a bio blog about genetics, genomics, and biotechnology
Posts Tagged ‘cancer’
Josh: So while this research is very interesting, I would first like to call attention to biologists’ odd sense of humor. Apparently, SMAD4 stands for “Mothers against decapentaplegic homolog 4”. This is obviously some type of a joke made from MADD, but the bizarre sense of humor doesn’t stop here. Who can forget the signaling molecule Sonic Hedgehog (SHH), bride of sevenless (BOSS), frizzled, dishevelled, amongst many others that are escaping me at the moment.
Tumour suppressor genes do not necessarily require both alleles to be knocked out before disease phenotypes are expressed. Research published in BioMed Central’s new open access journal PathoGenetics reveals that only one allele of SMAD4 has to be damaged to put a person at risk of pancreatic and colorectal cancer.
Riccardo Fodde led a team of researchers from Erasmus MC, Rotterdam, who investigated SMAD4, a tumor suppressor gene implicated in pancreatic and colorectal cancer. They found that having one mutated SMAD4 allele was associated with the development of gastrointestinal polyps. This research is the first to address the molecular and cellular consequences of SMAD4 damage on a genome-wide scale.
This high quality research is typical of that which will be published in PathoGenetics, an open access journal created to meet the need for a resource focused solely on the pathogenesis of genetic diseases. The journal’s co-Editors in Chief are Professor Stylianos Antonarakis and Professor Andrea Ballabio. Ballabio said, “PathoGenetics will give scientists a unique opportunity to publish exciting research on the molecular mechanisms underlying the manifestations of disease phenotype”.
PathoGenetics will focus on both in vitro and in vivo studies on the cascade of events leading from gene mutations or genomic rearrangement to disease. The discovery of novel molecular and metabolic pathways relevant to disease pathogenesis will be given specific emphasis. The first issue includes a review by James Lupski and colleagues that deals with mechanisms for human genomic rearrangements and a groundbreaking piece on the methodology of knock-in vector construction by Nicholas Hastie and colleagues. According to Antonarakis, “Given its unique characteristics, PathoGenetics is likely to become the ideal journal for scientists from different backgrounds to publish and read exciting research on disease pathogenesis”.
Source: BioMed Central
Smad4 haploinsufficiency: a matter of dosage. Paola Alberici, Claudia Gaspar, Patrick Franken, Marcin M Gorski, Ingrid de Vries, Rodney J Scott, Ari Ristimäki, Lauri A Aaltonen, Riccardo Fodde. PathoGenetics 2008, 1:2 (3 November 2008)
Kevin: Our growing understanding that some cancers are viral in origin starts to make cancer seem a lot less mysterious. I’m optimistic about continued progress in this important area.
University of Pittsburgh scientists are uncovering more evidence that a virus they recently discovered is the cause of Merkel cell carcinoma, an aggressive and deadly form of skin cancer.
The findings, published in this week’s early online edition of the Proceedings of the National Academy of Sciences, put to rest the possibility that MCV infects tumors that already have formed. If that were the case, the virus would be a passenger rather than the driver of the disease.
Experiments in human tumors reveal that the cancer develops in two steps: during infection, the Merkel cell polyomavirus, or MCV, integrates into host cell DNA and produces viral proteins that promote cancer formation. Tumors occur when a mutation removes part of a viral protein needed for the virus to reproduce and infect other healthy cells, explained senior investigator, Patrick Moore, M.D., M.P.H, professor of microbiology and molecular genetics at the School of Medicine and director of the Molecular Virology Program at the University of Pittsburgh Cancer Institute. The virus then can spread only as the cancer cells themselves multiply.
Clearly, “MCV infects normal cells before they turn into cancer cells,” Dr. Moore noted. “The virus could not have infected a tumor afterwards because it can no longer replicate. It looks very much like MCV is the culprit that causes the disease.”
The researchers propose two possible reasons why these mutations develop: If viral replication continues, the immune system could recognize the intruder to eliminate diseased cells, or the viral replication itself will lead to the death of the cancer cells. Both of these possibilities provide promising leads to find better ways to kill Merkel cell cancer cells without harming healthy tissues.
Also, “this research shows evolution within tumors on a molecular level,” Dr. Moore pointed out. “You can see the specific molecular steps.” The team’s current work could account for known risk factors for Merkel cell carcinoma such as UV exposure and ionizing radiation, which damage DNA and can lead to the viral mutations.
