Breast cancer accounts for nearly 1 in 3 cancers diagnosed in U.S. women [2]. In October 2010, the National Breast Cancer Coalition (NBCC) called for a vaccine for breast cancer with a deadline of 2020. Almost a year later, GE’s healthymagination initiative has also focused on breast cancer with a target of 2020.

Modeled after GE’s ecomagination challenge, which resulted in over 5,000 submitted ideas and $134 million in investments and partnerships by GE, the new healthymagination challenge focuses on improving early detection of breast cancer at the molecular level. GE’s first healthymagination Challenge is an open call to action for oncology researchers, businesses, students, and healthcare innovators. Through the Challenge, GE and its venture capital partners will award up to $100 million to fund the best ideas to improve breast cancer diagnostics. The are several goals to the Challenge:

1. Improve early breast cancer detection and allow for more accurate diagnosis
2. Better understand tumors associated with triple negative breast cancer, which is less responsive to standard treatments and is typically more aggressive
3. Better understand the molecular similarities between breast cancer and other solid tumors

Jeff Immelt, CEO and Chairman, GE, said [3]:

We envision a day when cancer is no longer a deadly disease. When you add our cutting edge cancer detection technologies to the innovative ideas of our new partners, it’s a powerful formula for tackling cancer and helping doctors and researchers improve care.

In partnership with O’Reilly Media, the effort will also feature a special focus on data (CEO and founder, Tim O’Reilly, is an advocate for using data science to spur innovation). A series of code-a-thons or “data challenges” will be held to engage the data science community in finding new applications for breast cancer data.

To enable analysis and further accelerate innovation, GE is also investing in the development of a first-in-kind “super database” that will consolidate clinical, pathology, therapy and outcomes data. The database will be available in collaboration with leading cancer research organizations, as well as NGO and government groups, starting with relevant cancer data from GE’s Medical Quality Improvement Consortium (MQIC); Clarient, a cancer diagnostics and GE Healthcare Company; The Premier healthcare alliance; and the U.S. Department of Health & Human Services.

In addition, Immelt also said that GE will invest $1 billion over the next five years on research and development programs to expand its suite of advanced technologies and solutions for cancer detection and treatment. At the September event, GE presented several new technologies:

1. GE SenoCase, a new concept in mobile mammography that will deliver breast cancer screening capabilities to millions of women around the world who lack access to existing screening options
2. GE PET Tracer, a new Positron Emission Tomography (PET) tracer technology in development that will inform doctors if cancer treatments are working, very early in the course of treatment, by measuring new blood vessel formation in tumors
3. GE SenoBright Contrast Enhanced Spectral Mammography (CESM), a technique that helps radiologists localize a known or suspected breast cancer lesion

Lastly, GE announced a three-year partnership with Susan. G Komen for the Cure to forge first-in-kind programs that bring the latest breast cancer technologies to more women in the United States and around the world. Initially, these programs will run in Wyoming (one of the most rural states in the U.S.), Saudi Arabia and China.

GE will publicly track progress against this cancer initiative at healthymagination.com.

References

1. GE Launches New Commitment to Accelerate Cancer Fight: Integrated Tech Portfolio and Collaboration with Doctors and Researchers to Deliver Better Care to 10M Patients by 2020. GE reports. 2011 Sep 15.
2. Breast Cancer Facts & Figures 2011-2012. American Cancer Society. Accessed 2011 Nov 17.
3. GE and Partners Aim to Speed Fight Against Cancer, Starting with Breast Cancer. Healthymagniation press release. 2011 Sep 15.

One of the major differences between this most recent study and previous analyses of the relationship between alcohol and breast cancer is that the new study was very high-power, meaning that the number of participants was quite large (nearly 75,000 women). The sheer number of study subjects allowed researchers to determine the relationship between low-level drinking and cancer risk with much higher confidence than previous studies, with their fewer participants, had allowed. Another strength of the new study is that it was longitudinal, taking place over 28 years. However, the participants were not assigned to treatment conditions, and the researchers relied upon self-report to track alcohol consumption. Both of these somewhat weaken the results of the study, though in largely unavoidable ways. Self-report relies upon participants to accurately report their alcohol consumption, and can result in inaccurate data if participants misremember or misrepresent their drinking. Further, study results are generally more powerful and more easily generalized to the population if participants are assigned randomly to conditions. Assigning participants helps to remove confounding factors that could partially or fully explain the results. For instance, the researchers reported that the majority of women who drank a moderate amount of alcohol on a regular basis had lower BMI, were more likely to have had natural menopause, and were more likely to be smokers.

