#Study charts'genomic biography'of form of leukemia A new study by scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard offers a glimpse of the wealth of information
that can be gleaned by combing the genome of a large collection of leukemia tissue samples. By analyzing genetic material in chronic lymphocytic leukemia (CLL) and normal tissue from more than 500 patients,
researchers identified dozens of genetic abnormalities that may drive the disease, including two that had never before been linked to human cancer.
They began to trace how some of these abnormalities affect the course of the disease and its susceptibility to treatment.
And they started tracking the evolutionary path of CLL as its ever-churning genome spawns new groups and subgroups of tumor cells in a single patient.
This type of information is critical as the treatment of CLL is geared increasingly to the unique genetic features of each patient's tumor.
Traditional chemotherapy regimens are now being supplemented by drugs that target the specific set of delinquent genes within cancer cells."
"Sequencing the DNA of CLL has taught us a great deal about the genetic basis of the disease,
"said Catherine Wu, MD, of Dana-Farber, the Broad Institute of MIT and Harvard, and Brigham and Women's Hospital, a senior author of the study, which is being published today by the journal Nature."
"Previous studies, however, were limited by the relatively small number of tumor tissue samples analyzed, and by the fact that those samples were taken at different stages of the treatment process,
from patients treated with different drug agents.""In our new study, we wanted to determine
if analyzing tissue samples from a large, similarly-treated group of patients provides the statistical power necessary to study the disease in all its genetic diversity-to draw connections between certain mutations and the aggressiveness of the disease,
and to chart the emergence of new mutations and their role in helping the disease advance,
"she continued.""Our results demonstrate the range of insights to be gained by this approach.""""This study also provides a vision of
what the next phase of large scale genomic sequencing efforts may look like, "said Dan Landau MD, Phd, of Dana-Farber, the Broad Institute of MIT and Harvard,
and Brigham and Women's Hospital, a first author of the study.""The growing sample size allows us to start engaging deeply with the complex interplay between different mutations found in any individual tumor,
as well as reconstructs the evolutionary trajectories in which these mutations are acquired to allow the malignancy to thrive and overcome therapy."
"Wu and her team collected tumor and normal tissue samples from 538 patients with CLL, 278 of
whom had participated in a German clinical trial that helped determine the standard treatment for the disease.
They performed whole-exome sequencing (WES) on each sample, reading the genetic code letter by letter in sections of DNA that hold the code for making proteins.
An analysis of the data yielded a broad range of insights:""The breadth of our findings shows what we will be able to achieve as we systematically sequence
and analyze large cohorts of tumor tissue samples with defined clinical status, "remarked Gad Getz, Phd, of the Broad Institute and Massachusetts General Hospital, co-senior author of the paper."
"Our work has enabled us to discover novel cancer genes, begin to chart the evolutionary path of CLL,
and demonstrate specific mutations affect patients'response to therapy. These discoveries will form the basis for precision medicine of CLL and other tumor types
#Massive screen of drug combinations may find treatment for resistant, BRAF-mutant melanoma A team of Massachusetts General Hospital (MGH) investigators has discovered a new combination of drugs that may be effective against one of the deadliest cancers, malignant melanoma.
The combination-pairing a drug targeted against mutations in the BRAF gene with a second drug that targets another important signaling pathway-was discovered through one of the largest screens of cancer drug combinations conducted to date.
Findings from the study conducted at the MGH Cutaneous Biology Research center and Center for Molecular Therapeutics have been published in the open-access journal PLOS ONE."
"We wanted to see whether very-large-scale screening across a diverse collection of cancer cell lines and a large number of drugs could yield new combinations for patients with cancer,
"says Adam Friedman, MD, Phd, of the CBRC and the MGH Cancer Center, who led the study."
"By conducting such a screen, we found one specific combination of agents that are already being used clinically that potentially could be used for a specific group of patients-those with BRAF-mutant cancers."
