Using Genetic Abnormalities in Tumors to Kill Cancer

It is common for cancers, once they are treated by standard therapies, to return in different forms. Teresa McKeown had breast cancer that returned eleven years later in the triple-negative disease. After the detection of the cancer, a tumor had started to grow making it hard to eat while filling her abdomen with fluids. She had weeks to live, but everything changed though clinical trials at Moores Cancer Center. The test revealed genetic abnormalities inside tumors and found a large number of them in McKeown’s tumor. Doctors suggested she take Opdivo, which was used to treat melanoma, and could be used to kill cells in McKeown. After two infusions of the drug, her tumor markers dropped significantly, and within eight weeks, McKeown was back to living a cancer-free life.

How Opdivo works in the body

Although the story of Teresa is miraculous, it shows the important of sequencing the genomes of tumors. This practice, known as comprehensive tumor profiling, allows researchers to see the mutant genetics in the DNA of tumors and is slowly becoming a major part of cancer treatment. Running the profile of tumors allows doctors to determine the correct drugs that are able to fight the genetic mutations, although it might not be the intended use (using melanoma drugs to treat breast cancers).

Every individual with cancer is different, so individuals suffering from the same cancers may have tumors with completely different profiles. The FDA also approved 31 target therapies that allow individuals to be treated for their various cancer forms.

Looking at tumors is not new. For example, oncologists have checked specific mutations in tumors (BRAF in melanoma, ROS1, ALKr, EGFR in lung cancer. However, the use of the complete sequencing of tumors allows for a more detailed approach for the tumors and the treatments. Although this process is beneficial, many cancer doctors are not on board because most individuals don’t benefit from it. The reality is that the profiling of tumors is beneficial when there are not other options for treatments.

I think that the profiling of tumors can be very beneficial for cancer patients. I unfortunately lost my father from lung cancer because it seemed like none of the treatments were helping. As the article states, they check for specific mutations in lung tissue of tumors, however, it would be interesting to see if a complete profile would have impacted what drugs he would have taken. I am always so interested in cancer and cancer genetics. Thinking that there is no other solution for people is disheartening, but seeing that you are able to treat different mutations with non-traditional drugs gives hope. Although there is not complete consensus on this technique, it seems like it can be a viable test to do for individuals. Overall, I am satisfied seeing growth in cancer treatment techniques and shows that we are one step further to curing all cancers. 

Lung Cancer Biomarkers Identified

An article on Science Daily states the new findings of Yafang Li and researchers at Dartmouth college. They have identified three new lung cancer biomarkers. There are two causes behind lung cancer, the environment and genes. It is well known that smoking causes lung cancer but there are actually gene variants that affect a person's susceptibility to smoking. These genes are the culprits behind the development of lung cancer. The biomarkers found are called novel single-nucleotide polymorphisms (SNPs) and they emphasize the vulnerability of developing lung cancer. In other words, a person's smoking behavior, which increases their chance of obtaining lung cancer, is influenced by these three SNPs. An article on Genetic Engineering and Biotechnology News reinforces the findings, showing the p-values in the study that were used to identify the three SNPs.
 
 I believe this new finding is a tremendous step in the treatment for those with lung cancer. As technology advances, research does too, which enables us to better understand certain diseases and come up with an effective plan to cure those diseases. However, the research study was only done in a Caucasian population. Therefore, the genes found might not be the same in other ethnicities. I believe the research team should expand their findings in other populations. The research team is determined to do so and test other populations so more gene-smoking interactions are found.
https://www.sciencedaily.com/releases/2017/10/171028081456.htm
https://www.genengnews.com/gen-news-highlights/novel-lung-cancer-biomarkers-identified/81255101

Gene Editing Tool Used in a Human For the First Time

A gene tool that may have extraordinary promise in curing myriad diseases has been used in a human for the first time.

According to Nature, scientists at West China Hospital in Chengdu injected cells edited by CRISPR-Cas9 into a patient with aggressive lung cancer on Oct. 28.