Any one of these factors might have impacted breast cancer risk (smoking is the one with the most obvious plausible mechanism), or an unidentified third variable that occurred more commonly among low to moderate drinkers could have increased risk of breast cancer.

The results of the JAMA study are interesting, and certainly support the results of many other studies: cancer risk increases with increasing alcohol consumption. However, the results of this study aren’t necessarily reason in and of themselves to cease all alcohol consumption. Studies also suggest that low to moderate alcohol consumption (about 1-2 drinks per day for men, and one drink per day for women) increases HDL and decreases risk of cardiovascular disease, heart attack and stroke [5,6]. This is because regular, limited amounts of alcohol prevent the buildup of smooth muscle cells in blood vessels that leads to the narrowing of the arteries.

While breast cancer certainly gets more media attention than heart disease, especially where it comes to women’s health, the U.S. Centers for Disease Control and Prevention (CDC) report that heart disease is the number one cause of death in women, resulting in more than a quarter of all female deaths. In an article written for the journal Circulation, Dr. Rose Marie Robertson discusses the misperceptions that so many women have about the relative dangers of health threats [7]. She notes that the vast majority of women believe cancer is their greatest health threat, while fewer than 10% recognize heart disease as such.

Therefore, while few doctors would recommend introducing alcohol for the sole purpose of lowering the risk of heart disease (since alcohol consumption is associated with a number of negative health effects), it would be shortsighted to cease moderate alcohol consumption for the purpose of preventing breast cancer, given its positive impact on the heart. To their credit, the authors of the new JAMA study recognize this, and advise women to talk to their doctors about alcohol, breast cancer, and heart disease.

References

1. Chen et al. Moderate Alcohol Consumption During Adult Life, Drinking Patterns, and Breast Cancer Risk. JAMA. 2011 Nov 2;306(17):1884-1890.
   View abstract
2. Smith-Warner et al. Alcohol and breast cancer in women: a pooled analy- sis of cohort studies. JAMA. 1998 Feb 18;279(7):535-40.
   View abstract
3. Dumeaux et al. Useoforalcon- traceptives, alcohol, and risk for invasive breast cancer. Cancer Epidemiol Biomarkers Prev. 2004 Aug;13(8):1302-7.
   View abstract
4. Longnecker et al. Risk of breast cancer in relation to lifetime alcohol consumption. J Natl Cancer Inst. 1995 Jun 21;87(12):923-9.
   View abstract
5. Ronksley et al. Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ. 2011 Feb 22;342:d671. doi: 10.1136/bmj.d671.
   View abstract
6. De Oliveira E Silva et al. Alcohol consumption raises HDL cholesterol levels by increasing the transport rate of apolipoproteins A-I and A-II. Circulation. 2000 Nov 7;102(19):2347-52.
   View abstract
7. Robertson RM. Women and cardiovascular disease: the risks of misperception and the need for action. Circulation. 2001 May 15;103(19):2318-20.
   View abstract

Anna Barker’s TEDMED talk last year focused on the history of The War on Cancer, her projects within the National Cancer Institute, and where research is badly needed. TEDMED is a three day annual conference where cutting-edge science and technology leaders “connect, understand and inspire” to advance the art of health and medicine with new ideas, the latest science and innovative technology. Barker’s talk provides a brief history on The War on Cancer and an overview on a number of cancer programs initiated over the last decade. Check out Anna Barker’s talk below.

References

1. World Cancer Report 2008. International Agency for Research on Cancer. World Health Organization. 2008.
2. Cancer. World Health Organization. Accessed 2011 Nov 1.
3. Global Economic Cost of Cancer. American Cancer Society. 2010 Aug 16.
4. Anna Barker joins ASU to lead Transformative Healthcare Networks. ASU News. 2011 Aug 31.