Merkel cell cancers are rare, occurring in about 1,500 Americans annually. Half of patients who have advanced disease die within nine months of diagnosis, and two-thirds die within two years. The elderly and people with compromised immune systems are at greater risk of developing the cancer, which arises in skin nerve cells that respond to touch or pressure.
In a paper published in Science in January, Dr. Moore and his wife, Dr. Yuan Chang, who co-directs their lab, reported their identification of the virus and that it could be found in 80 percent of Merkel cell tumors. They cautioned that although up to 16 percent of the population carries MCV, very few will develop cancer.
There is no treatment for MCV infection right now, but identifying the agent and understanding how it triggers disease could lead to targeted interventions, Dr. Moore said.
Source: University of Pittsburgh Schools of the Health Sciences
The original paper: Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma. Huichen Feng, Masahiro Shuda, Yuan Chang, Patrick S. Moore. Science 22 February 2008:Vol. 319. no. 5866, pp. 1096 – 1100
The followup discussed here will be appearing in the upcoming early edition of the PNAS.
Josh: I’ve been waiting for a study such as this to come out. We will never be able to successfully fight off cancer with drugs alone. Cancer is a normal part of life; many cells in each of our bodies are cancerous, but our immune systems successfully destroy them. When people are actually diagnosed with cancer, the immune system for some reason stopped recognizing the cells as cancerous. This technique basically fixes that, allowing the body to fight it off. I’m not surprised in the slightest that all traces of cancer were gone.
The next step is to try this in humans, probably just testing the immune response first, then introducing it to some cancer patients. I see no reason why this can’t be applied to all other types of cancer, as long as they have some type of unique, recognizable receptor or surface marker.
Perhaps I’m just an optimist, but I’m holding out hope that this is the beginning of the end of the search for a cure to cancer.
Researchers at Wayne State University have tested a breast cancer vaccine they say completely eliminated HER2-positive tumors in mice – even cancers resistant to current anti-HER2 therapy – without any toxicity.
The study, reported in the September 15 issue of Cancer Research, a journal of the American Association for Cancer Research, suggests the vaccine could treat women with HER2-positive, treatment-resistant cancer or help prevent cancer recurrence. The researchers also say it might potentially be used in cancer-free women to prevent initial development of these tumors.
HER2 receptors promote normal cell growth, and are found in low amounts on normal breast cells. But HER2-positive breast cells can contain many more receptors than is typical, promoting a particularly aggressive type of tumor that affects 20 to 30 percent of all breast cancer patients. Therapies such as trastuzumab and lapatinib, designed to latch on to these receptors and destroy them, are a mainstay of treatment for this cancer, but a significant proportion of patients develop a resistance to them or cancer metastasis that is hard to treat.
This treatment relied on activated, own-immunity to wipe out the cancer, says the study’s lead investigator, Wei-Zen Wei, Ph.D., a professor of immunology and microbiology at the Karmanos Cancer Institute.
“The immune response against HER2-positive receptors we saw in this study is powerful, and works even in tumors that are resistant to current therapies,” she said. “The vaccine could potentially eliminate the need to even use these therapies.”
The vaccine consists of “naked” DNA – genes that produce the HER2 receptor – as well as an immune stimulant. Both are housed within an inert bacterial plasmid. In this study, the researchers used pulses of electricity to deliver the injected vaccine into leg muscles in mice, where the gene produced a huge quantity of HER2 receptors that activated both antibodies and killer T cells.
“While HER2 receptors are not usually seen by the immune system when they are expressed at low level on the surface of normal cells, a sudden flood of receptors alerts the body to an invasion that needs to be eliminated,” Wei said. “During that process, the immune system learns to attack cancer cells that display large numbers of these receptors.”
They also used an agent that, for a while, suppressed the activity of regulatory T cells, which normally keeps the immune system from over-reacting. In the absence of regulatory T cells, the immune system responded much more strongly to the vaccine. Then, when the researchers implanted HER2-positive breast tumors in the animals, the cancer was eradicated.
“Both tumor cells that respond to current targeted therapies and those that are resistant to these treatments were eradicated,” Wei said. “This may be an answer for women with these tumors who become resistant to the current therapies.”
Wei’s lab is the first to develop HER2 DNA vaccines, and this is the second such vaccine Wei and her colleagues have tested more extensively. The first, described in a study in 1999, formed the model of a vaccine now being tested by a major Pharmaceutical company in early phase clinical trials in the U.S. and in Europe in women with HER2-positive breast cancer.