"Friedman notes that, even with the increasing number of drugs targeting specific molecular abnormalities that drive tumor growth,
most patients are treated only with one such drug at a time. Most of those treated with targeted-therapy drugs will relapse within a year,
often because their tumors have become resistant, and some tumors never respond to the targeted drugs.
While combining anticancer drugs appears a promising strategy, the sheer volume of drugs currently in use or in development-more than 500,
which could make up more than 100,000 two-drug combinations-makes testing each potential combination in clinical trials challenging.
Previous efforts to screen potential drug combinations only analyzed use of a few drugs against a limited number of cell lines
or lines in which genomic variations were understood poorly. This study utilized 36 well-characterized melanoma cell lines assembled by the MGH Center for Molecular Therapeutics to test all possible combinations of more than 100 oncology drugs,
two-thirds of which are currently in clinical use. More than 5, 775 potential drug combinations, as well as each single drug, were screened against each cell line,
looking for effects on the number and viability of tumor cells. While several combinations showed synergistic effects-with some drugs sensitizing the cells against several other drugs-most combinations increased the response of only one or two cell lines
implying that the vulnerability of an individual patient's tumor to these combinations depends on its unique genetic signature.
Since around half the cases of malignant melanoma are driven by mutation in the BRAF gene, the team focused on combinations that might address intrinsic resistance to the BRAF inhibitor vemurafenib.
They found that combining that drug with the cediranib, an investigational drug that targets a group of proteins known to be involved in blood vessel formation,
had synergistic effects against cell lines that were resistant to treatment with vemurafenib alone but not those sensitive to single-agent therapy.
They also tested this combination in animal models into which two resistant cell lines had been grafted,
and found significant synergistic effects against both tumor models.""We need to confirm this synergistic activity of vemurafenib
and cediranib across a broader range of melanoma models, investigate why the particular combination is effective,
and find biomarkers that predict which patients with BRAF-mutant melanoma should receive this combination,
"says Friedman, who is a research fellow in Dermatology at Harvard Medical school.""What is really exciting is that these drugs are already in the clinic;
in fact a clinical trial for a similar combination is already underway at another research center. We may be able to quickly improve on the selection criteria for this trial
and identify patients whose tumors might respond.""He adds, "This study was actually a pilot project for a much larger effort within the Center for Molecular Therapeutics to map responses against drug combinations across hundreds of cancer cell lines, not just melanoma,
and look for novel combinations that will benefit subsets of patients regardless of the particular type of tumor they have.
Since our collection of cell lines is annotated completely genetically -which means that mutations and expression changes in each line's genes have been documented-we should be able to identify in advance patients who will benefit from specific combinations.
Beyond the specific combination we focused on this study should help others understand the technical challenges of analyzing such a large combination dataset
#The first'molecular labels'that predict the organs where metastases will discovered form Understanding why a tumour metastasises in specific organs
and do not in others is one of the top goals of oncology, and also one of the oldest. 126 years ago, The british physician, Stephen Paget, formulated his'seed and soil theory,
'which advocates that metastasis requires the dispersal of tumour cells,'seeds, 'as well as a welcoming environment,'fertile soil',in the recipient organ.
However, since then"the progress made in deciphering the mechanisms that guide metastasis to specific organs has been insufficient"
write the authors in the report published in'Nature'.'In recent years, Héctor Peinado, Head of the Microenvironment and Metastasis Group at the Spanish National Cancer Research Centre (CNIO), David Lyden from Weill Cornell Medical College,
and Jaqueline Bromberg from the Memorial Sloan Kettering Cancer Center, have developed a theory that supports Paget's'seed
and soil'theory. Ayuko Hoshino and Bruno Costa-Silva, co-first authors in this publication, together with Peinado and Lyden, have collected evidence that tumours release millions of vesicles carrying representative samples of their proteins and genetic content.
The current work corroborates its existence, since it confirms that exosomes play a crucial role in the formation of metastasis in precise organs.
