Archive for the ‘genetic research’ Category

In the common cold, scientists find new hope for cancer treatment

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Posted 26 Aug 2010 — by James Street
Category Virus, genetic research



Posted by Laura Blue Thursday, August 26, 2010 at 5:34 pm
Submit a Comment • Related Topics: cancer medicine

New research on viruses may translate into new therapies to beat cancer, scientists say.

Molecular biologists at the Salk Institute have uncovered a previously unknown mechanism that allows adenoviruses – culprits behind the common cold as well as other illnesses — to beat the body’s immune system. Since adenoviruses and tumor growths both overcome our natural cellular defenses in a similar way, understanding one disease process can give us good clues for ways to fight the other, scientists hope.

Here’s how it works. Previous research has shown that the “p53″ protein is both a tumor suppressor, preventing cancer growth, and also important for keeping adenoviruses in check. When cancer invades one of the body’s cells, p53 will try to kill the cell outright to prevent the cell from being overrun. Adenoviruses also need to overcome p53 to replicate. Tumors and adenoviruses, therefore, have both adapted mechanisms of their own to knock out p53.

Scientists already knew about one mechanism by which adenoviruses can repress p53 function. But in the newly released research, published in the journal Nature, the Salk scientists analyzed adenoviruses with several induced mutations and discovered a second, previously unknown repressor of p53. That gives them a better idea of how adenoviruses overcome the body’s immune response to replicate successfully — and it hints at better ways to create new, genetically engineered viruses that would target and destroy tumors without otherwise causing harm to humans.

It sounds complicated. But Kevin Ryan, a molecular biologist and cancer researcher who was not involved with the study, explains why this finding is so important. Writing in an editorial published in the same journal issue as the original research, he says:

Undoubtedly, the greatest significance of this study will be its contribution to devising strategies to treat cancer. Adenoviruses must inactivate p53 so that they can replicate and subsequently induce the breakdown of the infected cell. Because many tumours lack p53 function, researchers have engineered viruses that lack E1B-55k [the previously known mechanism to wipe out p53] with the idea that these viruses would replicate selectively in tumour cells lacking p53 but not in normal cells, eventually leading to the death of the tumour cells.

In other words, scientists have already tried to engineer new viruses that would thrive only in tumors, killing off cancers. If cancer invades a healthy cell and wipes out the p53 function, then the lack of p53 allows the adenovirus to go in and take over the cell. With some genetic engineering to make sure that the adenovirus has no ability to repress p53 itself, the specially created virus should be of little threat to healthy cells — only a threat to the cancerous cells, where p53 function is suppressed.

Viruses like this have already been created. Ryan continues, however:

Although these engineered viruses have proven to be therapeutically beneficial, their replication does not seem to depend on the p53 ‘status’ of the cell.

They also weren’t as successful as treatments as people might have liked.

[The new] finding that [the second, newly uncovered p53 repressor] E4-ORF3 also, at least partly, inactivates p53 function provides an explanation for why this would be the case. Following on from these insights is the exciting prospect that adenoviruses lacking both [of the p53-blocking mechanisms] could be selective and even more potent anticancer agents than viruses lacking just E1B-55k.

Read more: http://wellness.blogs.time.com/2010/08/26/in-the-common-cold-scientists-find-new-hope-for-cancer-treatment/#ixzz0xmKrwIkM

New Drugs Offer ‘Extraordinary Hope’ in Skin Cancer Fight

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Posted 26 Aug 2010 — by James Street
Category genetic research

A new drug may change the landscape of melanoma treatment, offering patients a treatment option that goes beyond anything previously used against the skin cancer, new research shows. Tests in people whose melanoma had spread show the drug was able to shrink tumors in most patients and, in a few cases, even wiped the growths out, scientists report in the Aug. 26 New England Journal of Medicine. The compound targets the protein encoded by a mutated version of the BRAF gene that underlies melanoma in roughly half of all patients.

sciencenews“This demonstrates for the first time that a targeted therapy can work in melanoma,” says Richard Marais, a molecular biologist at the Institute of Cancer Research in London. “This is an enormous advance in the field. It’s just unparalleled.”

Early-stage melanoma that is confined to a spot on the skin can be surgically removed and in most cases stopped. But patients’ prospects take a deadly turn if the cancer metastasizes, or spreads, to other parts of the skin or to internal organs. Chemotherapy drugs benefit fewer than 20 percent of such patients. Survival outlook varies with the extent of the cancer’s spread and the age of the patient, but it is usually measured in months, not years.