The American Academy of Pediatrics would like to correct false statements made in the Republican presidential campaign that HPV vaccine is dangerous and can cause mental retardation. There is absolutely no scientific validity to this statement. Since the vaccine has been introduced, more than 35 million doses have been administered, and it has an excellent safety record.

The American Academy of Pediatrics, the Centers for Disease Control and Prevention, and the American Academy of Family Physicians all recommend that girls receive HPV vaccine around age 11 or 12. That’s because this is the age at which the vaccine produces the best immune response in the body, and because it’s important to protect girls well before the onset of sexual activity. In the U.S., about 6 million people, including teens, become infected with HPV each year, and 4,000 women die from cervical cancer. This is a life-saving vaccine that can protect girls from cervical cancer.

References

1. American Academy of Pediatrics Statement on HPV Vaccine. American Academy of Pediatrics news release. 2011 Sep 13.

Scientists have discovered that individuals who carry a mutation in a gene called BRCA1-associated protein 1 (BAP1) are susceptible to developing two forms of cancer — mesothelioma and melanoma of the eye. When these individuals are exposed to asbestos or similar mineral fibers, their risk of developing mesothelioma, an aggressive cancer of the lining of the chest and abdomen, may be markedly increased.

Mesothelioma tumors are typically associated with asbestos and erionite exposure. Erionite is a naturally occurring mineral fiber similar to asbestos that is found in rock formations and volcanic ash. Deposits have been located in at least 12 states. However, unlike asbestos, erionite is not currently regulated by the U.S. Environmental Protection Agency as one of the six asbestos fibers [2]. Only a small percentage of people exposed to asbestos or erionite actually develop mesothelioma.

Mesothelioma is one of the deadliest forms of cancer, killing approximately 3,000 people each year in the United States, with half of those diagnosed dying within one year. Moreover, rates of new cases of mesothelioma in parts of the world, including Europe and China, have risen steadily over the past decade.

Michele Carbone, M.D., Ph.D., study co-leader and director of the University of Hawaii Cancer Center, said [3]:

This discovery is a first step in understanding the role of the BAP1 gene and its potential utility when screening for mutations in those at high risk. Identifying people at greatest risk for developing mesothelioma, especially those exposed to dangerous levels of asbestos and erionite worldwide, is a task made easier by virtue of this discovery.

Joseph R. Testa, Ph.D., study co-leader and Carol and Kenneth E. Weg chair in Human Genetics at Fox Chase Cancer Center, added [3]:

This is the first study to demonstrate that individual genetic makeup can greatly influence susceptibility to mesothelioma. People exposed to dangerous levels of asbestos or erionite, those with a strong family history of mesothelioma, or those who have been previously diagnosed with a rare tumor of the eye known as uveal melanoma, may benefit from this new discovery.

The researchers focused on two US mesothelioma families — one in Wisconsin and one in Louisiana — in which members were not exposed to asbestos or erionite. Family members developed a number of malignancies, including breast, ovarian, pancreatic and renal cancers, although mesothelioma predominated.

The scientists suspected that mutations in the BAP1 gene might underlie mesothelioma in people with a strong family history of the disease after noticing genetic changes in or near other stretches of DNA where the BAP1 gene is located. Looking more closely at two families with unusually high rates of mesothelioma, they saw that every person who had provided a sample and had developed mesothelioma or melanoma of the eye also carried mutations in the BAP1 gene. Further study led to sequencing the gene in 26 individuals who had developed mesothelioma but did not have a family history of the disease. Tumors from about 25 percent of this group carried mutations in the BAP1 gene, and in two cases the mutations were inherited. Both of the individuals with inherited mutations had previously developed melanoma of the eye.

The researchers hypothesize that when individuals with BAP1 mutations are exposed to asbestos, mesothelioma predominates over melanoma of the eye. Alternatively, the BAP1 mutation alone may be sufficient to cause mesothelioma, providing a cause for tumors that arise spontaneously without previous environmental exposure.