CRISPR is an acronym for "clustered, regularly inter-spaced, short palindromic repeats," which are patterns of DNA sequences that can be edited. Cas9 is a type of modified protein that works like a pair of scissors to snip out DNA sequences. CRISPR-Cas9 works by identifying problem sequences and modifying them, hopefully solving the problem they cause.

In the case of the Chinese patient, scientists edited a gene that hinders the cell's ability to launch an immune response, which also prevents it from attacking healthy cells. These modified cells will then, scientists hope, target the cancerous cells and destroy them.

The trial's main objective is to test the technique for safety. The Chinese team plans to treat 10 patients, and each will be monitored for six months for side effects.

"Everything is going as planned," Liao Zhilin, who handles the Chinese team's communications, told CNN.

However, there are also ethical questions surrounding gene-editing techniques. The ability to modify DNA, while it may eradicate thousands of diseases, also may allow researchers to explore morally gray areas of science, such as creating chimeras.

Meanwhile, the United States is also set to begin a human trial of CRISPR-Cas9 in early 2017, designed to treat several forms of cancer.

"I think this is going to trigger 'Sputnik 2.0', a biomedical duel on progress between China and the United States, which is important since competition usually improves the end product," Carl June, a scientific adviser to the U.S. trial and immunotherapy specialist at the University of Pennsylvania, told Nature.

CRISPR Gene-Editing Tested in Human Immune cells

The CRISPR/Cas9 gene-editing technology is allowing a Chinese team of scientists, lead by oncologist Lu You at Sichuan University in Chengdu, to repair genes in order to treat a disease.  As a part of a clinical trial, the Chinese team used CRISPR/Cas9 to treat a patient with non-small-cell lung cancer.  CRISPR/Cas9 has only ever been tested in lab animals, but this latest news, reported in the journal Nature, describes the researchers testing the gene-editing technique in a living person for the first time.

Dr. Lu and his team isolated immune cells from a cancer patient’s blood, and using the CRISPR/Cas9 technique, they genetically modified them to eliminate the function of the PD-1 gene which encodes for a protein that is capable of shutting down the body's natural immune response to cancer.  PD-1 was targeted because the protein allows cancer cells to proliferate.  Once the immune cells were cultured with modified genes, the modified cells were then injected back into the patient; the idea being that the modified immune cells won't be susceptible to being shut down as easily as the patients unmodified immune cells, (since the modified cells are unable to produce PD-1 protein).  Without producing PD-1 protein, the modified cells are thought to be able to combat against the cancer.

This technique is reported to allow the ability to edit any part of DNA of any organism, and it could potentially be used to cure diseases, engineer crops, and eradicate pathogens.  Jennifer Doudna, at the University of California, Berkeley, and Emmanuelle Charpentier, at the Max Planck Institute for Infection Biology in Berlin, first reported this discovery in the US back in 2012, and it was met with much controversy.  As a result, further public/private research was restricted, and it also lead some scientists to continue research in other countries.  The National Institutes of Health, (NIH), has an established Recombinant DNA Advisory Committee to review and make recommendations on any research studies that involves using gene-editing techniques on humans.  Though a conservative approach is important, I personally think it slows progress.

This could be one of the biggest biotechnology breakthroughs of our century.  It is an awesome example of personalized medicine, and I genuinely hope that China’s clinical trials are successful in providing the world insight to a completely new therapeutic approach to combat cancer.  The value of the research lies in its potential to be used in medical care to treat diseases.  I’d like to eventually see cell cultures and genetic manipulations be significantly automated/streamlined to allow them to become a mainstream option.  Similar therapies have already been shown to have amazing effects in blood-based cancers, but this is the first time that the cells were modified using the new CRISPR gene editing tool.  CRISPR/Cas9 gene-editing is described as being cost-effective and efficient, and if successful, China’s clinical studies could be very beneficial for all mankind.

