatments are generally effective in patients when the first-line therapy has failed, but can only be started promptly if viral monitoring is routinely available.
- Common bacterial infections: various bacteria can cause infections within the chest, skin and urinary tract bloodstream, for example, and the inability to fight these infections appears to a growing problem in healthcare. Estimates from Europe are that there are 25,000 excess deaths each year due to resistant bacterial hospital infections, and approximately 2.5 million avoidable days in hospital caused by AMR. In addition, the economic burden from additional patient illness and death is estimated to be at least ˆ1.5 billion each year in healthcare costs and productivity losses.
What can be done about AMR?
The five key areas that the report highlights could tackle the problem of AMR are as follows:
Surveillance of antimicrobial use
Tracking antimicrobial use (in particular antibiotic use and looking at the emergence and spread of resistant strains of bacteria is a key tactic in the fight against AMR. This can provide information, insights and tools needed to guide policy and measure how successful changes in prescribing may be. This can happen both locally and globally.
AMR is a global problem but, at present, there appears to be wide variation in the way regions and countries approach AMR surveillance. This means there is a long way to go before it can be carried out worldwide.
Rational use in humans
Antimicrobials can obviously be important or even lifesaving in appropriate situations, but it is just as important to prevent unnecessary use of antimicrobials, which can lead to resistance. Putting this into practice worldwide is said to be difficult, but rationalising antimicrobial use has had a demonstrable impact on AMR in some cases.
Rational use in animals
Antibiotics are said to be used in greater quantities in food production than in the treatment of disease in human patients. Also, some of the same antibiotics or classes are used in animals and in human medicine. This carries the risk of the emergence and spread of resistant bacteria, including those capable of causing infections in both animals and people.
The problems associated with the use of antibiotics in animal husbandry, including in livestock, poultry and fish farming, are reportedly growing worldwide without clear evidence of the need for or benefit from it. There are said to be major differences in the amounts of antimicrobials used per kilogram of meat produced in high-income countries, and actions need to be taken by national and international authorities to control this.
Infection prevention and control in healthcare facilities
The hospital environment favours the emergence and spread of resistant bacteria. The report highlights the importance of infection-control measures to prevent the spread of microbes in general, regardless of whether they are resistant to antimicrobials. Many facilities and countries are reported to have progressed well since 2001, implementing many recommendations on infection control and prevention, although gaps and challenges still remain.
Innovations
Lastly, the report describes how innovative strategies and technologies are needed to address the lack of new antimicrobials being produced. As the report says, while antimicrobials are the mainstay of treatment for infections, diagnostics and vaccines play important complementary roles by promoting rational use of such medicines and preventing infections that would require antimicrobial treatment. So far, new products coming on to the market have not kept pace with the increasing needs for improvements in antimicrobial treatment. However, current challenges to new research developments can be both scientific and financial.
Can these strategies really stop AMR?
While AMR poses a significant threat to health in the future, the situation does not appear to be irretrievable. The WHO report and an accompanying press release highlight some examples of success stories over the past years:
- In Thailand, the "Antibiotic Smart Use" programme is reported to have reduced both the prescribing of antibiotics by prescribers and the demand for them by patients. It demonstrated an 18–46% decrease in antibiotic use, while 97% of targeted patients were reported to have recovered or improved regardless of whether they had taken antibiotics.
- A pharmacy programme in Vietnam reportedly consisted of inspection of prescription-only drugs, education on pharmacy treatment guidelines and group meetings of pharmacy staff. These measures were reported to give significant reduction in antibiotic dispensing for acute respiratory infections.
- In Norway, the introduction of effective vaccines in farmed salmon and trout, together with improved fish health management, was reported to have reduced the annual use of antimicrobials in farmed fish by 98% between 1987 and 2004.
- In 2010, the University of Zambia School of Medicine was reported to have revised its undergraduate medical curriculum. AMR and rational use of medicines were made key new topics to ensure that graduates who enter clinical practice have the right skills and attitudes to be both effective practitioners and take a role in fighting AMR.
How can I help?
There are times when antibiotics are necessary or even vital. However, as patients and consumers, it is important to remember that antibiotics or other antimicrobials are not always needed to treat our illnesses, and we should not expect them in every situation.
For example, the common cold is caused by a virus, which means it does not respond to antibiotics. However, people may expect to be given antibiotics by their doctor when they are affected, even though they offer no direct benefit and could raise the risk of bacteria becoming resistant. Furthermore many common viral and bacterial infections such as coughs, throat and ear infections and stomach upsets, are “self-limiting” in healthy people, which means they will generally get better with no treatment at all.
If, on the other hand, you are prescribed an antimicrobial, it is important to take the full course as directed. Taking only a partial course of an antimicrobial may not kill the organism but may expose it to a low dose of a drug which can then contribute to resistance.