References

1. Testa et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nature Genetics. Published online 2011 Aug 28.
   View abstract
2. Erionite. North Dakota Departement of Health. Accessed 2011 Aug 29.
3. NIH-funded researchers discover genetic link to mesothelioma. NIH News press release. 2011 Aug 28.

NBC Nightly News aired an intriguing story last night about dogs who have the ability to detect ovarian cancer [1]. The story referenced a new study published in the European Respiratory Journal that focused on canine scent detection for the diagnosis of lung cancer [2].

The outcome of a patient with lung cancer, like many other cancers, depends in large part on early diagnosis. Exhaled breath of patients may represent the ideal lab specimen for cancer screening. However, current diagnostic sensor technologies are unable to identify a clear target. German scientists used four sniffer dogs to test the strength of the presence of an as-of-yet unknown compound in the breath of patients with lung cancer.

That as-of-yet unknown compound is a biomarker — a protein or set of proteins specific to lung cancer that, by nature of the tumor being in a patient’s lungs, is exhaled.

In the study, researchers had patients with blow into test tubes filled with a fleece material that absorbs compounds suspended in the breath. Following a rigid scientific protocol, sniffer dogs were presented with exhalation samples from either 110 healthy individuals, 60 patients with confirmed lung cancer or 50 patients with chronic obstructive pulmonary disease (COPD). The dogs were trained to lie down next to test tubes that came from patients with lung cancer. Scientists analyzed patient history, drug administration and clinicopathological data to identify potential bias or confounders.

The results are impressive. Lung cancer was identified by the four dogs with an overall sensitivity of 71% and a specificity of 93%.

The detection of lung cancer was independent of the patient having COPD as well as the presence of tobacco smoke and food odors.

Although two drugs were identified as potential cofounders — meaning the dogs may have been detecting drugs used to treat lung cancer rather than the cancer itself — the results are still intriguing. Researchers are working on a follow-up study to determine if the dogs react to other types of cancer [3].

Check out a video of the NBC News story below:

References

1. Trained dogs can help detect cancer. NBC Nightly News. 2011 Aug 18.
2. Ehmann et al. Canine scent detection in the diagnosis of lung cancer: Revisiting a puzzling phenomenon. Eur Respir J 2011. Published ahead of print.
3. Fine dog noses sniff out lung cancer. Robert-Bosch-Krankenhaus. 2011 Aug 18.

Neurofibromatosis (NF) is a genetically-inherited disorder that causes tumors to grow on nerve tissue. There are three main types of NF tumors: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis. NF1 is the most frequent of the three tumor types affecting one in every 3,000 people. The severity of symptoms range from benign ‘cafe au lait’ patches on the skin, to small dermal tumors on the surface of the skin, to larger “plexiform” neurofibromas that are associated with deep nerve structures, to malignant tumors of the nerve sheath.

Previous studies have shown that loss of the gene neurofibromin (Nf1) during mouse embryo development causes defects in bone and cartilage development [2-3]. One of the observed changes was an increase in the expression of the transcription factor SRY-BOX 9 (SOX9), which regulates cartilage differentiation and was recently found to be highly expressed in NF1-related tumors supporting cell survival [4]. German researchers hypothesized that some of the cartilage specific genes regulated by SOX9 might prove to be relevant biomarkers of NF1 tumors. They tested this hypothesis by analyzing expression of the SOX9 target gene melanoma-inhibitory activity (MIA) in tumor and serum samples from NF1 patients.

In a mouse Nf1 model, Mia was expressed at higher levels than in control mice. In humans, MIA was expressed in all tumors from NF1 patients. MIA serum level was determined in 42 NF1 patients and in 22 healthy individuals. Linear regression analysis revealed an association between total internal tumor load and the number of subcutaneous tumors (i.e. tumors under the skin).

Serum levels were significantly higher in NF1 patients than in healthy controls. MIA serum levels were significantly higher in NF1 patients with plexiform neurofibromas and with high tumor load than in patients without such tumors. Notably, MIA serum levels correlated significantly with internal tumor burden. The data indicate that elevated MIA serum level may be indicative of an increased internal tumor load.