The Difference Between Cancer Mutation Patterns in Smokers and in Non-Smokers

     Gene mutations in any organism can have several causes. Smoking, however, has been known to increase the risk of around 17 cancers, including lung cancer, bladder cancer, kidney cancer, and many more. Tobacco smoke is a complex mixture of chemicals, at least 60 of which are carcinogens. A new analysis shows that DNA in cancerous tissues of smokers are different from those in cancerous tissues of non-smokers. Cancer geneticist Ludmil Alexandrov and his international research team conducted an experiment in which they analyzed and examined mutational signatures and DNA methylation in DNA extracted from 5000 genome sequences, half of which were from smokers. What showed the increase in cancer risks in smokers were the mutational signatures 2,4,5,13, and 16. 

    
  
     Signature 4 mutation signals damage to guanine and it appears in DNA of cells which were exposed to chemicals from burnt products, such as tar in cigarette smoke. This signature was found in non-smokers' tumors, but less often. Smokers with lung squamous cancer, lung adenocarcinoma and larynx cancers had high numbers of signature 4 mutations, while cancers of oral cavity, pharynx, and esophagus had much less signature 4 mutations. Even though the reason why these tissues didn't have as much signature 4 mutations, despite being the most directly exposed to smoke, is unclear, the team speculates that these tissues might metabolize smoke differently.

     Another difference observed between the smoker's damaged DNA and that of non-smokers was the presence of signature 5 mutations. This signature normally shows up in all cancer types but its cause is still unknown. However, it is known that it increases with age and the analysis revealed that the more a person smoked, the more signature 5 mutations were present. Smokers with lung adenocarcinoma also appeared to have more signature 2 and 13 than non-smokers with the same disease. These could have resulted from overactive DNA editing machinery. However they are found in many types cancer and it's still unclear how smoking influenced the increase in these signatures. Signature 16 has only been found in liver cancer tumors, but it was in a higher number in smokers' damaged DNA than in those of non-smokers. It's correlation to smoking is also unknown.

     The researchers took into account the pack years smoked (1 pack year = one pack of cigarettes per day per year) and found a positive correlation between pack years and the number of mutational signatures. This information helped them calculate the mutations caused by smoking for each cancer type in the tumors they researched. The results were that one pack year leads to 150 mutations in a lung cell, 97 in a larynx cell, 39 in the pharynx cell, 23 in the oral cavity cell, 18 in the bladder cell, and 6 in a liver cell.

     I think that this information is very important for the public, so that it can bring better awareness to how harmful smoking is and how important it is to help treat people with smoking addictions. I hope that more answers can be found about how the signatures mentioned in the previous paragraph cause cancer and what the correlation between these mutations and smoking is, because this information can also help identifying the causes of other cancers due to these mutations.

Links:

• https://www.sciencenews.org/article/cancer-mutation-patterns-differ-smokers-nonsmokers

• http://science.sciencemag.org/content/354/6312/618.full

Dormancy of Lung Cancer

Over 40,000 people are diagnosed with lung cancer each year, with fewer than 10% surviving for at least five years after diagnosis, despite positive steps being made against the disease.

Scientist from Cancer Research UK discovered that lung cancer can remain dormant for about 20 years before turning into an aggressive disease. The team studied lung cancer from seven patients -  including smokers, ex-smokers and never smokers. They found that after the first few genetic mutations that cause lung cancer, the disease can exist undetected for many years until new faults/mutations trigger the rapid growth of the disease.

Cancerous mass of cells in the upper right lobe of the lung.

During the time, when the disease is expanding, different genetic faults appear at different sites of the tumor. And every distinct section of the tumor that is developing, is genetically unique. The wide variety of faults found within the tumor in the lung explain why targeted treatment are not very successful. The biopsy of a lung helps in identifying only one specific gene mutation. So when the attack is done on the mutation it will only affect that particular gene leaving the other sites of the tumor (with different genetic faults) unaffected and developing.