The new drug is called PLX4032. Its impressive showing is actually the second dose of good news about melanoma to arrive this summer. In the Aug. 19 NEJM, scientists reported that another experimental drug, called ipilimumab, seems to extend survival in people with metastatic melanoma, and the Food and Drug Administration has fast-tracked its review of that drug.

A third study, published in 2008, found that melanomas arising from a much less common mutation — in a gene called C-kit — were susceptible to the leukemia-fighting drug Gleevec, or imatinib.

“This creates extraordinary hope for many melanoma patients,” says Alan Spatz, a pathologist at McGill University in Montreal. “For the first time in 40 years we have accumulated three studies that show extremely promising results.”

In the new study, medical oncologist Keith Flaherty of Harvard Medical School and Massachusetts General Hospital in Boston and a team of U.S. and Australian researchers treated 48 patients who had BRAF-related metastatic melanoma with PLX4032, which was devised by scientists at the pharmaceutical company Plexxikon in Berkeley, Calif. The drug neutralizes the mutant BRAF protein and stops it from triggering cell growth.

Of the 48 patients, 37 experienced tumor shrinkage of at least 30 percent. In three patients, the tumors resolved completely. This tumor suppression lasted from three months to about two years. Some patients remain on the drug.

On average, the patients getting the treatment relapsed after nearly eight months, Flaherty says. That happens because the tumors develop ways to subvert the effects of PLX4032. Those changes are the target of study now.

But the relapse rate hasn’t discouraged observers. “Patients are very rarely cured with a single drug in cancer,” Marais says. “You typically need a cocktail.”

Keiran Smalley, a molecular pharmacologist at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla., notes that metastatic melanoma is exceptionally hard to treat anyway. “I think people in the field hadn’t really believed that these kinds of responses would even be possible,” he says.

The other two new approaches to fighting melanoma target other biological pathways. Early tests suggest Gleevec or similar drugs such as nilotinib (sold as Tasigna) could thwart melanoma stemming from a mutation in the C-kit gene by stopping its rogue protein from sending growth signals to cells. But the C-kit mutation is uncommon, and such patients typically don’t have the BRAF mutation. So combining those drugs with PLX4032 wouldn’t yield an additional benefit, Marais says.

Ipilimumab might offer the possibility of a one-two punch since it works by unfettering the body’s own T cells — immune shock troops — to fight cancer. As such, it may have an additive effect when used in combination with PLX4032, Marais says.

Flaherty says a trial is being discussed now that would use both drugs against BRAF-mutation melanoma — employing PLX4032 to catch the cancer in its early stages and ipilimumab to “improve immune surveillance” and mop up tumor cells that evade the effects of PLX4032. “You’d like to think these two things would complement each other,” he says.

“This is clearly a turning point” in melanoma treatment, says study coauthor Paul Chapman, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City. “It’s the first time we’re actually treating the genetics of the tumor.” In the past, melanoma metastases were all treated about the same, he says. “Now we have the advantage of knowing their genetic differences and we are able to exploit that.”

Read More http://www.wired.com/wiredscience/2010/08/new-melanoma-drugs/#ixzz0xmIPSkEp

Research increases possibilities of personalising treatment of infant osteosarcoma

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Posted 14 Aug 2010 — by James Street
Category Chemotherapy, Drug, Individualized treatment, genetic research

2009/2/18

A team of specialists at the University Hospital of Navarra have revealed the existence of genetic variants that have greater resistance to a specific treatment and a greater toxicity of the pharmaceutical drug in some child patients affected by osteosarcoma. The team investigated the mechanisms of the illness in order to obtain a personalised therapeutic treatment in the future.

In concrete, the research focused on the analysis of the side effects due to the administration of methotrexate in a hundred of such patients.

This medication was chosen because, to treat infant osteosarcoma, high levels of dosage are administered – in terms of grammes – being a multiplication by a thousand of the methotrexate dosage given in other, frequently-occurring cancer diseases, such as leukaemia. Such high dosage can cause very important toxic effects, and thus the need to know the genetic mechanisms bearing on the resistance to treatment and the tolerance to the pharmaceutical drug, explained Doctor Ana Patiño, main research author of the article to be published in the scientific journal, The Journal of Pediatrics, the second with the greatest world impact in its speciality.