Since there was an observed association between total internal tumor load and the number of plexiform tumors, a larger study will be necessary to reveal the relative contributions of internal, subcutaneous and possibly also cutaneous tumors to elevated MIA levels. Provided that the correlation can be confirmed in a larger cohort of NF1 patients, MIA could be a valuable biomarker for internal tumor load.

References

1. Kolanczyk et al. MIA is a potential biomarker for tumor load in neurofibromatosis type 1. BMC Med. 2011 Jul 4;9(1):82. [Epub ahead of print]
   View abstract
2. Kolanczyk et al. Multiple roles for neurofibromin in skeletal development and growth. Hum Mol Genet 2007, 16:874- 886.
   View abstract
3. Elefteriou et al. ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab 2006, 4:441-451.
   View abstract
4. Miller et al. Integrative genomic analyses of neurofibromatosis tumours identify SOX9 as a biomarker and survival gene. EMBO Mol Med 2009, 1:236-248.
   View abstract

The cooperative research and development agreement has been established as a shared commitment to move therapies for rare blood cancers into clinical proof-of-concept studies so that promising treatments can eventually be commercialized. The agreement is among the University of Kansas Medical Center, The Leukemia & Lymphoma Society (LLS), the NIH Therapeutics for Rare and Neglected Diseases (TRND) program and the Hematology Branch within the National Heart, Lung and Blood Institute (NHLBI).

Christopher P. Austin, M.D., director of the TRND program, currently administered by the National Human Genome Research Institute, a part of NIH, said:

The goal of this collaboration, called The Learning Collaborative (TLC) is to bridge the gap in time and resources that often exists between basic research and human testing of potential new treatments and accelerate and make more efficient the delivery of improved therapies to patients with rare blood cancers. As a result of our work, as the TLC name implies, we plan to learn more about and improve the drug development process for all diseases.

Roy A. Jensen, M.D., director of The University of Kansas Cancer Center, added:

This agreement recognizes that academic, philanthropic and patient organizations have a role — and a responsibility — to be active leaders in the drug discovery process. I hope this agreement can serve as a model to other academic and patient communities.

The collaboration’s first project is a pilot effort under the TRND program that focuses on further development of an existing small molecule drug used to treat arthritis called auranofin. Auranofin will be evaluated as a treatment for relapsed chronic lymphocytic leukemia (CLL) — one of the four major types of leukemia and one that typically affects older people. The goal is to accelerate the development of this drug and complete preclinical through clinical trial studies within two years, at which time an industry partner will be engaged.

Approximately 15,000 people in the United States receive a diagnosis of CLL each year. CLL is currently treated with various chemotherapies, but patients eventually reach a stage where they become resistant to this treatment and can die as a result. In addition, chemotherapy can be quite toxic, whereas auranofin has received regulatory approval and was demonstrated to be reasonably safe and effective in the treatment of arthritis.

Adrian Wiestner, M.D., Ph.D., an investigator in the NHLBI’s Hematology Branch, said:

Chronic lymphocytic leukemia is a complex disease that, while treatable, cannot be cured with chemotherapy. There is an especially urgent need to develop novel therapies for chemotherapy-resistant disease, and through this agreement the Hematology Branch can bolster its clinical and translational research program in this disease as well as other hematologic conditions with unmet clinical needs.

Dr. Louis J. DeGennaro, Ph.D., LLS executive vice president and chief mission officer, said:

Development of new therapies for diseases like the blood cancers poses both scientific and economic challenges. Partnerships are the key to addressing this significant unmet medical need and LLS is proud to add our expertise to this collaboration.

The Institute for Advancing Medical Innovation (IAMI) at the University of Kansas, focuses on research and education with an emphasis on product development and commercialization of novel medical innovations to accelerate the numbers and quality of new drugs and devices, and ensures an entrepreneurial focus of the next generation of innovators. IAMI leverages the Kansas region’s impressive history in drug development by partnering with nearby companies to perform all the functions needed to take innovative products to market.