In order to ensure complete safety, Wei says the current test vaccine uses HER2 genes that are altered so that they cannot be oncogenic. The receptors produced do not contain an “intracellular domain” – the part of the receptor that is located just below the cell surface and transmits growth signals to the nucleus. The first vaccine was also safe, she says, but contained a little more of the native HER2 receptor structure. “With this vaccine, I am quite certain the receptor is functionally dead,” she said.
“The greatest power of vaccination is protection against initial cancer development, and that is our ultimate goal with this treatment,” Wei said.
Source: American Association for Cancer Research
DNA Vaccination Controls Her-2+ Tumors that Are Refractory to Targeted Therapies. Paula J. Whittington, Marie P. Piechocki, Henry H. Heng, Jennifer B. Jacob, Richard F. Jones, Jessica B. Back, and Wei-Zen Wei. Cancer Res 2008 68: 7502-7511. doi: 10.1158/0008-5472.CAN-08-1489
Josh: This is an extremely high penetrance mutation. More doctors and physicians need to be trained to order genetic tests for mutations such as this for their patients, especially those with a family history of colorectal cancer. If someone has this mutation, chances are they are going to get colorectal cancer, so routine screenings may be enough to save their life…preventative medicine at its best.
About one-third of colorectal cancers are inherited, but the genetic cause of most of these cancers is unknown. The genes linked to colorectal cancer account for less than 5 percent of all cases.
Scientists at Northwestern University’s Feinberg School of Medicine and colleagues have discovered a genetic trait that is present in 10 to 20 percent of patients with colorectal cancer. The findings strongly suggest that the trait is a major contributor to colorectal cancer risk and likely the most common cause of colorectal cancer to date.
If a person inherits this trait — which is dominant and clusters in families — the study found the lifetime risk of developing colorectal cancer is 50 percent, compared to 6 percent for the general population. The study will be published August 14 in an advanced on-line report in the journal Science.
“This probably accounts for more colorectal cancers than all other gene mutations discovered thus far,” said Boris Pasche, M.D., a lead author of the paper and director of the Cancer Genetics Program at the Feinberg School and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Pasche also is a physician at Northwestern Memorial Hospital.
“The reasonable expectation is this finding will save some lives,” Pasche said. “We will be able to identify a larger number of individuals that are at risk of colorectal cancer and, in the long term, maybe decrease the cases of colorectal cancer and of people dying from it by being able to screen them more frequently.”
Colorectal cancer is the second leading cause of cancer death in the U.S.
The trait, which has been named TGFBR1 ASE, results in decreased production of a key receptor for TGF-beta, the most potent inhibitor of cell growth. With less of this vital protective substance to inhibit cell growth, colon cancer can more easily develop.
In 1998, Pasche and colleagues discovered the first mutation of this gene and in 1999 they showed that it was linked to a higher risk of colorectal cancer.
The results presented in this new study are the first to show that decreased production of this receptor for TGF-beta was present in 10 to 20 percent of patients with colorectal cancer. Decreased production of the same receptor was present in only 1 to 3 percent in healthy control groups.
The findings, which are based on a Caucasian population, need to be confirmed in other studies and may show strong variation between ethnic groups, Pasche said.
Pasche expects that a clinical test will soon be developed that could be offered to families with a history of colorectal cancer and other individuals to determine whether they carry this mutation.
Source: Northwestern University
Germline Allele-specific Expression of TGFBR1 Confers an Increased Risk of Colorectal Cancer. Laura Valle, Tarsicio Serena-Acedo, Sandya Liyanarachchi, Heather Hampel, Ilene Comeras, Zhongyuan Li, Qinghua Zeng, Hong-Tao Zhang, Michael J. Pennison, Maureen Sadim, Boris Pasche, Stephan M. Tanner, and Albert de la Chapelle. Science. Published online August 14 2008; 10.1126/science.1159397 (Science Express Reports)
University of Florida College of Pharmacy researchers have discovered a marine compound off the coast of Key Largo that inhibits cancer cell growth in laboratory tests, a finding they hope will fuel the development of new drugs to better battle the disease.
The UF-patented compound, largazole, is derived from cyanobacteria that grow on coral reefs. Researchers, who described results from early studies today (Aug. 7) at an international natural products scientific meeting in Athens, Greece, say it is one of the most promising they’ve found since the college’s marine natural products laboratory was established three years ago.