Notable amongst the team participating in the study is the biologist/biochemist Doctor Marta Zalacain, who suffered an osteosarcoma when she was 11 years old, and for which she was treated and cured at the University Hospital by a team led by Dr Sierrasesúmaga, the group with which she is currently working on the mechanisms of this illness.

Large group of patients

The work was drawn up for a group of 100 patients, one of the largest in the world, given the scant incidence of the illness (estimated annually at one person per million inhabitants).

To give an idea of the importance of the group studied by Doctor Sierrasesúmaga, Director of the Department of Paediatrics at the University Hospital of Navarra and specialist in infant cancer, it can be pointed out that, in all of Spain, 45 child patients suffering from osteosarcoma are detected on average each year there.

Thus, the hundred patients under study is a very large number and, moreover, it is a particularly exceptional study in that it provides access to its genetic material, to the tumour material and to all the complete clinical data of the hundred patients studied.
70% survival rate at the University Hospital

The survival prognosis of infant patients with osteosarcoma at the University Hospital of Navarra, including the metastasic ones, is about 70%, compared to the 60-65% average at other international centres of reference in the treatment of this oncological illness.

As a consequence of this high survival rate, added Doctor Patiño, the concern is also with the quality of life of survivors. The goal of the research work is focusing on finding therapeutic tools that minimise the toxic effects of treatment and maximise the therapeutic effects.

Observing the genetic variants of the genes involved in the methotrexate metabolism, they have shown that some of these variants are associated with different toxicity of the pharmaceutical drug and, accordingly, obtain better or worse therapeutic effects, stated the specialist.

In concrete, the research team studied genetic variants of children in which the tumours prove themselves to be intrinsically resistant to the medical treatment. These are the patients for whom it is necessary to administer high levels of methotrexate in order to obtain a good response.

To obtain these data, the researchers were able to work closely with the Department of Pharmacology at the University Hospital of Navarra, where the kinetics of the drug in the blood was analysed for each of the patients in the study.

In this way, explained Ms Patiño, they monitored the children to see if they had eliminated the amount of drug left over after the required therapeutic effect had taken effect, given that, otherwise, significant toxicity could be caused.

As a result of the research, the specialists have identified the genetic variant responsible for this greater methotrexate toxicity affecting certain children with osteosarcoma.

Although, for the moment, the genotype has not yet changed the treatment of the illness, the aim is to gradually intensify this type of genetic study through analysis the results of which can be readily obtained – in a matter of 90 minutes.

In this way, what is involved is the location of new genes and thus being able to adjust the dosage of the various pharmaceutical drugs that we administer, in order to maximise the therapeutic results and minimise the toxicity in each one of the patients treated, concluded the researcher.

First Diagnostic Test to Predict Prostate Cancer Recurrence

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Posted 13 Aug 2010 — by James Street
Category Diagnostic, Individualized treatment, Molecular, Prostate Cancer, genetic research

Myriad Genetics Launches PROLARIS(TM): First Diagnostic Test to Predict Prostate Cancer Recurrence
Globe Newswire
March 02, 2010: 08:36 AM ET

SALT LAKE CITY, March 2, 2010 (GLOBE NEWSWIRE) — Myriad Genetics, Inc. (Nasdaq:MYGN) today announced the launch of PROLARIS™, a 46-gene prognostic test which quantitatively determines the risk of recurrence in patients who have undergone prostatectomy surgery.

For the first time, physicians now have a direct molecular measure of a prostate tumor’s capacity to divide and grow by examining the mechanics of growth at the molecular level. PROLARIS is the Company’s eighth molecular diagnostic product and the first of two that are planned to be launched this year.

“After undergoing a radical prostatectomy, men often worry about their continuing risk of cancer recurrence,” said Peter R. Carroll, M.D., M.P.H., Professor and Chair, Urology, University of California, San Francisco. “PROLARIS may offer very important information to the patient and his physician about the risk of his cancer recurring.”

PROLARIS is a molecular diagnostic assay that offers urologists a more accurate way of determining a prostate cancer patient’s risk of recurrence. The new molecular diagnostic test is based on cell growth and tumor biology and provides rigorous, quantitative measures of the expression levels of multiple genes related to progression of the cell cycle.

The test identifies patients at low risk of disease recurrence with 95% certainty giving these men confidence that additional aggressive treatment with the accompanying toxicity and adverse events is likely unwarranted. Conversely, men with high PROLARIS scores would be considered for more intensive screening and adjuvant therapy to address their more aggressive disease.