The Leukemia & Lymphoma Society (LLS) is the world’s largest voluntary health organization dedicated to funding blood cancer research, education and patient services. LLS’s mission: cure leukemia, lymphoma, Hodgkin’s disease and myeloma, and improve the quality of life of patients and their families. Since the first funding in 1954, LLS has awarded more than $700 million in research funding.

The National Institutes of Health (NIH) Therapeutics for Rare and Neglected Diseases (TRND) program is a congressionally mandated program to encourage and speed the development of new drugs for rare and neglected diseases. This unique program creates a drug development pipeline within the NIH and is specifically intended to stimulate research collaborations with academic scientists, non-profit organizations, and pharmaceutical and biotechnology companies working on rare and neglected illnesses. The TRND program provides an opportunity to partner with, and gain access to, drug development scientific capabilities, expertise and resources in a collaborative environment with the goal of moving promising therapeutics into clinical testing.

Source: NIH News

In December 2010, VBI researchers discovered a four-nucleotide repeat (AAAG) in the estrogen-related receptor gamma (ESRRG) gene, which indicates an individual’s genetic susceptibility to breast cancer [2]. Longer DNA sequences of the repetitive microsatellite were much more likely to be present in breast cancer patients than healthy volunteers; patients with a greater number of copies of the repeat in the promoter region of the ESRRG gene have a 3-fold higher cancer susceptibility rate than those who do not.

In the present study, instead of focusing on a single gene, the scientists created a design for a new DNA microarray that allowed them to measure the over 2 million microsatellites in the human genome in a single experiment. They evaluated the global microsatellite content in the genomes of 72 cancer, cancer-free, and high risk patient and cell line samples.

A unique, reproducible and statistically significant motif of 18 pattern-specific microsatellite families was identified in germline and tumor DNA from breast cancer patients but not in germline DNA of cancer-free patients or in breast cancer patients with BRCA1 or BRCA2 mutations.

These 18 pattern-specific microsatellite families suggest a new mechanism disrupting the genome in cancer patients and may represent a new breast cancer risk biomarker.

The repetitive motifs were also more pronounced in the germlines and tumors of colon cancer tumor patients (3/6 samples) and microsatellite unstable colon cancer cell lines. Although there were only 9 colon cancer samples, it suggests a more general role for microsatellites in the genome. The pattern on the microarray serves as the biomarker that can measure the amount of risk an individual has for developing cancer in the future.

Harold “Skip” Garner, VBI executive director who leads the institute’s Medical Informatics and Systems Division, explained:

We have now arrived at a new biomarker — an indicator that could be used to evaluate the amount of risk that you have for developing cancer in the future. This is part of an effort to understand their (microsatellite) role in the genome and then proceed on directly towards something that is of utility in the clinic. What just came out in our paper is a description of the technology that allows us to very quickly and efficiently and inexpensively measure these two million places using a uniquely designed microarray … It’s the pattern on that microarray that provides us the information we need.

You can watch an interview with Dr. Garner discussing the research and its future implications below:

References

1. Galindo et al. Sporadic breast cancer patients’ germline DNA exhibit an AT-rich microsatellite signature. Genes Chromosomes Cancer. 2011 Apr;50(4):275-83. doi: 10.1002/gcc.20853. Epub 2011 Jan 14.
   View abstract
2. Genetic Biomarker for Risk of Breast Cancer Identified in “Junk” DNA. Biomarker Commons. 2010 Dec 20.

In the 1980s, a mutated kinase was identified that caused white blood cells to grow in this uncontrolled manner and caused chronic myeloid leukemia (CML). The mutated kinase is a hybrid formed from two halves of different proteins that is created when pieces of chromosome 9 and 12 switch segments in white blood cells. The drug imatinib was developed in the 1990s by Brian Druker of Oregon Health and Science University and Charles Sawyers of Memorial Sloan Kettering to block this mutant kinase, called BCR-ABL (breakpoint cluster region — abelson murine leukemia viral oncogene homolog 1). In the years that it has been on the market, imatinib (marketed by Novartis as Gleevec) has transformed CML from a death sentence — patients were often given three to five years to live after diagnosis — to a manageable condition, with a five year survival rate exceeding 90%.

