Cancer scientists discover new way breast cancer cells adapt to environmental stress

ScienceDaily (May 14, 2011) — An international research team led by Dr. Tak Mak, Director, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Hospital (PMH), has discovered a new aspect of "metabolic transformation," the process whereby tumour cells adapt and survive under conditions that would kill normal cells.

See Also:Health & MedicineBreast CancerCancerBrain TumorLymphomaSkin CancerOvarian CancerReferenceHeat shock proteinHealth benefits of teaBRCA1Metastasis

The findings, published May 15 in Genes and Development, show how breast cancer cells can thrive when deprived of their usual diet of glucose (sugar) and oxygen by turning to fatty acids for energy generation.

"Our results demonstrate that a protein not previously associated with breast cancer is involved in helping these cells to adapt to starvation conditions and to continue their uncontrolled growth," says Dr. Mak, principal investigator and Weekend to End Breast Cancer Chair in Breast Cancer Research at PMH. Dr. Mak is also a Professor at the University of Toronto in the Departments of Medical Biophysics and Immunology.

In the lab, researchers used an anticancer drug called rapamycin to block a molecular signalling pathway within breast cancer cells that stimulates sugar metabolism. However, instead of dying of starvation, the cells continued to multiply. The team also observed an increase in these cells of carnitine palmitoyltransferase 1C (CPT1C), a protein usually found only in the brains of healthy individuals. Moreover, cells engineered to produce high levels of CPT1C were also able to adapt their metabolism as a survival technique.

"In other words," says Dr. Mak, "The cancer cells acted like cheaters on a diet and found a new food source in fatty acids.

"The fact that CPT1C becomes expressed under conditions of metabolic stress highlights the resilience of cancer cells. They are able to adapt to environmental challenges and find alternative sources of food in order to flourish where healthy cells would not survive."

"Our discovery that deprivation of either sugar or oxygen spurs CPT1C expression in tumour cells marks this protein as a potential target for new drug development," says Dr. Mak.

"We also demonstrated that cells that were prevented from using CPT1C to cope with a disruption in sugar metabolism became more sensitive to environmental stress. These findings represent an important stepping stone to developing targeted therapies that can block cancer cells from adapting to environmental challenges and surviving efforts to kill them."

This most recent discovery builds on Dr. Mak's impressive body of work, which has led to important breakthroughs in immunology and our understanding of cancer at the molecular level. Dr. Mak is known for his 1984 landmark scientific paper on the cloning of the genes for the T cell receptor, a key component of the human immune system.

The research published May 15 was financially supported by grants from the Canadian Institutes of Health Research, The Princess Margaret Hospital Foundation, The Canadian Cancer Society, the Forschungskredit of the University of Zurich and Oncosuisse.

Email or share this story:

Surgeon caseload, practice setting affect treatment of small kidney tumors

ScienceDaily (May 14, 2011) — Patients with small kidney tumors are more likely to be offered treatment options based on surgeons' case volume and type of practice than on tumor characteristics, a Mayo Clinic study has found. Fellowship-trained surgeons who practice in academic medical centers with high volumes of patients with kidney tumors were 70 to 80 percent more likely to follow American Urological Association (AUA) guidelines by recommending partial nephrectomy. Surgeons in private practice who see few patients with kidney tumors more often offered radical nephrectomy: removal of the entire kidney.

See Also:Health & MedicineKidney DiseaseToday's HealthcareBrain TumorWounds and HealingCancerOvarian CancerReferenceRenal cell carcinomaKidneyDialysisExcretory system

Mayo Clinic researchers presented their findings during the AUA Annual Meeting in Washington.

"There is wide variability in how renal masses are managed. We must recognize these discrepancies may be due to different perceptions of technical feasibility in performing a partial nephrectomy," says Christopher Weight, M.D., of Mayo Clinic's Department of Urology. "What we're encouraging is a discussion between physicians and patients about all options available. Some patients may benefit from a referral to surgeons with more experience with renal tumors."

The study shows that as kidney tumors get larger and more complex, all surgeons tend to offer a radical nephrectomy. However, the tumor complexity that may result in one surgeon recommending total removal of the kidney may be well below a more experienced surgeon's threshold. Approximately 45,000 Americans require radical or partial nephrectomy each year.

Other study investigators include Simon Kim, M.D., Christine Lohse, Stephen Boorjian, M.D., R. Houston Thompson, M.D., and Bradley Leibovich, M.D., all of Mayo Clinic; and Rodney Breau, M.D., and Paul Cripsen, M.D., formerly of Mayo Clinic.

Email or share this story:

Plasticity of hormonal response permits rapid gene expression reprogramming: Gene expression reprogramming may allow cancer cell growth as well as normal differentiation

Obesity linked to higher risk of prostate cancer progression

ScienceDaily (May 16, 2011) — Even when treated with hormone therapy to suppress tumor growth, obese men face an elevated risk of their prostate cancer worsening, researchers at Duke University Medical Center have found.

See Also:Health & MedicineMen's HealthProstate CancerUrologyProstate HealthObesityDiseases and ConditionsReferenceGeneral fitness trainingUrologyMetastasisTestosterone

The research, reported at the American Urological Association annual meeting on May 15, 2011, advances the link between obesity and prostate cancer, which has generated research interest in recent years as the incidence of both conditions remains high and often overlaps.

"Over the past decades, there has been increasing prevalence of obesity in the U.S. and Europe, and a high rate of prostate cancer that is the second-most lethal cancer for men," said Christopher J. Keto, M.D., a urologic fellow at Duke University Medical Center and lead author of the study.

An estimated one in six U.S. men will be diagnosed with prostate cancer during his lifetime, according to the American Cancer Society; additionally, one in three U.S. men are obese.

To examine the role obesity may play in prostate cancer, Keto and colleagues at Duke identified 287 men whose diseased prostates had been removed at five U.S. Department of Veteran Affairs hospitals from 1988-2009.

Because their cancers had reappeared, the men had also been given androgen deprivation therapy (ADT). The chemical inhibits production of the male hormone testosterone, which fuels prostate tumors.

Men in the study group who were overweight or obese had a three-fold increased risk of cancer progression compared to normal-weight men, despite receiving the same treatment.

Additionally, overweight men had more than a three-fold increased risk of their cancer spreading to the bone compared to normal-weight men, while obese men had a five-fold increase in the risk of metastases.

Keto said additional studies are needed to determine why heavy men fare worse than normal-weight men, even when treated similarly. One area of scrutiny may be the dosage of ADT.

"We think perhaps obese men may require additional ADT," Keto said. "The dose is the same regardless of weight, while most drugs are dosed according to weight."

Stephen J. Freedland, M.D., associate professor of urology in the Duke Prostate Cancer Center and senior author of the study, said the findings build upon the Duke group's broader research efforts into the connection between obesity and prostate cancer.

"By being thematic in our research we can really get to the bottom of something," Freedland said. "The study supports a growing body of literature showing that obese men with prostate cancer do worse. Our next step is to figure out why."

Freedland said knowing that heavy men are at higher risk for bad outcomes could lead to better interventions. He said the Duke group has launched a new trial to test the effects of diet and exercise on overweight and obese men whose prostate cancer treatment includes hormone therapy.

"If obesity is bad for prostate cancer, we may have to be more aggressive in our treatment," he said. "Ultimately, we aim to learn why, which in turn can lead us to better treatments for these men."

In addition to Keto and Freedland, study authors included William J. Aronson, M.D.; Martha K. Terris, M.D.; Joseph C. Presti, M.D.; Christopher J. Kane, M.D.; and Christopher L. Amling, M.D.

The study was funded by the Department of Defense, U.S. Department of Veterans Affairs, the National Institutes of Health, and the AUA Foundation/Astellas Rising Star Award.

Email or share this story:

Study reveals need for personalized approach in treatment of acute myeloid leukemia

ScienceDaily (May 16, 2011) — A new discovery in mice by researchers at Wake Forest Baptist Medical Center may one day allow doctors to spare some patients with acute myeloid leukemia (AML) from toxic treatments, while also opening the door for new therapeutic research.

See Also:Health & MedicineLeukemiaLung CancerCancerGenesDiseases and ConditionsLymphomaReferenceLeukemiaHodgkin's lymphomaMetastasisLymphoma

AML, the most common form of acute leukemia seen in adults, is an aggressive form of cancer that primarily affects the elderly. Despite years of research, outcomes for most patients remain poor, particularly for one subset of patients with a specific mutation of the FLT3 receptor.