These data support that the'soil'is as important as the'seed'in the metastatic process.
and pancreas cancer to the liver--metastasis is reduced in these organs. LAYING THE GROUNDWORK The researchers have discovered also the molecular signals that intercede in the reaction of the recipient tissue
inflammation is associated a process with cancer. These results represent the identification of potential new pharmacological targets,
"The study was performed using human and mouse tumour cell lines, preclinical mouse models, as well as plasma from cancer patients.
The latter served for the preliminary study of the predictive power of the integrins identified, that is,
whether analysis of the exosome integrins alone will make it possible to know in which organs there could be metastasis."Our work suggests that a high level of certain integrins in the plasma of patients with breast cancer
and pancreas cancer seems to predict the organ where the metastasis will occur, "says Peinado."
"But these data will have to be validated on larger cohort studies and predictive tests must be developed."
This work is the result of an international, multidisciplinary and multi-institutional collaboration, which involves obtaining multiple cellular and preclinical models,
as well as human samples. The search for these models has been carried out over the last three years with the participation of many teams,
whose mutation leads to the aggressive growth of a common and deadly type of lung cancer in humans.
This enzyme, called Epha2, normally polices a gene responsible for tissue growth. But when Epha2 is mutated,
and quickly develop tumors. The new work, published the week of November 2, 2015 in PNAS, suggests that Epha2 could be a new target for a subset of lung cancer,
which affects nonsmokers as well as smokers, and is the leading cause of cancer-related deaths worldwide."
"Sometimes there are hundreds of mutations in the genes of a patient's tumors, but you don't know
whether they are drivers of the disease or byproducts,"says senior author Inder Verma, professor of genetics and holder of Salk's Irwin and Joan Jacobs Chair in Exemplary Life science."
"We found a new way by which to identify cancer suppressor genes and understand how they could be targeted for therapies."
"Two gene mutations in particular are known to spur the growth of human tumors: KRAS and p53. Though both genes have been studied heavily,
they are difficult to therapeutically target, so the Salk team decided to look at genes that might police KRAS and p53 instead.
The researchers narrowed in on the 4, 700 genes in the human genome related to cellular signaling--specifically,
genes that have the ability to tamp down cell growth and proliferation. Then the team adapted a genetic screening technique to quickly
and efficiently test the effect of these thousands of genes on tumor development. In animal models, the Salk team found that 16 of these cell-signaling genes produced molecules that had a significant effect on KRAS-and p53-related tumors.
Of these 16 molecules one especially stood out: the Epha2 enzyme, originally discovered in the lab of another Salk scientist, Tony Hunter.
Previously, Epha2's significance in lung cancer was unclear, but the team discovered that its absence let KRAS-associated tumors grow much more aggressively."
"With a mutation in KRAS, a tumor forms in 300 days. But without Epha2, the KRAS mutation leads to tumors in half the time, 120 to 150 days,"says Verma,
who is also an American Cancer Society Professor of Molecular biology.""This molecule Epha2 is having a huge effect on restraining cancer growth
when KRAS is mutated.""Mutated KRAS is a common culprit in approximately 10 to 20 percent of all cancers, particularly colon cancer and human lung cancer."
"Since activating Epha2 led to the suppression of both cell signaling and cell proliferation, we believe that the enzyme might serve as a potential drug target in KRAS-dependent lung adenocarcinoma,
"says Narayana Yeddula, a Salk research associate and first author of the paper. A 10-year national project called the Cancer Genome Atlas mapped the genomes of hundreds of patients for over 20 different cancers
and uncovered a number of related genetic mutations, though the role of these mutations has not been understood well in lung cancer (especially adenocarcinoma,
which makes up almost a quarter of all lung cancers). From the Cancer Genome Atlas data, the Salk team found that genetic alterations of Epha2 were detected in 54 out of 230 patients with adenocarcinoma.