The Company is performing additional clinical validation studies to expand the utility of PROLARIS. In one such recently completed study of 365 prostate cancer patients, 98.5% of prostate cancer patients with a low (favorable) PROLARIS score survived their disease after 10 years, compared to 57.6% of the patients receiving a high (unfavorable) score who died of prostate cancer within 10 years.

“PROLARIS is a valuable additional tool that will enable urologists to provide an accurate, individualized recurrence risk score to men who have undergone a radical prostatectomy,” stated Mark C. Capone, President, Myriad Genetic Laboratories, Inc. “We view PROLARIS as the first of a strong emerging stable of RNA signature tools based on fundamental tumor biology which Myriad will offer to the urology/oncology community.”

In the United States, 192,000 men are diagnosed with prostate cancer each year and 80,000 men will undergo a radical prostatectomy, a surgical procedure that removes the prostate gland and some surrounding tissue. Approximately 35% of these men will eventually have a biochemical recurrence indicating the return of their prostate cancer. Current models based on clinical variables cannot effectively predict in which of these men the disease will recur.

Myriad will introduce PROLARIS to urologists and oncologists through its established oncology sales force and new urology sales team in the coming weeks. The cost for PROLARIS is $3,400.

Clinical Data on PROLARIS to be Presented

The clinical validation and scientific data supporting PROLARIS will be presented at the 2010 Genitourinary Cancers Symposium on March 5-7, 2010 in San Francisco. The abstract of the presentation entitled: “Cell Cycle Genes Predict Recurrence After Radical Prostatectomy” by Dr. Gregory P. Swanson and colleagues will be publically released on  the American Society of Clinical Oncology’s website, www.asco.org on Wednesday, March 3, 2010 at 6:00 pm Eastern.

About Myriad Genetics

Myriad Genetics, Inc. is a leading molecular diagnostic company focused on developing and marketing novel predictive medicine, personalized medicine and prognostic medicine products. Myriad’s news and other information are available on the Company’s Web site at www.myriad.com.

Myriad, the Myriad logo, BRACAnalysis, Colaris, Colaris AP, Melaris, TheraGuide, Prezeon, OnDose, and Prolaris are trademarks or registered trademarks of Myriad Genetics, Inc. in the United States and foreign countries. MYGN-G

The Myriad Genetics, Inc. logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=6336

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the timing and manner of the launch and introduction of PROLARIS to urologists and oncologists; the planned launch of a second molecular diagnostic product this year; the degree of certainty in identifying patients at low or high risk of disease recurrence with PROLARIS; the consideration or role of the PROLARIS score or results in subsequent medical management decisions; the timing, completion and results of additional clinical validation studies to expand the utility of PROLARIS; the value and utility of PROLARIS to provide accurate individualized recurrence risk scores to men who have undergone radical prostatectomy; the Company’s anticipated offering of a strong emerging stable of RNA signature tools based on fundamental tumor biology; the initial cost for PROLARIS of $3,400; and the presentation of clinical data on PROLARIS at the 2010 Genitourinary Cancers Symposium on March 5-7, 2010 in San Francisco. These “forward-looking statements” are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by forward-looking statements. These risks and uncertainties include, but are not limited to: the risk that sales and profit margins of our existing molecular diagnostic products may decline or will not continue to increase at historical rates; the risk that we may be unable to develop or achieve commercial success for additional molecular diagnostic products in a timely manner, or at all; the risk that licenses to the technology underlying our molecular diagnostic products and any future products are terminated or cannot be maintained on satisfactory terms; risks related to delays or other problems with manufacturing our products or operating our laboratory testing facilities; risks related to public concern over our products; risks related to regulatory requirements or enforcement in the United States and foreign countries and changes in the structure of healthcare payment systems; uncertainties about our ability to obtain new corporate collaborations and acquire new technologies on satisfactory terms, if at all; the development of competing products and services; the risk that we or our licensors may be unable to protect the proprietary technologies underlying our products; the risk of patent-infringement claims or challenges of our patents; risks of new, changing and competitive technologies and regulations in the United States and internationally; and other factors discussed under the heading “Risk Factors” contained in Item 1A in our Annual Report on Form 10-K for the year ended June 30, 2009,which has been filed with the Securities and Exchange Commission, as well as any updates to those risk factors filed from time to time in our Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. All information in this press release is as of the date of the release, and Myriad undertakes no duty to update this information unless required by law.