At a microscopic level, each cell's surface is covered in proteins that allow for signals on the outside of a cell to "turn on" various activities inside that cell. FLT3 is one of those receptor proteins. Mutations of the FLT3 receptor are among the most common mutations seen in the disease -- affecting about 20 to 30 percent of AML patients -- and have been associated with worse prognosis.

A new study, published recently in the journal Experimental Hematology, reveals that one particular mutation of the FLT3 receptor, called internal tandem duplication (ITD), alters the patient's responsiveness to standard therapy.

"This research uses a mouse model to define the changes in chemotherapy response that the presence of the FLT3-ITD causes," said Timothy S. Pardee, M.D., Ph.D., an assistant professor of hematology and oncology and lead author of the study. "While its affect on prognosis has been well documented, its affect on therapy response has been poorly understood."

Pardee and colleagues used mice that had leukemia, either with or without the FLT3-ITD, to examine the effects of the mutation on responsiveness to two drugs used in combination as standard chemotherapy treatment for AML patients: cytarabine and doxorubicin. Both drugs work by altering the DNA of cells in different ways, causing them to essentially commit suicide.

The researchers found that the presence of the FLT3-ITD mutation makes cells resistant to doxorubicin, but makes them extra sensitive to cytarabine, when the drugs are administered separately. More importantly, the mutation causes the cells to be resistant overall to the combination of the two drugs, the most common clinical application.

When the mutation occurs, it is a cancer-initiating event. The receptor is no longer able to turn itself off, so it continuously signals the cells to grow and repair damage, such as the damage intentionally caused by doxorubicin.

"The mice who had this mutation seemed to be able to repair certain kinds of DNA damage, specifically, the double strand DNA breaks that the doxorubicin creates," Pardee said. "The FLT3-ITD mutation is telling the cell to repair itself at a pace that keeps up with the amount of damage the drug is designed to cause. If you have a cancer cell that you're trying to kill by doing a certain type of damage and that cell is better at repairing that kind of damage, you have to do more damage to get the cell to die. The mice that were treated with just doxorubicin died at the same rate as those that received no treatment at all."

And, while the FLT3-ITD mutation seems to make cells more sensitive to the impact of cytarabine when exposed to just the one drug, the mutation lessens the impact of the combination of the two drugs together.

"It's almost like the doxorubicin is protecting the cancer cells somewhat from the impact of the cytarabine, which is trying to kill the cell," Pardee said. "When this mutation is present, there is no benefit to adding the doxorubicin. The amount of leukemia does not lessen with the use of it."

Doxorubicin falls into a class of extremely toxic drugs known as anthracyclines. As with other chemotherapy agents, they are known to cause hair loss. However, they are also known to suppress normal cells in the bone marrow and to cause cardiac toxicity. Treatment with drugs of this class can directly injure the heart muscle and sometimes even cause heart failure, Pardee explained.

"Virtually every AML patient in America and Europe who can handle this combination of drugs will receive this standard treatment under current practice guidelines," Pardee said. "More studies are needed to determine the applicability of these findings in humans, but this study shows, in an animal model, that those with the FLT3-ITD mutation are deriving no benefit from the addition of doxorubicin.

"We're hopeful that in the future, these findings will lead to more personalized patient care," he said. "The 'one-size-fits-all' approach to treating AML needs to be re-examined."

In addition to investigating ways to personalize approaches in treatment, Pardee said that future research may focus on developing drugs that can be combined with cytarabine in patients with this mutation and be effective, perhaps by inhibiting the FLT3 receptor or working in ways other than creating double strand DNA breaks.

This research was funded by several sources including the Leukemia and Lymphoma Society, National Cancer Institute, and Wake Forest University Comprehensive Cancer Center. Johannes Zuber, M.D., and Scott W. Lowe, Ph.D., of the Cold Spring Harbor Laboratory, in New York, appear as co-authors on the paper. Lowe is also affiliated with Howard Hughes Medical Institute, in New York.

Email or share this story:

Detecting lung cancer early: Researchers lay foundation for future blood test

ScienceDaily (May 16, 2011) — A person's blood reveals whether he or she has lung cancer, according to researchers at the University of Bonn in Germany. In collaboration with colleagues at the Cologne University Hospital, they are developing a blood test for smokers which could save human lives in the future, since the earlier a lung tumor is detected, the better the chances of survival are.

See Also:Health & MedicineLung CancerLung DiseaseDiseases and ConditionsBrain TumorColon CancerCancerReferenceMetastasisLung cancerTumor suppressor geneTumor

The study has just been published in the journal Clinical Cancer Research.

Scientists working with Professor Dr. Joachim L. Schultze have identified over 480 molecules whose concentration in the blood changes when a person develops lung cancer. These molecules are present in the blood cells either in increased or decreased quantities. "In lung cancer patients, typical patterns which can be detected with a measuring program thus emerge," explains Prof. Schultze. The molecules are nucleic acids which form in the body when certain genes are transcribed.

The changes in the blood also occur if the tumor is still in a very early stage. In lung cancer, there are four different stages, explains Prof. Schultze: "The prognosis for patients in stage 3 and 4 is still very poor even today; even with the most modern therapies, the point of death can only be postponed." Lung cancer in stage 1, on the other hand, can be treated surgically and it can even be cured in many cases. "Today, however, a tumor is seldom detected so early, namely in only about 15% of all cases. If a simple screening blood test would increase this percentage, a large proportion of lung cancer patients could survive," says Prof. Schultze. By contrast, to date, over 80% of all lung cancer patients die within two years after diagnosis, since the tumor is already too far advanced.

Screening for lung cancer: Results within a day

In the future, a lung cancer screening test may become part of routine practice: The doctor takes a blood sample from his/her patient, and within 24 hours, he knows with a high degree of certainty whether the patient has lung cancer or not − even if the patient does not yet have any symptoms.

For many years, the team working with Prof. Joachim Schultze has investigated the blood of over 200 smokers. About half of them had lung cancer; the others were either entirely healthy or suffered from another lung disease. "It was important to us that a subsequent test not only be able to differentiate lung cancer patients from healthy subjects, but also from persons with chronic lung diseases." The researchers then examined the research subjects' blood using biochips for certain nucleic acids and in doing so, they found the typical patterns.

The researchers are presently planning an analogous but much larger study with ten times as many patients, in order to confirm the results. If the present results prove to be true in such a study, there would no longer be anything standing in the way of developing the blood test to the point of being ready to be put on the market.

Email or share this story:

Abcc10 may be effective in extending the effectiveness of anticancer drugs

ScienceDaily (May 16, 2011) — Today's anticancer drugs often work wonders against malignancies, but sometimes tumors become resistant to the effects of such drugs, and treatment fails. Medical researchers would like to find ways of counteracting such resistance, but first they must understand why and how it happens. New findings by Fox Chase Cancer Center researchers identify one protein, Abcc10 (also known as Mrp7), as being intimately involved in resistance to certain drugs used to treat breast, ovarian, lung, and other cancers. The results suggest that blunting the activity of Abcc10 might help counter resistance and extend the effectiveness of these anticancer drugs.

See Also:Health & MedicineLung CancerCancerColon CancerBrain TumorLeukemiaHIV and AIDSReferenceChemotherapyHeat shock proteinNanomedicineEmbryonic stem cell

The findings appear in the May 16, 2011 issue of the journal Cancer Research.

In earlier work, Elizabeth A. Hopper-Borge, Ph.D., an assistant professor at Fox Chase, showed that Abcc10 confers resistance to a number of anticancer agents, particularly taxanes, which include paclitaxel (Taxol) and docetaxel (Taxotere). These drugs--originally derived from the Pacific yew tree--work by disrupting cell division, thus arresting the growth and spread of tumors. The initial finding that Abcc10, a member of a ubiquitous family of proteins called ATP-binding cassette transporters, thwarts taxanes' anti-tumor activity was something of a surprise, says Hopper-Borge, because none of the other family members seem to have that ability.

In the new research, Hopper-Borge and colleagues wanted to further explore, in both cultured cells and mice, the role of Abcc10. They developed a "knockout" mouse, in which the gene that codes for Abcc10 was missing, or knocked out. These mice appeared normal and healthy in every other respect, suggesting that Abcc10 is not essential for overall health and survival.

The researchers isolated cells from the knockout mice and tested the cells' reactions to taxanes and two other anticancer drugs, vincristine and Ara-C. Compared to cells from normal mice that still possessed the gene for Abcc10, the knockout mouse cells were much more sensitive to the drugs.

Abcc10 and its ilk work by pumping drugs out of cells, so one might expect to see the drugs accumulating in cells that lack Abcc10, and that's exactly what Hopper-Borge's group saw. It had been suggested that other proteins might take over for Abcc10 if that protein were knocked out, but the researchers found no evidence suggesting that had happened.