The team also found, surprisingly, that the loss of Epha2 activated a pathway commonly associated with cancer (dubbed Hedgehog) that promotes tumor growth."
"Oddly, among human lung cancer patients with Epha2 mutations, around 8 percent of patients actually have high Epha2 expression.
So, in some instances, Epha2 is not suppressing tumors and may be context-dependent. Therefore, we need to carefully evaluate the molecule's function
when designing new therapeutics,"adds Yifeng Xia, a Salk staff researcher involved in the work k
#Cancer cells use secret tunnels to communicate and smuggle cancer signals their neighbors A new discovery published in the Nov. 2015 issue of The FASEB Journal shows that cancer cells use previously unknown channels to communicate with one another and with adjacent non-cancerous cells.
Not only does this cast an important light on how cancer metastasizes and recruits cellular material from healthy cells,
but it also suggests that these physical channels might be exploitable to deliver drug therapies."
"I hope that the tools we have developed, especially the mouse model, will be used by academics to isolate healthy cells modified by tumors,
and by the pharmaceutical industry in the quest for novel anticancer drugs that block tumor-organ communication,
"said Anne Burtey, Ph d.,study author from the Department of Biomedicine, at the University of Bergen in Bergen, Norway."
"I also hope the knowledge we provide here is paving the way to engineer'super-spreading'agents,
with increased abilities to diffuse within tumors and even reach the healthy cells involved in tumor progression."
"To make this discovery, Burtey and colleagues studied the exchange of molecules between cells, by color-coding them with red or blue cellular fluorescent'dyes'or'tags.'
'Blue cells were cultured co with red cells and monitored to see if they exchanged cellular material, such as proteins.
They observed that the function a protein involved in the transport of proteins and organelles within cells (called'Rab8'),was affected,
suggesting that this protein is a key regulator of cell-cell communication in cancer. Live cell imaging confirmed that the transfer is contact-dependent.
Importantly, the scientists experiments also showed that this process occurs in vivo. Using two groups of mice that had green (healthy cells) and red (human cancer cells) fluorescent tags,
they observed a transfer of red material into the green healthy cells of the mice's mammary fat pads."
"Mexican drug lords are not the only ones who use secret tunnels to move material across seemingly impenetrable borders,
"said Gerald Weissmann, M d.,Editor-In-chief of The FASEB Journal.""At the cellular level, it appears that cancer cells do the same thing.
Now that we know these tunnels exist we can shut them down or use them to deliver lifesaving therapies
#New research opens door to understanding human tonsil cancer Researchers at Simon Fraser University and the BC Cancer Agency have developed a groundbreaking method to identify
and separate stem cells that reside in the tonsils. Their research, which sheds new light on the fight against oral cancer, is published today in the journal Stem Cell Reports.
While stem cells in many other body tissues have been studied well, little is known about these stem cells,
says researcher Catherine Kang, a Phd student in the Department of Biomedical Physiology and Kinesiology and lead author of the paper.
Ninety per cent of human tonsil cancers show evidence of HPV (human papillomavirus) infection. But little is known about its role in causing these cancers.
Researchers suspect it is a key player, as HPV is the major risk factor for cervical cancer.
Kang, who is working with BPK professor Miriam Rosin, director of the BC Oral Cancer Prevention Program,
and UBC professor Connie Eaves of the Terry Fox Laboratory, was interested in finding out why the tonsil is particularly susceptible to HPV
and wondered if it might have something to do with the stem cells of the tissue that coats the tonsils.
When she purified these cells and made them incorporate a cancer-causing gene normally transmitted by HPV,
the cells grew abnormally in a special tissue culture system, and created what one might imagine what the beginning stages of human tonsil cancer would look like."
"This is a very exciting finding, as it is the first stage of human cancer development that researchers need to learn how to detect
and eliminate,"says Kang. The study shows how it can now be done and then studied at will in a petri dish using cells isolated directly from human tonsils.