The study also shows the role of smoking towards the development of lung cancer. Many of the early defects are caused by smoking. But as these mutations evolve and develop these become less important. Majority of the mutations are caused by a new process that generates mutations within the tumor, which is  controlled by a protein called APOBEC.

Professor Nic Jones, Cancer Research UK’s chief scientist, said: “This fascinating research highlights the need to find better ways to detect lung cancer earlier when it’s still following just one evolutionary path." He added that Cancer Research UK was funding a study called TRACERx based on this work. The new study is studying 100s of lung cancer patients as they evolve over time to eventually find out how they are becoming resistant to treatments.

I think building on this research will help scientists and researchers understand  how the mutations of lung cancer develop and track its path down. The next crucial step would definitely be to  find the right medications to attack all the various sites of the genetic mutations in the lung cancer tumor.The fact that smoking has a very little impact on the mutations that fully trigger lung cancer was very fascinating. I hope this research reaches its full potential and more lives are saved.

Article: http://www.cancerresearchuk.org/about-us/cancer-news/press-release/2014-10-09-researchers-reveal-lung-cancer-can-stay-hidden-for-over-20-years

Related Article: Symptoms of Lung Cancer - http://www.lungcancer.org/find_information/publications/163-lung_cancer_101/266-symptoms

Individualized treatment plans for metastatic cancer patients prolong survival rate

Specialists at the National Cancer Institute have discovered a way to prolong the life of lung cancer patients whose cancer has spread to other parts of the body. Metastatic cancer is the term used for cancer that has spread from a place where it first started and contains the same types of cells as the original tumor. Scientists extract DNA from the tumor and then analyze the mutations by using a special test called a PCR. A PCR or polymerase chain reaction is a biochemical technology used to amplify a single or a few copies of a piece of DNA, generating thousands to millions of copies of a particular DNA sequence. Based on the information gained from the test, specialists can develop personalized treatment plans including oral drugs and biomarkers that can sometimes be more beneficial than traditional chemotherapy or radiation techniques. Arrieta Rodriquez is the head of the Laboratory of Experimental Oncology and Translational Medicine Studies at the National Cancer Institute and reveals some amazing statistics. "We have achieved an improvement of 80 percent in the metastatic stage and three times the survival. i.e., 30 months with good quality of life, while chemotherapy the response is just 30 percent in some cases".  If you have had cancer or are currently undergoing cancer treatment and would like to help this research group on their current project, a public questionnaire is available that asks questions regarding your quality of life. (The page is in Spanish, but browsers such as Google Chrome allow it to be translated to English.)

Picture A shows primary lung tumor (arrow) with mediastinal nodal metastasis (bold arrow). Picture B is after three cycles of chemotherapy, which shows a large reduction (almost completely gone) in the primary tumor (arrow) but and increase in size and uptake of mediastinal nodes (bold arrow). Also, Picture B shows the appearance of new metastasis (arrowhead) in the lymph node of the armpit. 

Picture from: http://journal.sajc.org/article.asp?issn=2278-330X;year=2013;volume=2;issue=3;spage=171;epage=178;aulast=Sharma

Testing Lung Cancer Patients for Gene May Aid Treatment, Study Finds

Recent research has found that lung cancer patients that carry a rare gene mutation may have extended survival rates when they take a drug typically specified for breast cancer. Medications that target human epidermal growth factor receptor 2, HER2, proteins delay the progression of the specific lung cancer. These proteins targeted by the drugs only are the results of 5 percent of lung cancers, therefore this method can not be used widely. However, if more every lung cancer patient is tested for the HER2 protein, it increases the possibility that doctors are able to detect this interaction and elongate survival.



Any progress in the cancer business is essential to the future treatments of different cancers. It is apparent that if more patients are testing for these proteins created in a gene mutation, the chances of survival are increased. I truly wish that this testing becomes more popular and more patients are offered the chance of slower progression and longer survival.