CONTACT:  Myriad Genetics, Inc.
Suzanne Barton, Director, Investor Relations
(801) 584-1138
sbarton@myriad.com

Researchers find powerful predictor of bone cancer prognosis

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Posted 11 Aug 2010 — by James Street
Category Osteosardoma Research, genetic research, genetic research

January 7, 2010

(PhysOrg.com) — Scientists at the University of Toronto and The Hospital for Sick Children (SickKids) have discovered a powerful new tool that can help predict the prognosis for patients with bone cancer and help doctors more accurately determine how aggressively they need to treat specific patients.

They found that the presence of a specific type of genetic mutation found in the tumours results in poorer outcomes for patients with osteosarcoma – the most common bone cancer in children and adolescents. The study is published in the current issue of Cancer Research.

The research team analyzed tumour DNA from osteosarcoma patients and found a novel region called osteo3q13.31, which contains three genes that were previously not known to be involved in the disease.

They used the presence or absence of a mutation in these genes – known as an osteo3q13.31 deletion – as an indicator to predict the disease outcome in osteosarcoma.

They studied 49 patients and found that a deletion resulted in poorer outcomes.

“This marker is an incredibly powerful tool. If the deletion is present, this suggests that the patient would need more aggressive therapy than if it is absent,” says principal investigator Dr. David Malkin, Paediatric Oncologist and Senior Scientist at SickKids, and Professor in the Department of Paediatrics at the University of Toronto.

“Hopefully, we would be able to avoid over treating patients who don’t need the most aggressive therapy, while ensuring that we aren’t under treating those who do.”

The advent of high-resolution technologies allowed the scientists to look at regions of DNA with much more clarity.

The scientists used a high-resolution tool called single-nucleotide polymorphism (SNP) array to look at copy number alteration (CNA).

CNA is a genetic phenomenon that occurs when some regions of the DNA are duplicated or deleted. Normally genes are present in two copies, with one copy inherited from each parent. CNAs are often found in osteosarcoma.

Every year, there are about 300 new cases of osteosarcoma in Canada, most of which occur in adolescents and young adults. The survival rate of about 65 per cent has not changed in about two decades.

While the first step is to use the new marker as a prognostic tool, Malkin says it may eventually be used as a therapeutic target, ultimately leading to improved survival rates for osteosarcoma.

Down the road, the marker may also be able to help determine prognosis in tissue cancers including carcinomas and sarcomas, he explains.

The research was supported by the Canadian Institutes of Health Research and SickKids Foundation.

Provided by University of Toronto (news : web)

Why Pfizer Can’t Cure Cancer

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Posted 06 Aug 2010 — by James Street
Category Finance and Politics of cancer research and treatment, genetic research
By ROBERT LANGRETH

Part 1 in a series

Pfizer is pouring resources into new cancer drugs, but the results have been mediocre. Its most promising cancer drug in testing helps just 5% of lung cancer patients with a particular tumor mutation. Numerous Pfizer cancer trials in broader populations have fizzled. AstraZeneca and other drug companies aren’t doing much better. Most new cancer drugs slow progress of the disease by just a few months.

Cancer geneticist Garth Anderson of Roswell Park Cancer Institute thinks he knows why so many cancer drugs are flopping. If his theory is right, it calls into question the whole premise behind big pharma’s rush to test targeted cancer drugs in common tumors, like colon cancer, breast cancer, and lung cancer. It hints that investors, instead of pouring money into the next cancer-drug startup, may want to place their bets on companies developing better tumor imaging and minimally invasive surgery techniques that could have a bigger impact.

“For the past decade, the whole thrust has been to find the targets, find the drug, and cure the patients. It is failing,” Anderson says. For the vast majority of cancers, “the targeted therapies cannot work.”  He predicts that as more cancer drugs fail in big trials, and drug companies lose money on targeted therapies, “eventually people will wake up and abandon this approach.”

The theory behind targeted cancer drugs is simple: find the key gene mutations driving growth of tumors and then devise drugs that block those mutated proteins. This theory led to breakthrough drugs like Novartis’ Gleevec for chronic myeloid leukemia and Roche’s Herceptin for certain breast cancers.

The flaw in this logic, Anderson says, is that common tumors simply don’t have a few key mutations that can be targeted. They have so much genetic damage that it may be impossible to safely destroy them with drug that hit just one or two bad genes. The problem, Anderson says, is something called genomic instability.  Essentially, it means that tumors are mutating like crazy.