Links To The Headlines
Health chief warns: age of safe medicine is ending. The Independent, March 16 2012
Resistance to antibiotics could bring "the end of modern medicine as we know it", WHO claim. The Daily Telegraph, March 16 2012
Why a sore throat could soon be fatal: Bugs are becoming more resistant to antibiotics, warn health chiefs. Daily Mail, March 16 2012
Links To Science
WHO: The evolving threat of antimicrobial resistance - Options for action. March 16 2012
Lately, we have been asked to believe that quite a few events in Afghanistan are anomalies, and should not be taken as more broadly representative of anything.
Accidents happen, and sometimes really bad things happen, but they don't reflect anything deeper about our war that should trouble us.
There was the burning of the Korans. Much of the Western media's coverage of this story has been farcical. For example, at the
Huffington Post, we learn that they were "tossed in a pile of garbage" before being set on fire. We are not told how many Korans, but it was an "accident". They were accidentally thrown into the trash, then accidentally set on fire. That sounds plausible.
Anonymous officials also claimed that "they contained extremist messages or inscriptions". So they were accidentally put in the trash, and accidentally burned on purpose because they had extremist messages in them. However, we can rest assured that coalition forces will receive training, which will "include the identification of religious materials, their significance, correct handling and storage".
We are supposed to believe that soldiers were previously unaware it may be insensitive to throw holy books in the trash and set them on fire. One can only imagine what might happen if a bunch of Torahs were thrown in the trash and set on fire. Two thousand Afghans protested in the streets, apparently unaware of the "respect the US military has for the religious practices of the Afghan people". After
three days of protests, seven Afghans had been killed. And yet, Afghanistan's president, Hamid Karzai obediently declared that "we have found that American soldiers mistakenly insulted the Koran and we will accept their apology". Something like: whoops, accidentally threw your Korans in the trash and set them on fire!
Then there was the allegedly
rogue American soldier who went on a shooting spree, killing 16 civilians. The AP story notes that Karzai "has repeatedly demanded the US stop killing Afghan civilians". It just hasn't really mattered much.
"This has been going on for too long. You have heard me before. It is by all means the end of the rope here."
Obviously, the occupying coalition is not bound by trivialities like listening to the president of the country. The Reuters story reports:
"I don't want any compensation. I don't want money, I don't want a trip to Mecca, I don't want a house. I want nothing. But what I absolutely want is the punishment of the Americans. This is my demand, my demand, my demand and my demand," said one villager, whose brother was killed in the nighttime slaughter.
Furious Afghans and lawmakers have demanded that the soldier responsible be tried in Afghanistan, but despite those calls, the U.S. staff sergeant was flown out on Wednesday.
Well, we can get a sense of how concerned the US is about Afghanistan's sovereignty, and about ensuring that the soldier is brought to justice. Indeed, Karzai and others doubt only one man was responsible. However, it appears Afghanistan will not be permitted to investigate further.
Then there was the story of the
three American soldiers, "appearing to urinate on three apparently lifeless men" in Afghanistan: "Have a great day, buddy".
Tariq Ali notes that Guantanamo prisoners "alleged that their guards pissed on them from above and that some of the drops fell not just on them, but the Korans they were reading. At the time nobody thought fit to say that such acts 'were not consistent with core values'."
Thankfully, however, "the commanders of US forces in Afghanistan on Friday ordered American troops to treat the bodies of killed enemies and civilians with 'appropriate dignity and respect'." Now that they've received this order, they will treat dead bodies with "dignity and respect". The implications of what happened before this order, and the order's apparent necessity, don't require much comment.
Except: perhaps this order could have come earlier. Like, before an army
staff sergeant admitted that he "cut fingers off the corpses of three Afghan civilians". This was part of the trial for a group of five soldiers who
allegedly killed Afghan civilians "for sport", and seven more who covered up the killings.
This group "cut 'trophies' from the bodies of the people they killed", and posed "with the dead bodies of defenceless Afghan civilians they killed" as "trophy" photos. Perhaps this would have been prevented, if only the commander had previously ordered them to treat bodies with appropriate respect and dignity.
It may be said that these are all anomalies, but plainly if these things keep happening, and they always seem to happen in wars, they are not. Part of the answer is that soldiers in an occupying army are trained to be what would in other contexts be recognised as sociopaths. They are supposed to be willing, at a moment's notice, to kill another human being. And then continue on with their duties. An ordinary person would not be able to manage this. If you can persuade them that the enemy they are fighting is evil, and that the people they kill don't matter like normal people, then they will be more effective soldiers. But they will be less decent human beings. And if you are a soldier in an occupying army, fighting an unjust war, the moral problem becomes more acute. For if you are hated, you will quickly find it difficult to distinguish between the enemy, and the population you are supposedly there to liberate. And so, you will start to justify to yourself being inhumane towards the enemy, which becomes increasingly ill-defined, and increasingly associated with the general population.