An initial set of papers in the Journal of the American Chemical Society also has garnered the attention of other scientists, and the lab is racing to complete additional research. The molecule’s natural chemical structure and ability to inhibit cancer cell growth were first described in the journal in February and the laboratory synthesis and description of the molecular basis for its anticancer activity appeared July 2.
“It’s exciting because we’ve found a compound in nature that may one day surpass a currently marketed drug or could become the structural template for rationally designed drugs with improved selectivity,” said Hendrik Luesch, Ph.D., an assistant professor in UF’s department of medicinal chemistry and the study’s principal investigator.
Largazole, discovered and named by Luesch for its Florida location and structural features, seeks out a family of enzymes called histone deacetylase, or HDAC. Overactivity of certain HDACs has been associated with several cancers such as prostate and colon tumors, and inhibiting HDACs can activate tumor-suppressor genes that have been silenced in these cancers.
Although scientists have been probing the depths of the ocean for marine products since the early 1960s, many pharmaceutical companies lost interest before researchers could deliver useful compounds because natural products were considered too costly and time-consuming to research and develop.
Many common medications, from pain relievers to cholesterol-reducing statins, stem from natural products that grow on the earth, but there is literally an ocean of compounds yet to be discovered in our seas. Only 14 marine natural products developed are in clinical trials today, Luesch said, and one drug recently approved in Europe is the first-ever marine-derived anticancer agent.
“Marine study is in its infancy,” said William Fenical, Ph.D., a distinguished professor of oceanography and pharmaceutical sciences at the University of California, San Diego. “The ocean is a genetically distinct environment and the single, most diverse source of new molecules to be discovered.”
The history of pharmacy traces its roots back thousands of years to plants growing on Earth’s continents, used by ancient civilizations for medicinal purposes, Fenical added. Yet only in the past 30 years have scientists begun to explore the organisms in Earth’s oceans, he said. Fewer than 30 labs exist worldwide and research dollars have only become available in the past 15 years.
HDACs are already targeted by a drug approved for cutaneous T-cell lymphoma manufactured by the global pharmaceutical company Merck & Co. Inc. However, UF’s compound does not inhibit all HDACs equally, meaning a largazole-based drug might result in improved therapies and fewer side effects, Luesch said.
Since 2006, Luesch and his team of researchers have screened cyanobacteria provided by collaborator Valerie Paul, Ph.D., head scientist at the Smithsonian Marine Station in Fort Pierce. They check the samples for toxic activity against cancer cells and last year encountered one exceptionally potent extract — the one that ultimately yielded largazole.
To conduct further biological testing on the compound, Luesch and his team have been collaborating with Jiyong Hong, an assistant professor in the department of chemistry at Duke University, to replicate its natural structure and its actions in the laboratory.
Luesch said that within the next few months he plans to study whether largazole reduces or prevents tumor growth in mice.
Luesch has several other antitumor natural products from Atlantic and Pacific cyanobacteria in the pipeline.
“We have only scratched the surface of the chemical diversity in the ocean,” Luesch said. “The opportunities for marine drug discovery are spectacular.”
Source: University of Florida
Josh: Normally, I would say it’s probably not the best idea to give gene therapy to cancer patients as a treatment. The reason being that current gene therapy delivery systems have the tendency to cause cancer. However, in this case, which such low survival rates, I think any treatment is worth trying.
Researchers at the Virginia Commonwealth University Massey Cancer Center and the VCU Institute of Molecular Medicine have published findings that implicate a new chemoprevention gene therapy (CGT) for preventing and treating pancreatic cancer, one of the most lethal and treatment-resistant forms of cancer.
In the July issue of Molecular Cancer Therapeutics, the researchers showed that combining a dietary agent with a gene-delivered cytokine effectively eliminates human pancreatic cancer cells in mice displaying sensitivity to these highly aggressive and lethal cancer cells.
Cytokines are a category of proteins that are secreted into the circulation and can affect cancer cells at distant sites in the body, including metatases. The cytokine used in this study was melanoma differentiation associated gene-7/interleukin-24, known as mda-7/IL-24. … Continue Reading »
Researchers in Germany have discovered that methadone, an agent used to break addiction to opioid drugs, has surprising killing power against leukemia cells, including treatment resistant forms of the cancer.
Their laboratory study, published in the August 1 issue of Cancer Research, a journal of the American Association for Cancer Research, suggests that methadone holds promise as a new therapy for leukemia, especially in patients whose cancer no longer responds to chemotherapy and radiation.