Cancer of oropharynx, or the tonsils in particular, is an important health concern with rising incidence worldwide, especially in men.
The researchers, including Dr. Raj Kannan of the BC Cancer Agency's Terry Fox Laboratory,
say this new method will now allow these next steps to go forward not just here,
#A newly discovered tumor suppressor gene affects melanoma survival Of the hundreds of genes that can be mutated in a single case of melanoma,
only a handful may be true"drivers"of cancer. In research that appeared today in Nature Genetics,
a Weizmann Institute of Science team has revealed now one of the drivers of a particularly deadly subset of melanomas-one that is still seeing a rise in new cases.
This gene is identified a newly member of a group of genes called tumor suppressor genes.
It is mutated in some 5. 4%of melanomas. Furthermore its expression was found to be lost in over 30%of human melanomas;
and this loss, according to the finding, was associated with reduced patient survival. This discovery might open new doors to understanding how this cancer grows and spreads,
and it may lead in the future to new directions in treating this disease. Prof. Yardena Samuels and her team in the Institute's Molecular Cell biology Department were specifically searching for tumor suppressor genes in their database,
which consists of more than 500 melanoma genomes and exomes-protein-building sequences-making it the largest melanoma dataset to date.
As their name suggests, tumor suppressor genes normally inhibit cell growth, including that of cancer cells.
However, when mutated, they act like defective brakes on cellular proliferation. Thus studying these genes is crucial in cancer biology."
"The identification of targetable alterations in melanoma is need an urgent. An in depth understanding of the functional effects of mutations in these genes is the first step toward revealing the underlying mechanism of melanoma growth,
"says Dr. Nouar Qutob, a postdoctoral fellow in Samuels'lab who participated in this research. Indeed, the melanoma genome sequences contained mutations in known tumor suppressor genes,
but there was also a new gene that stood out in the team's search, named RASA2.
The researchers'next step was to conduct a series of functional experiments to understand exactly what this gene does.
They cloned both the normal protein and the most recurrent mutated versions to see their effects on melanoma cells.
They found that RASA2 regulates a key protein in the cell, called RAS. RAS has been identified as a major oncogene that contributes to the unchecked growth of cells.
When they restored the production of the protein in melanoma cells that harbored RASA2 mutations,
these cells stopped growing and eventually died. Patients with dysfunctional RAS pathways tend to have a worse prognosis than those with other types of melanoma,
and, until now, scientists have not managed to create drugs that can target this pathway.""As the RAS pathway is highly dysregulated in cancer,
the discovery of an alternative mechanism for its activation is likely to stimulate an avalanche of further research in this field,
and is highly likely to have direct clinical relevance. We are now going to focus on RASA2,
to find out what proteins it communicates with in healthy cells and melanoma, as well as in the cells'response to targeted therapy,
"says Samuels.""Most targeted cancer therapies nowadays work by inhibiting the products of oncogenes that are overactive in melanoma cells.
However, loss or mutations in tumor suppressor genes like RASA2 also contribute to melanoma development;
therefore, discovering and studying RASA2 targets and partners will be our next aim, "says Rand Arafeh,
a Phd student in Samuels'lab and lead author of the paper r
#DNA in blood can track cancer development and response in real time Scientists have shown for the first time that tumour DNA shed into the bloodstream can be used to track cancers in real time as they evolve
and respond to treatment, according to a new Cancer Research UK study published in the journal Nature Communications today (Wednesday).
Over three years, researchers at the University of Cambridge took surgical tumour samples (biopsies) and blood samples from a patient with breast cancer that had already spread to other parts of her body.
They carefully studied small fragments of DNA from dying tumour cells that are shed into the blood,
comparing them with DNA from the biopsy that was taken at the same point in time. The results show that the DNA in the blood samples matched up with that from the biopsies,
reflecting the same pattern and timing of genetic changes appearing as the cancer developed and responded to treatment.