Most common tumors have innumerable gene mutations driving their growth—and that these mutations are changing all the time.  In one study he did in 1999, he found 11,000 genetic changes in the DNA of colon tumors, indicating extensive DNA damage.

It gets worse: within a single large tumor, different cells may have different genetic mutations driving their growth, Anderson says. A drug that hits one of the mutations may shrink part of the tumor initially, but is doomed to fail in the long run—the rest of the tumor will just fill the gap. “It is like stepping on a jellyfish, you may hit part of it but it squirts out somewhere else,” he says. “It is a nightmarish problem.”

Anderson has been working on cancer genetics since 1971, when the idea of cancer-causing genes was new. “I told my parents that we will have this solved by 1980,” he recalls.  “The idea was that cancer is simple, a few bad genes, and we will go after them.”  He first realized that it was going to be far more difficult when data from his colon experiment was starting to roll in the mid 1990s.  At breakfast at a conference in Italy, “we grabbed some napkins and came up

with some numbers” for how many mutations each tumor cell would have.” The numbers were colossal. It was like, ‘oh sh-t, this is a different beast than we thought it was.’”  More detailed data since then has confirmed his early work. A recent Genentech paper in Nature looked at 1507 genes from 441 tumors and found a colossal 2576 genetic mutations.

Anderson is more optimistic about drugs that target tumor blood supply, such as Revlimid from Celgene. These may not be subject to the same resistance problems as targeted drugs that hit tumors directly, he says. Targeting bad genes will work in many less common cancers (such as chronic leukemia) that don’t have massive genetic damage and are driven by just a few genetic changes.  Drugs that boost the immune system against cancer, such the melanoma drug ipilimumab from Bristol-Myers Squibb, could also get around the many-gene-defects problem.

But he thinks much more attention needs to be shifted to developing better surgery methods that will allow surgeons to operate on more patients. “Surgery has been neglected so much. If you get the patient early enough you can cure them. It is crude but effective,” he says. Technology that boosted the number of operable cases would translate directly into higher cure rates. “Yet all the money and all the interest is in drugs.”

So why do drug companies continue to pour so much money into testing cancer drugs, if the odds are so slim?  There is the occasional breakthroughs like Gleevec from Novartis that extend survival for years. But the real reason is that sky-high prices and desperate doctors and patients means even a drug that barely works can sometimes make a bundle.

(In part II, a  more optimistic view)

Understanding apoptosis and its role in tumor development

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Posted 01 Aug 2010 — by James Street
Category genetic research

Scientists at Walter and Eliza Hall Institute in Melbourne have furthered the understanding of programmed cell death (apoptosis) and its role in tumor development.

Apoptosis is a vital process in the human body, as it removes damaged cells from our system. The process is understood to be protective against cancer formation and autoimmune diseases.

The discovery that have shifted the understanding about cell death, based on the study led by Professor Andreas Strasser from the institute’s Molecular Genetics of Cancer Division offers a broader understanding of cancer formation, the results will influence the direction of the ongoing development of a new type of anti-cancer drugs called BH3 mimetics.

Prof Strasser says, “Until now everybody believed that a failure of damaged cells to undergo suicide allowed mutated cells to proliferate, which contributes to tumor development.

“That’s certainly still true but we discovered that, in certain settings, the opposite holds – the body’s natural cell-suicide program can fuel tumor development.”

Based on their experiments, they found that repeated steps of cellular depletion and tissue regeneration, through activation of stem cells, could stimulate tumor formation.

For instance, when the body is exposed repeatedly to low doses of radiation, the DNA is many cells are damaged and there are repeated steps of cell death in the body’s tissues.

Prof Strasser says, “Attempts by the body’s stem cells to repopulate the depleted tissue can then actually drive the tumor development.”

“That’s because the radiation, while killing many cells within a tissue, will create mutations in some of the surviving stem cells. When such abnormal (mutated) stem cells repopulate the tissue, they will divide many times and this can promote the development of tumors.”

Another key element of the research is centered on what happens to mice exposed to radiation, if they lack a gene called Puma. The Puma gene is present in normal mice and it plays an important role in the destruction of cells with damaged DNA.

Prof Strasser says, “If normal mice -which have the Puma gene- are given a low dose of radiation it destroys around 80 per cent of the white blood cells.

“Tha does not kill the mouse but it does mean the stem cells in the bone marrow have to work extra hard to replenish the blood system. This can lead to the formation of tumors of white blood cells called leukaemias, if the stem cells doing the repopulating have cancer-causing mutations.