Christian Science Monitor journalist
Neil Shea described the gradual process, noting that:
they begin with small things. They'll insult Iraqis or Afghans behind their backs, and that's sort of the very mild beginning of it. And then they sort of move up the chain, if we can call it that, into more serious acts of aggression, where they'll kill animals or they'll beat somebody or treat them roughly, and it sort of builds up from there.
What I saw with these guys in Afghanistan when I was with them was that several of them had already been through multiple tours in Iraq and Afghanistan, and they had reached a point where they hated Afghans, they hated the country, and they were really not interested in doing any of the hearts and minds stuff anymore that's a crucial part of the mission. So by the time I reached these guys, they had already been sort of—they had been building up anger and aggression in strange ways for a number of years. And when I saw them, they had just shot a dog that had been a pet in an Afghan home that they had confiscated during the mission, and they treated Afghan civilians fairly roughly, and they took a few prisoners and treated them very roughly, as well. Nothing that would rise to necessarily the—sort of a crime at that time, but the way that they talked about things and the way that they sort of handled themselves was really aggressive. And it was only—it seemed to me only to be barely kept in check.
It is nice to think that our brave soldiers are there fighting the good fight against the Islamist fanatics of the Taliban. Yet US vice president
Joe Biden has explained that the Taliban per se is not the enemy. And the truth is that we have been trying to negotiate with the Taliban for years.
Karzai has even described the atmosphere of talks in 2011 as "brotherly". Perhaps
this is from gratitude, as the US has "pushed to take Taliban leaders off a United Nations blacklist, a move that would make it easier for them to travel abroad."
The objection we have to the Taliban is not that wish to impose a despotic version of Islam on Afghanistan. It is that they have not properly demonstrated a willingness to make Afghanistan a client state of the US. We are fighting in Afghanistan to prop up the corrupt, fraudulently elected government of Hamid Karzai, which is properly obedient.
It is reflective of the poverty of the Western media's coverage of the war that we have been so completely shielded from the nature of Karzai's regime. Throughout the Muslim world, the name Karzai is perceived as the archetype of a puppet of foreign occupation, like a Muslim Vidkun Quisling. As
As'ad AbuKhalil asked:
"is there any Muslim who is more hated and despised by Muslims than Hamid Karzai? This is a Muslim who cannot even walk in any Muslim city. Hell. He can't even walk in his own cities in Afghanistan, and has to be sequestered in the presidential palace in Kabul, protected by US guards, to stay alive."
Which is why he is also known as the "Mayor of Kabul". In
an interview with CNN, he replied to critics: "if I am called a puppet because we are grateful to America, then let that be my nickname."
Indeed, so notorious is the name of Karzai, a story on Palestine
in an Egyptian paper noted that Yasser Arafat had:
forced Abu Mazen to resign as prime minister in the wake of a vicious mudslinging campaign that had sunk to the depths of dubbing Abu Mazen the "[Hamid] Karzai of Palestine".
Such a comparison is considered a "vicious mudslinging campaign" - an insight into how our puppet is perceived. One could go on and on. The Washington Post
reported casually that during Zalmay Khalilzad's 19 months as US ambassador to Kabul:
No significant decision was made by Karzai in that time without Khalilzad's involvement, and sometimes his cajoling and prodding.
Or
the Afghan governor who Karzai sacked for criticising "a US air raid which killed at least 15 civilians".
The story of Karzai is of a puppet of the foreign occupying powers, who has
struck deals with misogynist, fundamentalist warlords to further extend his support influence. The result has not been impressive. A few weeks ago, the
Independent reported that Karzai:
has backed guidelines issued by Afghanistan's religious council that relegate women to the position of second-class citizens..."Men are fundamental and women are secondary," the 150-member Ulema Council said in a statement that was subsequently posted on Mr Karzai's own website. It also said that men and women should not mix in work or education, and that women must have a male guardian when they travel.
Not the first time Karzai has taken an appalling stand against women's rights.
Australia's role includes support for our "most vital local ally in Afghanistan, controversial warlord Matiullah Khan".
Strangely, Dutch forces have "refused to work" with him "because of his alleged connections to murder and extortion". The New York Times notes that Matiullah was "the head of the Highway Police in Oruzgan Province". A Western diplomat explained:
"The highway police was one huge drug smuggling operation."
One could pick out many more individual atrocities here or there. Apologists of the occupation may say they are not the point, which often reflects a kind of callousness to the suffering of the people of Afghanistan. Yet in a way, they only reflect a more fundamental point. We are fighting an unjust war. There will never be a just way to occupy another country. After more than 10 years, it is time we said enough.
Michael Brull is studying a Juris Doctor at UNSW. He tweets at @mikeb476. View his full profile
here.