 

 

For more information on the following article visit:http://health.usnews.com/health-news/news/articles/2013/04/22/testing-lung-cancer-patients-for-gene-may-aid-treatment-study-finds or http://www.medscape.com/viewarticle/803000


 

Biomarkers That Predict Chemotherapy Survival

According to Medical News Today, a "signature" of eight genes has been found that can predict a cancer patient's likelihood of surviving chemotherapy.  This print can also predict the amount of relapse-free survival time a patient has.  So, how is it done?

A team of investigators from Academia Sinica and the National Taiwan University College of Medicine identified genes that participate in cellular invasion, which is a large property of most cancer cells.  The reactions of these genes to 99 different anti-cancer treatments was observed and eight genes were found that could possibly affect the impact of chemotherapy.  It was found that there was a noticable variation between cells that did respond to chemotherapy treatment and cells that did not respond to chemotherapy treatment.  (There was some overlap.) 

Other clinical studies were done on breast cancer and lung cancer patients.  It was shown that the patients that had the eight gene signature that placed them in the low-risk category had a longer relapse-free period of survival than those in the high-risk group.

Gene Involved in Lung cancer

According to the Science Daily,  researchers have been identified the gene that involved in the growth and spread of non-cell lung cancer tumors. Person who carries these non-cells lung cancers usually, they have mutation on epidermal growth factor receptor (EGFR) gene. Due to the mutation on epidermal growth factor receptor, it causes the spread and growth of tumor. Researchers studied families who had this cancer which showed that mutation on EGFR also cause the increased communication of the Fn14 gene. Researcher noticed that higher communication of the Fn14 gene develops lung tumor formation; however, if Fn14 gene subdue, it reduces the metastasis in non-cell lung cancer.

[caption id="" align="alignright" width="360" caption="lung cancer"][/caption]

Another article according to Southern Medical Center, researcher found same gene mutation on EGFR gene for lung cancer. These gene mutations are highly found in adenocarcinomas type of lung cancer where both smokers and non-smoker are affected. Highly amount of mutation on EGFR gene found on nonsmokers rather than smoker. Also, another KRAS gene involved which signal the pathways of the EGFR which common in males than females. Researchers said that two pathways were identified which distinguish that KRAS gene mutation affect smokers and EGFR mutation affect non-smokers. Now, researcher are trying to look for better treatment. This article is inserting to me because two different gene involve in lung cancer also those are affected equally rather person smoke or not, it doesn't matter.

Gene Differences in Non-Smokers with Lung Cancer

Three separate genetic regions have been identified for those that have an increased risk of lung cancer for nonsmokers. This particular study focused on Asian women. Researchers analyzed data from 14 different studies that totaled about 14,000 Asian women. The researchers were able to identify three different genetic markers that were associated with Asian women who had never smoked. Two were found to be located on chromosome 6 and one on chromosome 10. This last marker was the most interesting of the three because previous research has not indicated this particular chromosome.



The study's co-author Dr. Nathaniel Rothman said, "Our study provides strong evidence that common inherited genetic variants contribute to an increased risk of lung cancer among Asian women who have never smoked." Another surprising part of this study was that the researchers did not find an association between the lung cancer risk and variations at a location on chromosome 15. This particular chromosome has been linked to a lung cancer risk in smokers. Therefore, this proves that the genetic variation in chromosome 15 may be related to actually smoking.More research will need to be conducted to show whether Asian women in particular are more prone to the effects of secondhand smoke. Overall, I found this information to be very useful. I would be interested to see whether or not other genetic markers could be identified for other populations.

Tobacco Exposure And Genetics Linked To Lung Cancer Risk

An article in Medical News Today reports about a study done on the genotype of the gene rs1051730-rs16969968. Studies show that this genotype is linked with objective measures of tobacco. This link indicates that lung cancer is mostly caused by the level of tobacco exposure.

The study was done by Marcus R. Munafò, Ph.D., of the School of Experimental Psychology at the University of Bristol and his team. In their research, they found that even after adjusting the self-reported cigarette consumption, the rs1051730-rs16969968 genotype is strongly linked to tobacco exposure through cotinine levels.