Next, the research team studied the effects of one particular taxane, paclitaxel, on mice and found that the knockout mice were more sensitive to the drug, as reflected in body weight, white blood cell count, and ability to survive escalating doses of the drug.

"After seeing the effects on white blood cells, we decided to look at the tissue types that produce white blood cells to see if we could actually see differences there," says Hopper-Borge. As expected, knockout mice treated with paclitaxel had smaller spleens and thymus glands and underdeveloped bone marrow, compared to normal mice treated with the same drug.

The results provide the first evidence from living organisms that Abcc10 is a cell's built-in protection against the effects of powerful drugs, and raises the possibility of using Abcc10 inhibitors to break down that resistance and sensitize tumor cells to anticancer agents. The fact that mice lacking the protein have no obvious health problems is encouraging, suggesting that Abcc10 inhibitors could be used in human patients without causing side effects that might be expected to result from interfering with the pump's normal functions.

Several Abcc10 inhibitors already have been identified, but they also inhibit other cellular transporters, which could have deleterious effects. For that reason, Hopper-Borge thinks the best approach may be developing inhibitors that work only in tumor cells or coming up with compounds that modulate, rather than completely inhibit the protein's activity.

But using such treatments in patients is still far in the future, she emphasizes.

"I'd like to stress that we did this work in a mouse model," Hopper-Borge says. "Our results so far suggest that this protein may be a clinically relevant target, but we need to do more studies to find out for sure."

Co-authors on the study include Timothy Churchill, Chelsy Paulose, Emmanuelle Nicolas, Joely D. Jacobs, Olivia Ngo, Andres J. Klein-Szanto and Martin G. Belinsky of Fox Chase; Yehong Kuang of Central South University, Changsha, China; Alex Grinberg and Heiner Westphal of the National Institute of Child Health and Human Development; and Gary D. Kruh of the University of Illinois at Chicago.

The research was supported by the National Institutes of Health.

Email or share this story:

Researchers examine procedure utilization trends in patients with clinically localized renal masses

ScienceDaily (May 15, 2011) — New techniques in science and technology allow the medical community to continually improve patient care and experience, but as these new procedures are introduced, physicians must closely consider the relative risks and benefits for each patient. Laparoscopic surgery offers the short-term benefits of smaller incisions, shorter hospital stays, and less pain during recovery, but are there negative consequences in the long run for some patients? Certain groups of patients, like those with localized renal masses, may be more appropriately treated through surgical techniques that focus on preserving as much functional kidney as possible--especially since emerging data suggests that a loss of kidney function can lead to higher long-term risks of morbidity and mortality.

See Also:Health & MedicineKidney DiseaseToday's HealthcareDiseases and ConditionsWounds and HealingMedical ImagingPersonalized MedicineReferenceExcretory systemDialysisLaparoscopic surgeryRenal cell carcinoma

A new study to be presented by researchers from Fox Chase Cancer Center on Saturday, May 14, 2011, at the AUA 2011 Annual Meeting, examines whether the rapid adoption of minimally invasive techniques on the national level has had a negative impact on utilization rates of partial nephrectomy for patients with clinically localized renal masses.

"The AUA guidelines for localized renal masses recommend that kidney preservation is paramount when treating localized masses, but the rise of the number of partial nephrectomies--procedures that remove only part of a person's kidney--over time is lower than expected," says Marc Smaldone, M.D., urologic oncology fellow and lead author on the study. "As patient care evolves over time, we would expect to see the number of kidney preserving procedures increasing. Unfortunately, our results demonstrate that radical nephrectomy rates have remained consistent, which may be due to the preferential adoption of laparoscopic nephrectomy over partial nephrectomy in community practice."

When treating a patient with a localized renal mass, doctors have many surgical options. In radical procedures, surgeons remove the entire kidney, while partial nephrectomy techniques focus specifically on tumor removal while preserving as much functional kidney as possible. Either procedure may be performed via an open procedure through a large incision or a minimally invasive (or laparoscopic) approach.

In their study, researchers at Fox Chase demonstrated a dramatic 58 percent decrease in the percentage of open radical nephrectomy procedures performed from 1995 to 2005. However, they also observed more than a two-fold increase in laparoscopic nephrectomies in comparison to kidney sparing procedures over the same time period. These results suggest that more urologists are opting for laparoscopic nephrectomy, which may be due to increased familiarity and technical ease over more complex open or laparoscopic kidney preserving procedures. As a result, there is not the expected increase in the number of kidney preserving operations being performed, and more patients than necessary are being exposed to the adverse long-term consequences of chronic renal insufficiency.

"Knowing what we do about the long-term risks associated with removing a person's kidney, such as higher rates of long-term morbidity, it is crucial that, as physicians, we are doing all we can to spare as much of the organ as possible," says Robert G. Uzzo, M.D., F.A.C.S., chairman of the department of surgery at Fox Chase and member of the AUA Guidelines Council. "In this study, we're seeing a preference for laparoscopic procedures when we should be seeing a preference for nephron-sparing procedures."

To investigate this issue, Fox Chase identified 6,716 patients who underwent surgery for clinically localized renal masses between 1995 and 2005, drawn from linked SEER-Medicare data. They then compared utilization rates over time of four differing surgical procedures: open radical nephrectomy (ORN), laparoscopic radical nephrectomy (LRN), open partial nephrectomy (OPN), and laparoscopic partial nephrectomy (LPN). Their results demonstrate that over the ten-year period, utilization of nephron-sparing techniques--or partial nephrectomy--only increased by 15.5%, whereas 77% of patients with localized tumors were still managed with radical nephrectomy in 2005.

"Studies like these highlight that practice patterns evolve slowly over time, but more research is necessary," says Smaldone. "We now need to further investigate which types of institutions are performing specific procedure types and which patients have access to kidney preserving surgeries. These studies will ultimately help to ensure that we are providing all patients access to the best possible care."

"It is important that patients seek out care from physicians with expertise in kidney preservation techniques," adds Uzzo. "The benefits of laparoscopy don't offset the consequences of removing a patient's entire kidney if it's avoidable, and often, at most expert centers, a patient can receive the benefits of both through a laparoscopic partial nephrectomy."

Co-authors on the study include Fox Chase researchers Alexander Kutikov, Daniel J. Canter, Brian L. Egleston, Rosalia Viterbo, Ervin Teper, David Y.T. Chen, Richard E. Greenberg, and Robert G. Uzzo.

Statistical support for this project was supported by Fox Chase Cancer's Keystone Program in Personalized Kidney Cancer Therapy. Established in 2008, this collaborative program brings researchers and clinicians from multiple disciplines together to investigate the biological mechanisms that lead to kidney cancer metastasis and to uncover the molecular signals that predict how an individual patient's kidney tumor will respond to therapies. Ultimately, the research supported by this privately-funded program will allow clinicians to optimize therapies for a given patient based on the unique molecular characteristics of his or her tumor.

Email or share this story:

Rapid growth may be appropriate trigger for treatment in patients with renal masses

ScienceDaily (May 15, 2011) — With an increase in abdominal imaging over the past decade, there has been an increase in the detection of incidental kidney cancer, which has led to concerns that we may be over-treating indolent disease. As part of this effort, clinicians have started to investigate the effectiveness of active surveillance (AS), or close observation as opposed to immediate surgery, for select patients with small renal masses (SRMs).

See Also:Health & MedicineLung CancerKidney DiseaseDiseases and ConditionsToday's HealthcareBreast CancerPersonalized MedicineReferenceHysterectomyMetastasisRenal cell carcinomaUrology

Fox Chase Cancer Center researchers have announced the results of its systematic review and pooled analysis, which for the first time combined several institutions' experience with active surveillance of small renal masses. Their goal was to identify trends in radiographic tumor growth rates and progression to either treatment or metastasis, and found that in select patients, active surveillance may be a viable option when surgery is risky due to poor health or advanced age.

Marc Smaldone, M.D., urologic oncology fellow at Fox Chase and lead author on the study, will present the results at the AUA 2011 Annual Meeting on Tuesday, May 17, 2011.

"Kidney cancer is most often a surgically treated disease, so studies such as this one, which help to confirm that active surveillance with curative intent can be an effective strategy for certain patients, are crucial," says Smaldone. "Surgery has substantial consequences for many patients with competing risks such as heart or lung disease. The ability to offer a management strategy that avoids the risks of potentially unnecessary surgery is an attractive concept in contemporary cancer treatment."