“Methadone kills sensitive leukemia cells and also breaks treatment resistance, but without any toxic effects on non-leukemic blood cells,” said the study’s senior author, Claudia Friesen, Ph.D., of the Institute of Legal Medicine at the University Ulm. “We find this very exciting, because once conventional treatments have failed a patient, which occurs in old and also in young patients, they have no other options.”
Methadone, developed in Germany in the 1930s, is a low cost agent that acts on opioid receptors, and thus is used as an opioid substitute to treat addiction. Scientists have found that opioid receptors also exist on the surface of some cancer cells for reasons that are not understood. One research group tested the agent in human lung cancer cell lines and found that it can induce cell death.
In this study, Friesen and her colleagues tested methadone in leukemia cells in laboratory culture because this cancer also expresses the opioid receptor. Theirs is the first study to look at use of the agent in leukemia, specifically in lymphoblastic leukemia T-cell lines and human myeloid leukemia cell lines.
They found that methadone was as effective as standard chemotherapies and radiation treatments against non-resistant leukemia cells, and that non-leukemic peripheral blood lymphocytes survived after methadone treatment.
To their surprise, they found that methadone also effectively killed leukemia that was resistant to multiple chemotherapies and to radiation. Probing the mechanism of methadone’s action, the researchers found that it activates the mitochondrial pathway within leukemia cells, which activates enzymes called caspases that prompt a cell into apoptosis, also known as programmed cell death. Chemotherapy drugs use the same approach, but methadone activated caspases in sensitive leukemia cells, and also reversed deficient activation of caspases in resistant leukemia cells.
Friesen said the research team is beginning to study methadone treatment in animal models of human leukemia, and she also says that other cancers might be suitable for treatment with the agent.
In this study, the single doses used to kill leukemia cells were greater than doses used to treat opioid addiction, but the researchers have since found that they can use a daily low dose of methadone to achieve the same effect. Friesen adds that while methadone can, itself, become addictive, that addiction is much easier to break compared to addiction to true opioids. “Addiction shouldn’t be an unsolvable problem if methadone is ever used as an anti-cancer therapy,” she said.
Source: American Association for Cancer Research
MIT biological engineers have developed a new imaging system that allows them to see cells that have undergone a specific mutation.
The work, which could help scientists understand how precancerous mutations arise, marks the first time researchers have been able to pinpoint the number and location of mutant cells—cells with a particular mutation—in intact tissue. In this case, the researchers worked with mouse pancreatic cells.
“Understanding where mutations come from is fundamental to understanding the origins of cancer,” said Bevin Engelward, associate professor of biological engineering and member of MIT’s Center for Environmental Health Sciences, and an author of a paper on the work appearing in this week’s online edition of the Proceedings of the National Academy of Science.
Peter So, professor of biological and mechanical engineering, Engelward and members of their laboratories developed technologies that made it possible to detect clusters of cells that appeared to be descended from the same progenitor cell.
Unexpectedly, more than 90 percent of the cells harboring mutations were within clusters. That offers evidence that the majority of mutations are inherited from another cell, rather than arising spontaneously in individual cells.
Since the type of mutation being studied (in this case a recombination event) occurs at a rate on par with other types of mutations, “it is as if we are peering in at the very general process of mutation formation, persistence and clonal expansion,” said Engelward.
“We think this raises the possibility that mutations resulting from cell division are a tremendous factor in increasing the mutagenic load,” she said.
The higher the mutagenic load, the more likely it is that cancer will develop.
Engelward and So started working together several years ago after a faculty retreat for MIT’s newly formed Biological Engineering Division. So was developing a new type of microscopy, known as two-photon imaging, and the researchers wondered whether it could be used to locate and image rare types of cells.
The team genetically engineered a strain of mice in which DNA would fluoresce if a mutation occurred in a particular sequence. That allowed them to use So’s newly developed high-resolution, high-throughput microscopy technique to detect individual cells that carry the mutation.
“The problem drove the development of a new imaging technology, which now can be used for lots of things,” said Engelward.
Lead author of the paper is Dominika Wiktor-Brown, a postdoctoral associate in biological engineering. Other authors of the paper are Hyuk-Sang Kwon, a research affiliate in the Department of Mechanical Engineering, and Yoon Sung Nam, a graduate student in biological engineering.
The work was truly a team effort between many people with very different areas of expertise, said Engelward. “The Department of Biological Engineering and the Center for Environmental Health Sciences are key in helping to bridge people across disciplines,” she said.
Source: Massachusetts Institute of Technology