The results revealed that mice that lacked the Puma gene were protected from tumor development. In mice that did not have the Puma gene that received loses doses of radiation, the white blood cells were not destroyed – thus mutated stem cells were not forced to become activated and divide to replenish the blood system.

The findings on the role of Puma gene in mice, according to Prof Strasser, suggested that risk of cancer was increased in people who experienced cycles of tissue destruction, followed by tissue re-population via stem cells.

He says, “Such cycles may account for liver cancers frequently associated with viral hepatitis C infection or alcohol-related liver damage.”

The study provided insight into the development of secondary cancers in patients who were cured of their primary cancer through the use of chemotherapeutic drugs that triggered DNA damage.

As for the new ongoing development of drugs to kill cancer cells – the BH3 mimetics, Prof Strasser said that chronic exposure to them could lead to the destruction of high numbers of normal cells that would then require replacement.

He believes that in certain circumstances, there is a chance of secondary tumor development, specifically in patients that are receiving chemotherapy or gamma-radiation which can cause cancer-causing mutations in stem cells.

Researcher identify the prostate cell that mutates into cancer

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Posted 29 Jul 2010 — by James Street
Category General Cancer Research, Prostate Cancer, genetic research

On July 29, 2010 UCLA researchers announced that they have identified the prostate cell that mutates into prostate cancer.

It was previously believed that prostate tumors were mutated luminal cells.  (Luminal cells line the prostate tubules.)

Immunologist Owen Witte of UCLA’s Jonsson Comprehensive Cancer Center and his colleagues have discovered that, contrary to the generally accepted hypothesis of luminal cell origin (prostate cancer cells resemble lumen cells) the mutations occur in basal cells which line the outside of the prostate tubules.   (Lumen ducts excrete prostate fluid from the prostate gland into the ejaculatory ducts.)

Owen and his team had originally developed a series of surface markers that allowed them to readily distinguish basal cells from luminal cells. They then showed that, in mice injected with human basal prostate cells, it is the basal cells that produce tumors.

These results were reported in the journal, Science.

A Ph.D student of Witte’s, Andrew Goldstein, is the lead author of the paper.

Genome Studies Start to Unravel Prostate Cancer’s Complexity

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Posted 29 Jun 2010 — by James Street
Category Prostate Cancer, genetic research, genetic research

Genome Studies Start to Unravel Prostate Cancer’s Complexity

Illustration of a DNA strand

Researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) have completed the largest genomic analysis of prostate tumors to date. The results, based on clinical and genomic information collected from 218 patients, provide an overview of the common genetic changes in the disease and point to new directions for research, including a way to potentially differentiate aggressive tumors from those that are not life threatening. The researchers have made the data available to the community through a public Web site, and a summary of the results appeared online last week in Cancer Cell.

“We now have a much better picture of the common genetic alterations in prostate cancer,” said lead investigator Dr. Charles Sawyers. Although more samples need to be analyzed, he continued, the results could provide a roadmap for designing future clinical trials in this disease. “When it comes to developing and testing targeted cancer drugs, you need to be able to subclassify patients, and you can’t do this intelligently until you know what the alterations are.”

This would change how doctors talk to patients about the disease and the need for adjuvant therapy or not, which is why this finding is so exciting.

—Dr. Jonathan Simons

Genome studies have yielded insights into glioblastoma and cancers of the lung, colon, pancreas, and breast, but prostate cancer has been a challenge. Prostate tumors are relatively small, and expert pathologists are needed to obtain adequate samples of tumor tissue. With a large prostate cancer program and skilled pathologists, MSKCC was able to overcome these challenges.

“Dr. Sawyers and his colleagues have made an extraordinarily important contribution to the field of prostate cancer research,” said NCI Deputy Director Dr. Anna Barker. “Certain tumors are going to be difficult to collect and analyze, but this study—which used high-quality samples and multidimensional data—now gives the community new opportunities to understand the disease.”

The researchers sequenced 157 genes that were known to be associated with prostate and other cancers. Mutations in these genes were rare. But when the researchers included additional information, such as DNA copy-number changes (gains and losses of DNA), they identified several genetic pathways, including the PI3K pathway, that were altered in nearly all metastatic tumors and many primary tumors.

“Just as we’ve seen in brain tumors, when you combine all these different sources of information, there is a uniform consistency of pathways that are altered in the disease,” said co-author Dr. Peter Scardino, chairman of the Department of Surgery at MSKCC. “We found many more abnormalities in localized prostate cancer than we expected.”