To further investigate the risks of cancer progression in patients undergoing active surveillance, Fox Chase researchers combined all the available individual data published by institutions examining the observation of small renal masses. The team identified and pooled a total of 18 institutional series, of which Fox Chase's experience represented the largest published series. The researchers then examined the pooled experience for trends in radiographic growth rates, tumor size at presentation, and progression to treatment or metastasis.

They found that, of the observed 936 SRMs in 880 patients, only a very small proportion -- 2.1% (18 patients) -- progressed to metastasis. Pooled analysis of progressors and non-progressors revealed significant trends including increased age, increased tumor size at presentation, and increased growth rates in the progression group. These metrics can be used to help determine if a patient should stop surveillance and undergo surgical intervention for his or her SRM. However, Fox Chase researchers learned that growth kinetics alone cannot predict a tumor's natural growth history. Therefore, active surveillance should not be considered an equivalent alternative to definitive surgical therapy, but it can be used as an initial short-term option for select patients who are poor surgical candidates.

"There is a perception that all cancers, once detected, should be treated immediately because they are all equally lethal, but what we've seen in this study is that small, asymptomatic kidney cancers can be managed through active surveillance," says Robert G. Uzzo, M.D., F.A.C.S., chairman of the department of surgery at Fox Chase and member of the AUA Guidelines Council. "As a medical community, we need to recognize this shift and begin to risk stratify patients and counsel them based on criteria other than the presence of small renal masses on scans."

While more research is necessary, this study suggests that growth kinetics may be the best measurement currently available for determining which patients should undergo immediate intervention and which should not. As a supplement to radiographic data, future biomarker discovery in conjunction with percutaneous -- or renal biopsy -- might ultimately influence management decisions on an individual patient basis. Based on these findings patients should seek out urologic oncology experts to help them understand the implications of small kidney cancers and avoid overtreatment.

Co-authors on the study include Fox Chase researchers Alexander Kutikov, Daniel J. Canter, Brian L. Egleston, Rosalia Viterbo, David Y.T. Chen, Richard E. Greenberg and Robert G. Uzzo.

Statistical analysis for this research was supported by Fox Chase Cancer Center's Keystone Program in Personalized Kidney Cancer Therapy. Established in 2008, this collaborative program brings researchers and clinicians from multiple disciplines together to investigate the biological mechanisms that lead to kidney cancer metastasis and to uncover the molecular signals that predict how an individual patient's kidney tumor will respond to therapies. Ultimately, the research supported by this privately-funded program will allow clinicians to optimize therapies for a given patient based on the unique molecular characteristics of his or her tumor.

Email or share this story:

Leucine deprivation proves deadly to malignant melanoma cells

ScienceDaily (May 16, 2011) — Whitehead Institute researchers have found that depriving human melanoma cells of the essential amino acid leucine can be lethal to the cells, suggesting a possible strategy for therapeutic intervention.

See Also:Health & MedicineSkin CancerBrain TumorStem CellsLymphomaDietary SupplementLung CancerReferenceEssential nutrientBiochemistryGlutamic acidCells of the stomach

The researchers observed the effect in melanoma cells with a mutation in the RAS/MEK signaling pathway -- the most common mutation found in the deadliest form of skin cancer.

Leucine is one of nine essential amino acids humans must ingest, as we are unable to synthesize them. These nine, along with 12 non-essential amino acids, are the building blocks of proteins used in muscle production and normal cell functions. Cellular amino acid levels and other nutrients are monitored by the mTOR pathway. Typically, when levels of one or more amino acids drop too low, the mTOR pathway is turned off, which activates a process called autophagy.

During autophagy, the cell attempts to boost amino acid levels by breaking down the cell's protein-based structures back into their amino acid components. This is similar to the entire body breaking down fat and muscle when it is on a diet. For a cell, autophagy is a short-term survival mechanism.

According to their paper published in the May 17 issue of Cancer Cell, researchers in the lab of Whitehead Institute Member David Sabatini found that melanoma cells with RAS/MEK pathway mutations short-circuit this chain of events.

"The odd thing is that if you remove this one essential amino acid, leucine, the melanoma cells don't activate autophagy," says Sabatini, who is also a professor of biology at MIT and a Howard Hughes Medical Institute (HHMI) investigator. "Because leucine is essential, they eventually die. Potentially, that could be used as a way of targeting the melanoma cells if one could mimic the lack of leucine."

When melanoma cells with RAS/MEK pathway mutations are deprived of leucine, mTOR does not sense it, so mTOR does not turn off, and autophagy never begins. Instead, the cells behave as if there were no nutrient shortage until they reach a metabolic crisis and die.

Although cells in a test tube can be deprived of leucine completely, removing leucine from a mouse or a human is almost impossible, due to large leucine reservoirs in muscles. To test how leucine deprivation works in an animal model, Joon-Ho Sheen, who is first author of the Cancer Cell paper, implanted human melanoma tumors with RAS/MEK pathway mutations into mice. He then fed the mice a leucine-free diet. Within a few days, the leucine concentration in the mice's blood dropped from about 110 micromoles to 60 or 70 micromoles. As the blood leucine levels dropped, so too did the leucine levels within the mice's cells. Still, the drop in leucine wasn't sufficient to kill the melanoma cells in vivo.

Sheen then gave the mice the drug chloroquine along with a leucine-free diet. Chloroquine, which is an anti-malaria drug, inhibits autophagy. With the one-two punch of chloroquine and a leucine-free diet, the melanoma cells died, significantly reducing tumor sizes compared with mice fed either a normal diet or a leucine-free diet without chloroquine.

For Sheen, these results raised more questions, particularly with regard to potential therapeutic applications.

"Thanks to the pioneering work by others in the autophagy field, we were able to show that leucine deprivation triggers apoptosis in melanoma cells. I think our work provides a framework, but there are many areas to fill in," says Sheen, who is a postdoctoral researcher in the Sabatini lab. "In practice, how can you deprive just leucine in humans? Maybe using some sort of enzyme that degrades leucine or a small molecule inhibitor that blocks leucine's uptake by cells. And we need a better way to target autophagy; chloroquine isn't very efficient at this. And those are just the immediate, foreseeable issues."

This research was supported by the National Institutes of Health (NIH), the U.S. Department of Defense (DoD), the Jane Coffin Childs Memorial Fund for Medical Research, and the American Brain Tumor Association.

David Sabatini's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

Email or share this story:

Cell rigidity linked to activity in proteins associated with cancer

ScienceDaily (May 16, 2011) — An unusual collaboration between cell and developmental biologists and physicists at UNC-Chapel Hill is providing insights into the relationship between the physical properties of cells and the signals that influence cell behavior.

See Also:Health & MedicineLung CancerStem CellsBrain TumorCancerOvarian CancerLymphomaReferenceHeat shock proteinMetastasisTumor suppressor geneNatural killer cell

In a paper published online May 15 in the journal Nature Cell Biology, a team led by Keith Burridge, PhD, Kenan distinguished professor of cell and developmental biology and a member of UNC Lineberger Comprehensive Cancer Center, and Richard Superfine, PhD, Taylor-Williams distinguished professor of physics and astronomy, demonstrates that exerting mechanical force on cells activates Rho GEF proteins through distinct signaling pathways. The Rho GEFs activate Rho proteins that are part of the RAS superfamily -- a class of proteins associated with cancer activity.

The cross-disciplinary team applied magnetic particles to cells and then used magnets to exert force on the cells -- creating extracellular tension.

"This experiment was only possible because we were able to bring together a team of physicists and cell biologists," said Burridge.

"It's very exciting because we have identified the entire pathway between the tension exerted on the cell to proteins that, in turn, activate other proteins that we know tend to be hyperactive in cancer," he added.

Scientists have long believed that the mechanical environment of cells affects their growth and properties. For example, solid tumor cells tend to have an altered stiffness. Other researchers have shown that the stiffer the cell matrix, the worse the prognosis. There is evidence that rigid tumors shed more cells, which escape the original tumor site and may lead to a greater chance of cancer spreading through metastasis.

"There has been a hypothesis that cell stiffness and tension create a vicious cycle leading to enhanced growth, more cell density, more tension, and larger tumors," said Burridge. "Innovation funding from the University Cancer Research Fund allowed us to identify the pathway and provided data that resulted in a grant renewal worth approximately $1.3 million over the next four years."

In addition to Burridge and Superfine, the research team included postdoctoral fellow Christophe Guilluy, PhD, and assistant professor Rafael Garcia-Mata, PhD, from the Department of Cell and Developmental Biology and graduate student Vinay Swaminathan, PhD, and assistant professor E. Timothy O'Brien, PhD, from the Department of Physics and Astronomy.