This research is significant because past studies were generally based on the participant's self-reported smoking habits, but this could have led to overlooking certain links.

 

Scientists "crack the code" of Cancer

Scientists have provided the genetic code of two types of common cancers, skin and lung cancer. They have been able to catalogue each error or abnormalities of the DNA present in a skin cancer called melanoma as well as lung cancer. The DNA code for the melanoma contained more than 30,000 types of errors and the lung cancer included more than 23,000 errors. In the case of the melanoma these errors are caused by too much sun exposure, while in lung cancer the errors are caused by cigarette smoke. Cracking this genetic code will give scientists great insight in treatments and development of cancer. For example, with this code experts can figure out that a typical smoker gains one new mutation or error for every 15 cigarettes they smoke, some of which can trigger cancer. These lists of errors can be studied to find precisely which environmental factors trigger different cancers. These lists can also be highly useful in the treatment of cancer. Researchers will be able to develop drugs that treat specific mutated genes and accordingly treat patients with specific genome mutations as well as develop tests to identify tumors much earlier. Scientists from around the world are already working on cataloguing the genes of other types cancer in hopes of new, similar treatment methods. Japan is working at liver cancer, India is working on mouth cancer, China is studying stomach cancer, the UK is studying breast cancer, and the US is looking at cancers of the brain, ovary, and pancreas. It is going to take an estimated five years to complete but cracking this genetic code is a big step in cancer research.

The Smoking Addiction Gene Complex

By studying the DNA marker profiles of smokers versus non-smokers it is clear to see variants among smokers that may trigger key smoking behaviors. An international research team associated three genes that contribute to the number of cigarettes smoked per day, one gene associated with the smoking initiation, and one other gene associated with smoking cessation (quitting). These variants lie on Chromosome 15, which has previously been linked to heavy smoking and nicotine dependence, in an area that also holds genes for nicotinic receptor genes.

These researchers gathered much data from the genome-wide association studies (GWAS) to effectively  link specific genes to smoking addiction. Because smoking is associated with many diseases like heart disease and cancer, GWAS was able to supply a lot of data that can help test the links between genetic variants and smoking in one single study.



At this time, testing one's genome for variants can not do anything to provide treatment for smoking addictions. Hopefully with more data, possible gene therapies can be used to increase the rate of smoking cessation among addicts.

 

The Genetics of Smoking

It is a well known fact that the carcinogenic properties of tobacco products can lead to lung cancer; however, genetic researchers are now suggesting a gene related to the tendency to smoke. Researchers at Icelandic deCODE say that portions of chromosome fifteen have certain SNPs, or single nucleotide polymorphisms, that attract the nicotine molecule. The researchers conducted a study of 13,945 smokers from Iceland and concluded that all of the severe smokers had a base pair involving a T in this loci, a correlation between a gene and smoking. In addition it was also found that having a T was popular amongst those who had been diagnosed with lung cancer. Although a relationship was found between the T variation and the likelihood of smoking, the researchers stated that it is not a precise indication as to whether or not someone would begin to smoke. However, it is still interesting to see that there may be a connection between our genes and our susceptibility to become a heavy smoker and even develop lung cancer.

Milk thistle extract helps cure lung cancer in mice

Researchers at the University of Colorado cancer center have recently conducted studies on a new relatively nontoxic substance; silibinin. Silibinin, a substance in milk thistle, has been found to inhibit the STAT1 and STAT3 upstream signal that leads to the expression of COX2 and iNOS, along with helping to decrease the spread of lung cancer. Both this findings have been researched and tested with in laboratory mice. The expression of COX2 and iNOS both increase production of tumor growth. The article concluded by quoting Alpna Tyagi “what was discovered is that STAT1 and STAT3 may be promising therapeutic targets in the treatment of lung cancer, no matter how you target them” and treatments that occur naturally, like silibinin, can aid in curing common illnesses.