Similar fusion genes (and proteins) have since been found in other blood cancers but had not been detected in solid tumors, such as those affecting the breast, prostate, colon, lung, and pancreas, thyroid, kidney and brain. Such solid tumors account for 80% of cancer deaths in the U.S. Some researchers thought that there were no fusions in solid tumors, while others thought they might be there but were more difficult to find because of the many chromosomal defects in these cancers. But in 2005 Arul Chinnaiyan at the University of Michigan found the first gene fusions in a solid tumor, in prostate tumors [1]. Since then he has found more in breast and stomach cancer and myeloma. And in 2007 Hiroyuki Mano and his group at the Japan Science and Technology Agency found one in non-small-cell lung cancer [2]. This fusion, EML4-ALK (echinoderm microtubule associated protein like 4 — anaplastic lymphoma kinase), is a tyrosine kinase like BCR-ABL. And like BCR-ABL, its formation drives tumor formation; so blocking it should halt tumor growth. Crizotinib, being developed by Pfizer, is a drug that blocks fusion proteins of anaplastic lymphoma kinase (ALK).

Three research studies in the October 28, 2010 issue of the New England Journal of Medicine (NEJM) highlight crizotinib’s therapeutic potential. Kwak et al. describe a study of 1,500 patients with non-small cell lung cancer [3]. Five-and-a-half percent of them had a fusion containing ALK, like the initial EML4-ALK fusion identified in Japan. Interestingly, most of the patients with the ALK fusions were non-smokers and their cancers were adenocarcinomas (meaning a cancer of epithelial tissue). Over 90% of these patients had already undergone at least one line of therapy, but even so, 57% of them responded well to crizotinib. Butrynski et al. report that crizotinib can also help patients with rarer cancers, like inflammatory myofibroblastic tumor (IMT) [4]. ALK rearrangements have been documented in about half of IMTs.

Unfortunately, though perhaps not surprisingly, drugs like crizotinib and Gleevec cannot be the last line of defense. Once they are administered, the kinases they target can mutate to resistant them. The third research study published in the NEJM, by Choi et al., enumerates the mutations in EML4-ALK that confer such resistance to crizotinib [5]. Additional kinase inhibitors are being developed to act as backup therapies for both crizotinib and Gleevec once drug resistance has occurred.

Although mutant kinase fusion proteins may cause only a small fraction of tumors, they still affect many people. If five percent of all patients with non-small cell lung cancer end up being positive for an ALK fusion, as suggested by the study of Kwak et al., that translates into 10,000 people every year in the U.S. alone. Crizotinib can also be used to fight ALK-positive non-Hodgkin’s lymphoma and neuroblastoma, a childhood cancer in which 10% of patients have mutations in ALK. Erlotinib is a kinase inhibitor targeting a different mutation that promotes tumor formation in another subset of non-small cell lung cancer patients. And a recent clinical trial of yet another kinase inhibitor made by Roche, RG7204, has had dramatic success targeting a specific mutation in advanced melanoma. But key to the success of these kinase inhibitors is ensuring that they are given to the patients harboring the appropriate mutations.

Although the treatment of cancer based on gene expression profiling has been used by oncologists in the clinic, currently there does not seem to be a method for determining which mutations caused a given tumor using morphological or histological means; molecular diagnostics are required. Such diagnostics will allow physicians to personalize medication regimens based an individual’s unique genetic makeup. With personalized medicine, therapeutic options can be chosen based on evidence, rather than instinct. Genotyping tumors should become standard practice in deciding which therapeutics to use against them. In the future, every cancer causing mutant will have a drug designed specifically to combat it and cancer therapy can be truly personalized.

References

1. Tomlins et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005 Oct 28;310(5748):644-8.
   View abstract
2. Soda et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007 Aug 2;448(7153):561-6. Epub 2007 Jul 11.
   View abstract
3. Kwak et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 Oct 28;363(18):1693-703.
   View abstract
4. Butrynski et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010 Oct 28;363(18):1727-33.
   View abstract
5. Choi et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010 Oct 28;363(18):1734-9.
   View abstract