In addition to the UCRF innovation grant, this research was supported by the National Institutes of Health and a Marie Curie Outgoing International Fellowship from the European Union Seventh Framework Programme.

Email or share this story:

Common anti-inflammatory coaxes liver cancer cells to commit suicide

ScienceDaily (May 16, 2011) — The anti-inflammatory drug celecoxib, known by the brand name Celebrex, triggers liver cancer cell death by reacting with a protein in a way that makes those cells commit suicide, according to a new study.

See Also:Health & MedicineBreast CancerLung CancerCancerColon CancerLiver DiseaseProstate CancerReferenceCOX-2 inhibitorAnalgesicNanomedicineAntiviral drug

Researchers also found that the combination of celecoxib with each of two chemotherapy drugs killed more liver cancer cells in culture, making those combinations more effective than either drug on its own.

"Each chemotherapy drug alone will reduce the growth of cancer cells, but when each single drug is combined with Celebrex, a greater growth suppression effect was observed," said Jiayuh Lin, senior author of the study and an associate professor of pediatrics at Ohio State University. "For clinicians, this research suggests the possibility of a new therapeutic strategy."

Celecoxib has this effect by acting on STAT3, a gene inside liver cancer cells that, when activated, allows those cancer cells to resist the effects of chemotherapy drugs. The researchers determined that the celecoxib molecule binds to STAT3 on so-called "hot spots," effectively blocking its ability to function.

Powerful computing techniques were employed before the researchers ever considered celecoxib as a potential treatment for cancer. Celebrex is a nonsteroidal anti-inflammatory drug, or NSAID, and a Cox-2 inhibitor, meaning it helps control inflammation by inhibiting an enzyme known as cyclooxygenase-2. It is most commonly prescribed to treat the pain of arthritis.

Chenglong Li, an assistant professor of medicinal chemistry and pharmacognosy at Ohio State, has developed computer simulations to identify optimal drug fragment combinations that attach simultaneously to proteins in ways that block the proteins' functions. By searching a database of existing federally approved drugs, he found that celecoxib was structurally similar to a template molecule that he had determined would most effectively bind to STAT3 and inhibit its function.

"Normally, STAT3 is persistently activated in cancer cells. If you have a good molecule that sticks to STAT3, it will prevent its activation," Li said. And when STAT3 is inhibited, cellular survival pathways are blocked that cause the cancer cell to chop itself up and die.

The research appears online and is scheduled for later print publication in the journal Cancer Prevention Research.

The biological portion of the study further defined the role of a pro-inflammatory protein in liver cancer's development. The protein, called interleukin-6, or IL-6, is a cytokine, a chemical messenger that causes inflammation, which can have both beneficial and damaging effects in the body. Previous research by other scientists has shown that high levels of IL-6 in the blood are associated with hepatocellular carcinoma, the most common type of liver cancer.

Lin and colleagues determined that IL-6 initiates a chemical reaction called phosphorylation of STAT3. That reaction activates STAT3 inside liver cancer cells, where STAT3 in turn activates at least three other known genes that allow the cells to resist the effects of chemotherapy.

The scientists treated five different types of hepatocellular carcinoma cells with two different doses of celecoxib for two hours, and followed by giving them IL-6 for 30 minutes. The pre-treatment with the lower dose of celecoxib inhibited IL-6's ability to start the reaction that activates STAT3. The higher dose blocked STAT3 altogether.

The researchers then treated a line of liver cancer cells with celecoxib in combination with two chemotherapy drugs: doxorubicin, which is used to treat breast, ovarian, gastric, thyroid and several other cancers, and sorafenib, which is the only chemotherapy medication approved by the Food and Drug Administration for liver cancer treatment. Its brand name is Nexavar.

With both drugs, the addition of celecoxib treatment reduced the number of viable liver cancer cells by anywhere from approximately 50 percent to more than 90 percent, depending on the doses. The combination of celecoxib and sorafenib also significantly limited the cancer cells' ability to form colonies, a key element of tumor growth and survival after the drug treatment.

"Because liver cancer has a very low five-year survival rate, it is most likely that even sorafenib alone may not be effective to cure the cancer," said Lin, also an investigator in Ohio State's Comprehensive Cancer Center and the Center for Childhood Cancer at Nationwide Children's Hospital. "We hope that using both drugs together could be more effective. Both celecoxib and sorafenib are already approved by the FDA, so we think this combined treatment should be able to be used in the clinic pretty quickly."

The fifth most common cancer in humans, liver cancer remains one of the most difficult to successfully treat. Patients' overall five-year survival rate is about 10 percent, according to the American Cancer Society.

These experiments were conducted in cell cultures. Further testing would be needed to determine celecoxib's effectiveness in human cancers, Lin noted.

And the powerful computational work led by Li, also an investigator in Ohio State's Comprehensive Cancer Center, is likely to lead to the development of new molecules with even more precise structural relationships with the proteins they are designed to block.

Li's method is called Multiple Ligand Simultaneous Docking. In this work, he used computer simulations to identify "hot spots" on the STAT3 protein -- tiny pockets to which molecules could most successfully attach to inhibit the protein's activity. He then searched through drug banks containing more than 7,500 existing and experimental medications to find the most suitable molecular fragments that could be pieced together to produce a new molecule shaped in such a way that it would fit into those pockets.

After designing a template molecule that would most effectively bind to STAT3, he compared that template to the 1,400 federally approved drugs already on the market.

"Celecoxib is almost identical to the molecule template. It attaches to STAT3 in three places. We can optimize celecoxib, and that is expected to come soon. But applying our technique to find those pieces and determining that they come from an existing drug makes the discovery process much faster," said Li, a key co-author of the paper and frequent research collaborator with Lin.

Li has termed this approach as in silico (computer-driven) drug repositioning or repurposing.

The discovery that celecoxib can bind to STAT3 also appears to apply to other cancers. Both Lin and Li were key authors on a recent paper that suggested that celecoxib's ability to block STAT3's function might also make it effective as a treatment for rhabdomyosarcoma, the most common soft tissue cancer in children and adolescents. This research was published in the April 15 issue of the journal Biochemical and Biophysical Research Communications.

Co-authors of the liver cancer and rhabdomyosarcoma studies include Yan Liu, Aiguo Liu and Suzanne Reed of the Center for Childhood Cancer at Nationwide Children's Hospital (Aiguo Liu is also affiliated with Tongji Hospital at Huazhong University of Science and Technology in Wuhan, China); and Huameng Li of Ohio State's Division of Medicinal Chemistry and Pharmacognosy and the Biophysics Graduate Program.

This work was supported by grants from the National Institutes of Health and the Department of Defense Congressionally Directed Medical Research Programs.

Email or share this story:

Low-dose sorafenib may improve therapy for head and neck cancer

ScienceDaily (May 16, 2011) — Adding low doses of the targeted agent sorafenib to the chemotherapy and radiation now often used to treat head and neck cancer might significantly improve patient care and quality of life, according to a new study by researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James).

See Also:Health & MedicineBrain TumorColon CancerLung CancerMind & BrainBehaviorMental HealthCaregivingReferenceMetastasisTumor suppressor geneNanomedicineRenal cell carcinoma

The findings suggest that adding sorafenib would maintain treatment efficacy while permitting the use of lower doses of chemotherapy and radiation and decreasing the treatment's harsh side effects. The triple combination was well-tolerated in an animal model.

About 49,200 new cases of head and neck cancer are expected in the U.S. this year, and 11,500 people are expected to die of the disease. Treatment is often unsuccessful because the tumors become resistant to both chemotherapy and radiation therapy.

"This pre-clinical study suggests that using low-dose sorafenib along with chemotherapy and radiation could have significantly milder side effects while maintaining effectiveness," says researcher and principal investigator Dr. Pawan Kumar, assistant professor of otolaryngology and a neck surgeon at the OSUCCC -- James.

"Our findings provide a scientific rationale to evaluate this combination strategy through a clinical trial," Kumar added.

The results of the laboratory and animal study are published online in the journal Molecular Cancer Therapeutics, and they include the following:

Sorafenib sensitized tumor cells to chemotherapy and radiation treatment by down-regulating DNA repair proteins (ERCC-1 and XRCC-1), and it decreased tumor angiogenesis by inhibiting VEGF-mediated signaling. The combination treatment was well tolerated in a mouse model and significantly inhibited tumor growth and tumor angiogenesis; low-dose sorafenib alone was an effective maintenance regimen. The combination treatment significantly inhibited tumor-cell migration, invasion and the formation of new tumor blood vessels in laboratory studies.