The results provide the first proof-of-principle that analysing tumour DNA in the blood can accurately monitor cancer within the body.
Study author Professor Carlos Caldas, senior group leader at the Cancer Research UK Cambridge Institute, said:"
"This definitively shows that we can use blood-based DNA tests to track the progress of cancer in real time.
The findings could change the way we monitor patients, and may be especially important for people with cancers that are difficult to reach,
as taking a biopsy can sometimes be quite an invasive procedure.""The patient in the study had had breast cancer that already spread to a number of other organs.
The researchers-part of a collaborative team effort involving the Carlos Caldas and Nitzan Rozenfeld laboratories at the Cancer Research UK Cambridge Institute-were even able to distinguish between the different secondary cancers
and examine how each of the tumours was responding to treatment. Professor Caldas added:""We were able to use the blood tests to map out the disease as it progressed.
We now need to see if this works in more patients and other cancer types,
but this is an exciting first step.""Dr Kat Arney, science information manager at Cancer Research UK, said:"
"Spotting tumour DNA in the bloodstream is a really promising area of research, and has the potential to give doctors valuable clues about a patient's disease without having to take repeated tumour samples."
"For now, surgical biopsies still play an important role in diagnosing and monitoring cancers. But this work gives us a window into the future,
where we'll use less invasive techniques to track the disease in real time
#Scientists paint quantum electronics with beams of light A team of scientists from the University of Chicago
and the Pennsylvania State university have discovered accidentally a new way of using light to draw and erase quantum-mechanical circuits in a unique class of materials called topological insulators.
In contrast to using advanced nanofabrication facilities based on chemical processing of materials, this flexible technique allows for rewritable'optical fabrication'of devices.
This finding is likely to spawn new developments in emerging technologies such as low-power electronics based on the spin of electrons or ultrafast quantum computers.
The research is published today in the American Association for the Advancement of Science's new online journal Science Advances
where it is featured on the journal's front page.""This observation came as a complete surprise,
"said David D. Awschalom, Liew Family Professor and deputy director in the Institute of Molecular Engineering at UCHICAGO,
and one of two lead researchers on the project.""It's one of those rare moments in experimental science where a seemingly random event--turning on the room lights--generated unexpected effects with potentially important impacts in science and technology."
"The electrons in topological insulators have unique quantum properties that many scientists believe will be useful for developing spin-based electronics and quantum computers.
However, making even the simplest experimental circuits with these materials has proved difficult because traditional semiconductor engineering techniques tend to destroy their fragile quantum properties.
Even a brief exposure to air can reduce their quality. In Science Advances, the researchers report the discovery of an optical effect that allows them to"tune"the energy of electrons in these materials using light,
and without ever having to touch the material itself. They have used it to draw and erase p-n junctions--one of the central components of a transistor--in a topological insulator for the first time.
Like many advances in science, the path to this discovery had unexpected an twist.""To be honest,
we were trying to study something completely different, "said Andrew Yeats, a graduate student in Awschalom's laboratory and the paper's lead author."
"There was a slow drift in our measurements that we traced to a particular type of fluorescent lights in our lab. At first we were glad to be rid of it,
and then it struck us--our room lights were doing something that people work very hard to do in these materials."
and their room lights happened to emit at just the right wavelength. The electric field from the polarized strontium titanate was leaking into the topological insulator layer,
changing its electronic properties. Awschalom and his colleagues found that by intentionally focusing beams of light on their samples,
the team measured their samples in high magnetic fields. They found promising signatures of an effect called weak anti-localization,
"One exciting aspect of this work is that it's noninvasive"said Nitin Samarth, Professor and Downsbrough Head of Physics at Penn State,
"In a way, the most exciting aspect of this work is that it should be applicable to a wide range of nanoscale materials such as complex oxides, graphene,
and transition metal dichalcogenides,"said Awschalom.""It's not just that it's faster and easier.
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