The researchers also identified a gene called NCOA2 that appears to play an important role in about 11 percent of prostate tumors. The protein encoded by this gene may drive prostate cancer by amplifying signals from the androgen-receptor pathway; this pathway plays a critical role in early- and late-stage prostate cancer.

Potential Biomarker

The analysis also revealed a striking association between changes in DNA copy number and the risk of recurrence after surgery, and this association could not be explained entirely by Gleason score. “This was one of the most exciting findings from the study,” said Dr. Scardino. “It offers the possibility of a biomarker that could be used to characterize the aggressiveness of prostate cancer, which is something we greatly need.”

Doctors currently do not have a way to distinguish between prostate cancers that require aggressive treatment and those that will cause no harm if left alone. Consequently, many men receive treatment unnecessarily. Genomic tests can provide prognostic information in breast cancer, for example, but none yet exists in this disease.

The new findings, if confirmed, represent a prototype for developing these kinds of prognostic tests for prostate cancer, said Dr. Jonathan Simons, CEO and president of the Prostate Cancer Foundation. “This would change how doctors talk to patients about the disease and the need for adjuvant therapy or not, which is why this finding is so exciting,” he added.

Dr. Scardino runs the Specialized Program of Research Excellence (SPORE) in prostate cancer at MSKCC, and his group has launched follow-up studies. The current work was done using frozen tumor specimens collected during prostatectomies. The researchers will now see whether copy-number changes are informative using paraffin-embedded tissues. If the answer is yes, they will test cells obtained from a needle biopsy.

The genome analysis also revealed that some patients whose tumors include a fusion of the genes TMPRSS2 and ERG are also missing part of chromosome 3. This fusion gene occurs in about half of all prostate cancers, and researchers have suspected that other genes also play a role in these cases.

“This deletion on chromosome 3 appears to be very strongly associated with the fusion,” said Dr. Sawyers. “The next steps are to see which genes in the region that is deleted are involved in the disease. We have a clear path forward.”

The TMPRSS2-ERG fusion was discovered in 2005 by University of Michigan researchers supported by NCI’s Early Detection Research Network. At the time, fusions were thought to be limited to cancers of the blood, but it is now known that these alterations are present in common cancers as well. About two dozen have been identified in prostate cancer.

New Class of Gene Fusions

Earlier this month, the Michigan group, led by Dr. Arul Chinnaiyan, reported a new class of prostate cancer gene fusions derived from the RAF pathway. One of these fusions involves the gene BRAF, which plays a role in melanoma. Drugs targeting BRAF are in clinical trials, and it appears, based on experiments in cells, that these drugs may be active in up to 2 percent of patients with prostate cancer, the researchers reported.

“The clinical promise of this discovery is that patients who have these RAF gene fusions may be candidates for drugs that target these changes,” said Dr. Chinnaiyan. “Some of the newer inhibitors, in particular, might be useful in treating this molecular subtype of prostate cancer as well as some other cancers.”

In the future, every man whose prostate cancer is biopsied is going to have his DNA read for gene fusions, just as women have their breast cancers tested for overexpression of the HER2 protein to determine whether they should receive trastuzumab (Herceptin), predicted Dr. Simons. “To cure every man of advanced prostate cancer, we’ll need at least 24 strategies,” he continued. “Now that we know what we’re facing, we can make research plans and do the work.”

Two prostate cancer genome sequences have been presented at scientific meetings and will likely be published later this year, Dr. Simons said. “It’s a complicated disease, but key properties of the disease are going from being in total darkness to full clarity. And that’s what is so amazing.”

For Dr. Barker, a founder of The Cancer Genome Atlas (TCGA) project with colleagues from the National Human Genome Research Institute, the MSKCC study is both exciting and gratifying. Dr. Sawyers and his colleagues essentially followed the TCGA approach by profiling high-quality tumor samples and integrating clinical and multiple kinds of genomic information into their analysis. As with TCGA, they made the results public so that investigators in the community can now mine the information for new insights.

The hope from the beginning of TCGA has been that the approach would be adopted by investigators performing cancer genomics studies in the community, said Dr. Barker. And now that this study has been completed, TCGA investigators will use the data when they launch an even larger study of prostate tumors in the future.

“This study gives us a much better starting point for prostate cancer than we’ve ever had before,” Dr. Barker said. “It’s a great day for cancer research, and an even better day for patients.”

—Edward R. Winstead