"Taken together, our results suggest a potentially novel strategy in which sorafenib combined with low doses of chemotherapy, radiation therapy, or both is as effective in the treatment of head and neck cancer as much higher doses used in existing treatment approaches," says study co-author Dr. Theodoros N. Teknos, professor of otolaryngology, director of head and neck oncologic surgery, and the David E. and Carole H. Schuller Chair in Head and Neck Oncologic Surgery. "As a result, it may be possible to design new treatment regimens that limit side effects of therapy without decreasing cure rates."

Funding from the National Cancer Institute and Joan's Fund supported this research.

Other Ohio State researchers involved in this study were Arti Yadav and Bhavna Kumar.

Email or share this story:

New biomarker predicts breast cancer relapse

ScienceDaily (May 16, 2011) — Researchers from Virginia Commonwealth University Massey Cancer Center have discovered a new biomarker related to the body's immune system that can predict a breast cancer patients' risk of cancer recurrence. This breakthrough may lead to new genetic testing that further personalizes breast cancer care.

See Also:Health & MedicineBreast CancerCancerBrain TumorDiseases and ConditionsOvarian CancerColon CancerReferenceMetastasisTumor suppressor geneBRCA1Tumor

The study, published in the journal Breast Cancer Research and Treatment, is the first to use tumor infiltrating immune cells located at the site of the tumor to predict cancer recurrence. Using tissue samples from breast cancer patients, researchers found that a specific, five-gene signature related to tumor infiltrating immune cells can accurately predict relapse-free survival. Currently, there are two main tests used to predict the risk of relapse in breast cancer patients, the Oncotype DX panel and the MammaPrint panel. Both of these tests focus on genes that are mainly expressed by tumor cells.

"We know that the body initiates an immune response when it detects cancer, and immune system cells are usually present at the site of the tumor," says the study's lead researcher, Masoud Manjili, D.V.M., Ph.D. assistant professor of microbiology and immunology at VCU Massey. "Our test differs from currently-used tests by looking for a biological response to the presence of cancer, and not relying on genes expressed by the actual cancer cells."

Tissue specimens were collected from female breast cancer patients and maintained in the VCU Massey Cancer Center Tissue & Data Acquisition and Analysis Core (TDAAC) over the past seven years. "We studied data from 17 patients. Of these patients, we had eight that relapsed within five years and nine that have remained cancer-free up to seven years," says Manjili. The five-gene signature was found to predict relapse in these patients with over 85 percent accuracy.

Manjili and his team will next study tissue samples from a larger patient sample to further validate the findings in this study. They also intend to test their findings in a long-term study of breast cancer patients undergoing treatment.

"Our findings could lead to clinical trials that test whether using immunotherapy prior to conventional treatments in breast cancer patients with a high risk of relapse could prime the patients' immune system, much like a vaccine, to prevent the likelihood of relapse," says Manjili.

Email or share this story:

A gene that fights cancer, but causes it too

ScienceDaily (May 17, 2011) — An international team of researchers, led by scientists at the University of California, San Diego School of Medicine, and the Eastern Hepatobiliary Surgery Hospital in China, say a human gene implicated in the development of leukemia also acts to prevent cancer of the liver.

See Also:Health & MedicineLiver DiseaseLeukemiaDiseases and ConditionsCancerPersonalized MedicineGene TherapyReferenceTumor suppressor geneTumorHepatocellular carcinomaMetastasis

Writing in the May 17 issue of the journal Cancer Cell, Gen-Sheng Feng, PhD, UCSD professor of pathology, and colleagues in San Diego, Shanghai and Turin report that an enzyme produced by the human gene PTPN11 appears to help protect hepatocytes (liver cells) from toxic damage and death. Conversely, the same enzyme, called Shp2, is a known factor in the development of several types of leukemia.

"The new function for PTPN11/Shp2 as a tumor suppressor in hepatocellular carcinoma (HCC) stands in contrast to its known oncogenic effect in leukemogenesis," said Feng. "It's a surprising finding, but one that we think provides a fresh view of oncogenesis. The same gene can have oncogenic or anti-oncogenic effects, depending upon cellular context."

Previous studies had determined that PTPN11 was a proto-oncogene. That is, dominant active mutations in the gene had been identified in several types of leukemia patients, as was an over-expression of the gene product Shp2. Feng and colleagues looked to see what happened when Shp2 was knocked out specifically in hepatocytes in a mouse model.

The result wasn't good: The mice got liver cancer.

Strikingly, deficient or low expression of PTPN11 was detected in a sub-fraction of human HCC patient samples by researchers at the Eastern Hepatobiliary Surgery Hospital in Shanghai, China. That work was led by Hongyang Wang, MD, PhD and a professor of molecular biology.

"The liver is a most critical metabolic organ in mammals, including humans," said Feng. "It has a unique regenerative capacity that allows it to resist damage by food toxins, viruses and alcohol. Shp2 normally acts to protect hepatocytes. Removing Shp2 from these liver cells leads to their death, which in turn triggers compensatory regeneration and inflammatory responses. That results in enhanced development of HCC induced by a chemical carcinogen."

Feng said the findings highlight the unique mechanism underlying HCC, but more broadly, they reveal new complexities in how different types of cancer begin. Indeed, the researchers say their work also uncovered pro- and anti-oncogenic activities in a gene transcription factor called Stat3.

"Our results indicate a requirement for Stat3 in promoting HCC development, which is consistent with the literature saying Stat3 is pro-oncogenic. But we also found that deletion of Stat3 in hepatocytes resulted in a modest, but significant, increase in HCC."

Feng said the findings underscore the need for caution in designing therapeutic strategies for treating HCCs and other types of cancers because the answer might also be the problem.

Funding for this study came, in part, from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health and the National Natural Science Foundation of China.

Email or share this story:

Patients referred to dermatologists skin lesions evaluations also found to have other skin cancers

ScienceDaily (May 17, 2011) — Among patients referred by non-dermatologists to dermatologists for evaluation of skin lesions suspected of being malignant, only apparently one-fifth were found to be cancerous, although dermatologists identified and biopsied other incidental lesions, approximately half of which were malignant, according to a report in the May issue of Archives of Dermatology, one of the JAMA/Archives journals.

See Also:Health & MedicineSkin CarePsoriasisSkin CancerWounds and HealingDiseases and ConditionsCosmetic SurgeryReferenceMole (skin marking)BlackheadUterine fibroidsCellulite

"More than one million skin cancers are diagnosed annually in the United States , with one in five Americans developing skin cancer during their lifetime," the authors write as background information in the article. "Non-dermatologists, particularly primary care physicians, play an important role in skin lesion assessment and initiation of referrals to the dermatologist."

Kate V. Viola, M.D., of the Robert Wood Johnson Clinical Scholars Program and Yale University School of Medicine, New Haven , Conn. , and colleagues sought to evaluate the proportion of suspicious lesions identified by non-dermatologists that are found to be malignant compared to the number of secondary skin lesions identified at the time of dermatology referral.

The authors evaluated medical records of 400 patients who were referred by a non-dermatologist to the dermatology service at the Veterans Affairs (VA) Connecticut Health System for evaluation of suspicious skin lesions between January 1, 2006 and December 31, 2009.

Of the 400 patients included in the study, the average age was 77.7 years, 98 percent were white men and 74 (18.5 percent) had a history of skin cancer. Most lesions (224 of 400 or 56 percent) were considered to be non-malignant by the consulting dermatologist, requiring no biopsy. Of the 176 lesions that needed biopsies, 88 were malignant according to the dermatopathology report, meaning 88 of 400 patients (22 percent) had an index lesion (lesions that prompted the referral) that was positive for cancer.

Dermatologists biopsied an additional 111 incidental lesions (secondary lesions identified, not the reason for referral), of which 61 (55 percent) were malignant. Twelve of 61 patients (19.7 percent) with a malignant incidental lesion had an index lesion that was not biopsied. Nearly half of all skin cancers identified were not the referral lesion, and 9.8 percent of the incidental lesions discovered by the dermatologist were melanomas.

In the present study, "a substantial proportion of malignant lesions was incidentally identified by the consulting dermatologist in addition to the primary lesion of concern," the authors write. The authors also suggest that "non-dermatologists may benefit from focused educational initiatives on skin cancer detection, particularly the significance of the total body skin examination and the expectations for and limitations of teledermatology."

Email or share this story:

New prostate cancer test more specific, sensitive than PSA test

ScienceDaily (May 17, 2011) — A new test for prostate cancer that measures levels of prostate specific antigen (PSA) as well as six specific antibodies found in the blood of men with the disease was more sensitive and more specific than the conventional PSA test used today, according to a study by researchers at UCLA's Jonsson Comprehensive Cancer Center.

See Also:Health & MedicineProstate CancerMen's HealthUrologyProstate HealthDiseases and ConditionsOsteoporosisReferenceUrologyMetastasisEmbryonic stem cellProstate cancer

The test, called the A

Breast cancer: New treatment avenue identified

ScienceDaily (May 17, 2011) — Researchers at the CHUM Research Centre (CRCHUM) and the Peter MacCallum Cancer Centre in Australia have identified a new avenue for treating breast cancer.

See Also:Health & MedicineBreast CancerCancerLung CancerOvarian CancerColon CancerSkin CancerReferenceMetastasisBreast cancerHealth benefits of teaTumor suppressor gene

In 20 to 30% of breast cancer patients, the over-expression of a particular protein (human epidermal growth factor-2) is the main cause of the proliferation of cancer cells. Over the past few years Herceptin® (trastuzumab) has become the standard treatment for this kind of cancer. While it is known that it blocks the activity of this protein, its exact mechanism of action has remained a mystery.

Professor John Stagg, a CRCHUM researcher, Professor Mark J. Smyth, with the Peter MacCallum Cancer Centre in Australia, and their colleagues have discovered that in addition to blocking cell proliferation, Herceptin also stimulates the production of interferons, which in turn activate immune cells called lymphocytes.

This study further supports the view that the presence of lymphocytes in tumours enhances treatment success. In addition to revealing the precise workings of Herceptin, this study also showed that combining Herceptin with a therapy that stimulates lymphocytes greatly increases its efficacy in animals.

"These findings open another avenue for breast cancer treatment for nearly a third of all women who are affected," notes Professor Stagg, who is also affiliated with the Faculty of Pharmacy at the University of Montreal and with the Institut du Cancer de Montréal. Clinical trials could get underway in the near future and pave the way for more targeted therapies.

This study was conducted in collaboration with the Peter MacCallum Cancer Centre, East Melbourne, Australia; Jules Bordet Institute, Brussels, Belgium; University of Melbourne, Australia; and Juntendo University, Tokyo, Japan;

The study was funded by the National Health and Medical Research Council of Australia, the Susan Komen Breast Cancer Foundation and the Victoria Breast Cancer Research Consortium (Australia).

Email or share this story:

Obstructive sleep apnea linked to cancer growth in mice

ScienceDaily (May 17, 2011) — A new study links the intermittent interruption of breathing that occurs in patients with obstructive sleep apnea (OSA) to enhanced proliferation of melanoma cancer cells and increased tumor growth in mice, according to researchers in Spain. The study also found tumor cells of OSA mouse models tended to contain more dead cells, indicating a more aggressive type of cancer.

See Also:Health & MedicineBrain TumorSleep Disorder ResearchCancerOvarian CancerLung CancerColon CancerReferenceHeat shock proteinMetastasisObstructive sleep apneaGlioma

The results of the study will be presented at the ATS 2011 International Conference in Denver.

"To our knowledge, this study is the first one providing experimental evidence that a high-rate intermittent lack of oxygen, or hypoxia, mimicking the one experienced by OSA patients enhances tumor growth," said Ramon Farre, PhD, professor of physiology at the University of Barcelona School of Medicine Biophysics and Bioengineering Lab.

Recurrent hypoxia is one of the hallmarks of OSA, which may affect around 5 percent of Americans. OSA has been associated with an increased risk of cardiovascular disease, including high blood pressure, as well as daytime sleepiness and a lower quality of life.

"Although earlier studies in animals have shown that lack of oxygen, or hypoxia, plays an important role in regulating the various stages of tumor formation and progression, the results obtained from human studies including large groups of OSA patients are not easy to interpret because there are other contributing conditions, most notably obesity," Dr. Farre added. "This well-controlled mouse model study allowed us to ensure that the only variable under study was intermittent hypoxia."

In this study, mice injected with melanoma tumor cells were divided among two groups. In the first group, mice were exposed to intermittent hypoxia, where oxygen was restricted for 20-second periods at a rate of 60 periods per hour for six hours per day, and normal oxygen levels for the remainder of the day. In the second group, mice received normal levels of oxygen (normoxia). Tumor volume was measured throughout the study and at the end of the study period. At the end of the 14-day study period, tumors from all mice were removed and weighed and tumor necrosis (indicated by the numbers of dead cells present) was measured to determine the aggressiveness of the tumors.

The authors found that while tumor volume progressively increased with time in both the intermittent hypoxia and control groups, the increase was higher in the mice subjected to intermittent hypoxia. Tumor weight and necrosis in the intermittent hypoxia group were almost two times that of the tumors in the control group.

"With the limitations of any animal model study, these results suggest that the intermittent hypoxia characterizing obstructive sleep apnea could enhance the growth of tumors," Dr. Farre said, adding that although the results were not entirely unexpected based on earlier studies connecting hypoxia with tumor growth, a link between breathing abnormalities specific to OSA and tumor progression had not previously been demonstrated.

"It was well known that continuous hypoxia promotes the growth of cancer cells and tumors," he said. "However, there were no data concerning the effects of the fast rate changes of oxygenation in sleep apnea on cancer."

Dr. Farre said the results of this study could have future clinical implications if the results are confirmed in large-scale human studies. "There are still several questions that need to be answered, both at the basic science and clinical levels," he said.

Future studies would need to evaluate whether intermittent hypoxia also triggers the initial formation of tumors and whether it promotes metastasis, or spread of tumors from one organ to another. Because this study focused on melanoma, Dr. Farre said additional studies should also explore whether intermittent hypoxia affects other types of cancer.

Extended population studies should also determine if there is a relationship between the incidence of cancer and the severity of OSA, as well as addressing the issue of obesity, which has been linked with OSA.

"Intermittent hypoxia is not the sole cancer-promoting challenge experienced by OSA patients," Dr. Farre said. "Obesity is also known to enhance cancer morbidity and mortality, and it is not clear to what extent intermittent hypoxia and obesity could interact to increase cancer growth in OSA patients.

Clarifying these questions certainly will require additional studies," he said. "If the current results in an animal model are confirmed by further clinical research, the public health impact of obstructive sleep apnea would be greater than currently known."

Email or share this story:

Coffee may reduce risk of lethal prostate cancer in men

ScienceDaily (May 18, 2011) — Men who regularly drink coffee appear to have a lower risk of developing a lethal form of prostate cancer, according to a new study led by Harvard School of Public Health (HSPH) researchers. What's more, the lower risk was evident among men who drank either regular or decaffeinated coffee.

See Also:Health & MedicineMen's HealthProstate CancerUrologyProstate HealthBreast CancerColon CancerLiving WellReferenceHealth benefits of teaUrologyMetastasisEmbryonic stem cell

The study was published May 17, 2011, in an online edition of the Journal of the National Cancer Institute.

"Few studies have specifically studied the association of coffee intake and the risk of lethal prostate cancer, the form of the disease that is the most critical to prevent. Our study is the largest to date to examine whether coffee could lower the risk of lethal prostate cancer," said senior author Lorelei Mucci, associate professor of epidemiology at HSPH. Lethal prostate cancer is cancer that causes death or spreads to the bones.

Prostate cancer is the most frequently diagnosed form of cancer and the second leading cause of cancer death among U.S. men, affecting one in six men during their lifetime. More than 2 million men in the U.S. and 16 million men worldwide are prostate cancer survivors.

"At present we lack an understanding of risk factors that can be changed or controlled to lower the risk of lethal prostate cancer. If our findings are validated, coffee could represent one modifiable factor that may lower the risk of developing the most harmful form of prostate cancer," said lead author Kathryn Wilson, a research fellow in epidemiology at HSPH.

The researchers chose to study coffee because it contains many beneficial compounds that act as antioxidants, reduce inflammation, and regulate insulin, all of which may influence prostate cancer. Coffee has been associated in prior studies with a lower risk of Parkinson's disease, type 2 diabetes, gallstone disease, and liver cancer or cirrhosis.

The study examined the association between coffee consumption and the risk of prostate cancer, particularly the risk for aggressive prostate cancer among 47,911 U.S. men in the Health Professionals Follow-Up Study who reported their coffee consumption every four years from 1986 to 2008. During the study period, 5,035 cases of prostate cancer were reported, including 642 fatal or metastatic cases.

Among the findings:

Men who consumed the most coffee (six or more cups daily) had nearly a 20% lower risk of developing any form of prostate cancer. The inverse association with coffee was even stronger for aggressive prostate cancer. Men who drank the most coffee had a 60% lower risk of developing lethal prostate cancer. The reduction in risk was seen whether the men drank decaffeinated or regular coffee, and does not appear to be due to caffeine. Even drinking one to three cups of coffee per day was associated with a 30% lower risk of lethal prostate cancer. Coffee drinkers were more likely to smoke and less likely to exercise, behaviors that may increase advanced prostate cancer risk. These and other lifestyle factors were controlled for in the study and coffee still was associated with a lower risk.

The results from this study need to be validated in additional populations that have a range of coffee exposure and a large number of lethal prostate cancer cases. If confirmed, the data would add to the list of other potential health benefits of coffee. The authors currently are planning additional studies to understand specific mechanisms by which coffee may specifically lower the risk of lethal prostate cancer.

The study was supported by the National Cancer Institute at the National Institutes of Health, the American Institute for Cancer Research, and the Prostate Cancer Foundation.

Email or share this story:

Important step towards early detection of breast cancer

ScienceDaily (May 18, 2011) — European researchers have developed a clinical PET system with the highest resolution and sensitivity in the market, specifically dedicated to breast cancer detection in early stages. The MAMMI (MAMmography with Molecular Imaging) device will allow doctors to start treatments one or even two years earlier than usual and also evaluate the patient's response to chemotherapy.

See Also:Health & MedicineBreast CancerCancerMedical ImagingColon CancerLung CancerWomen's HealthReferenceMammographyBreast cancerMetastasisNuclear medicine

Coordinated by José María Benlloch, researcher of the Spanish National Research Council (CSIC) and co-director of the Institute for Molecular Imaging Instrumentation (I3M), the MAMMI Project was created by a multidisciplinary team of eight European research institutions and companies, ranging from medical oncology and pharmacokinetics research to molecular imaging instrumentation, advanced image processing software and integrated electronics circuit design.

The device is currently installed in the National Cancer Institute in Amsterdam (Netherlands) and was previously set up at the clinic of the Technical University of Munich (Germany), where they have completed the clinical research and examined over fifty patients. The new system will shortly be installed in the Provincial Hospital of Castellón (Spain) and other international hospitals have shown their interest in purchasing it.

The most striking novelty of the mammogram is the way it captures the image. The patient lies face down on a special table, and enters a breast in one of the openings. Beside the stretcher, the specialist positions a trolley that incorporates the detection system based on a gamma ray sensor.

The picture is taken without compressing the breast thanks to the ring shape of the detector that surrounds the pendant breast. According to Dr Benlloch: "This significantly improves the visualisation and diagnosis because sometimes there are tumours that are very close to the base of the pectoral muscle."

This new mammogram also provides greater patient comfort. In this sense, the Biomechanics Institute of Valencia (IBV) assessed the company ONCOVISION in the design, manufacturing, and mechanical tests of the stretcher, and applied user-friendly design methodologies and ergonomic criteria. For example, lifting columns were added to the table to facilitate its use by the elderly and disabled.

The PET system

The other major innovation is the technique used. The traditional mammogram is an x-ray of mammary glands. MAMMI, however, is based on the PET technique (Positron Emission Tomography) for the diagnosis of breast cancer, which offers numerous advantages.

In the first stages of a cancer, the malignant cells replicate in an uncontrolled way and, after one to two years, cause a lesion that is visible with the current techniques. After that, the lesion extends and takes about another year until it can be felt.

While current diagnostic equipment is based on morphological images and does not recognize the cancer until there is a lesion, the MAMMI PET measures the metabolic activity of the tumour by locating the high glucose uptake of the cancer cells. This allows the specialist to detect the disease much earlier and numerous studies have confirmed that early detection reduces mortality by 29%.

Until now, whole-body PET scans were indicated for breast cancer patients or for people with a high risk of suffering the disease. However, the result is a low resolution image and therefore does not detect small tumours. "Our device, however, is devoted exclusively to breasts so the detectors are very close to this part of the body and show tumours in early stages," explains Luis Caballero, head of the project in ONCOVISION.

In comparison, MAMMI can see lesions as little as 1.5 mm, while the best of the systems that currently exist offers a resolution of 5 mm. The system generally improves the diagnosis of all patients, but it is especially effective for women with breast implants or young women whose breast density has always made obtaining a clear image difficult.

Assessment in later stages

The mammography device marketed by the Valencian company can also monitor whether the treatment the patient with breast cancer is following actually works. According to Dr Caballero: "By showing the uptake of glucose, the PET technique is the only one able to reveal whether there are still cancer tissues after an operation, since with the other techniques it is impossible to distinguish tumour tissue from the scar left by the operation."

Also, the PET reveals whether the therapies of radiation and chemotherapy are effective or need to be modified. As MAMMI is a more precise PET instrument, it ensures a better assessment of tumour activity and its response to therapy.

Email or share this story:

Half of prostate cancers could potentially benefit from new type of cancer drugs

ScienceDaily (May 19, 2011) — About half of prostate cancers have a genetic anomaly that appears to make tumor cells responsive to a new class of cancer-fighting drugs, a new study from the University of Michigan Comprehensive Cancer Center finds.

See Also:Health & MedicineProstate CancerBreast CancerMen's HealthUrologyCancerDiseases and ConditionsReferenceBRCA1BRCA2Tumor suppressor geneMetastasis

The drugs, called PARP inhibitors, are currently being tested in breast cancer patients with mutations in the BRCA1 and BRCA2 genes, which are found in up to 10 percent of all breast cancers.

Half of prostate cancers have a genomic rearrangement that causes the fusion of two genes called TMPRSS2 and ERG. This gene fusion, believed to be the triggering event of prostate cancer, was initially discovered in 2005 by U-M researchers led by Arul Chinnaiyan, M.D., Ph.D.

"This type of gene fusion occurs in about 50 percent of prostate cancers, but the genes involved have been notoriously difficult to target therapeutically. We found that instead of targeting the gene fusion product directly, we could block the function of critical interacting partners, such as PARP1," says Chinnaiyan, a Howard Hughes Medical Institute researcher, director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at the U-M Medical School.

Chinnaiyan is the senior author of the current study, which appears in the May 17 issue of Cancer Cell.

"Our studies suggest that the total population of patients who could benefit from PARP inhibition could be significantly expanded," says Chad Brenner, Ph.D. candidate at U-M, who is the first author on the study.

Working with prostate cancer models in cell lines and mice, researchers found that therapies using the PARP inhibitor Olaparib helped shrink tumors expressing the TMPRSS2:ERG gene fusion and blocked the ability of tumors to spread. Olaparib had no effect on tumors that did not have the gene fusion.

PARP inhibitors are not currently approved by the U.S. Food and Drug Administration, but initial trials in breast cancer patients indicate they can be administered safely and are well-tolerated.

Study authors Maha Hussain, M.D., and Felix Y. Feng, M.D., are currently working on two clinical trials based on these study findings to test if the TMPRSS2:ERG gene fusion could be used as to predict response to treatments, including a PARP inhibitor. These studies are not yet recruiting participants.

Prostate cancer statistics: 217,730 Americans will be diagnosed with prostate cancer this year and 32,050 will die from the disease, according to the American Cancer Society

Additional authors: Bushra Ateeq, Yong Li, Anastasia K. Yocum, Qi Cao, Irfan A. Asangani, Sonam Patel, Xiaoju Wang, Hallie Liang, Jindan Yu, Nallasivam Palanisamy, Javed Siddiqui, Wei Yan, Xuhong Cao, Rohit Mehra, Aaron Sabolch, Venkatesha Basrur, Robert J. Lonigro, Scott A. Tomlins, Christopher A. Maher, Kojo S.J. Elenitoba-Johnson, Kenneth J. Pienta, Sooryanarayana Varambally, all from U-M; Jun Yang, Nora M. Navone, from M.D. Anderson Cancer Center

Funding: National Institutes of Health, U-M Prostate Specialized Program in Research Excellence grant, Early Detection Research Network, U.S. Department of Defense, Prostate Cancer Foundation

The University of Michigan has received a patent on the detection of gene fusions in prostate cancer (US 7,718,369), on which Tomlins and Chinnaiyan are co-inventors. The diagnostic field of use has been licensed to Gen-Probe Inc. Chinnaiyan also has a sponsored research agreement with Gen-Probe.

Email or share this story:

Marker identifies breast cancer patients likely to respond to tamoxifen

ScienceDaily (May 22, 2011) — Cancer researchers at the Kimmel Cancer Center at Jefferson and an international team of collaborators have discovered a biomarker in breast cancer that may help identify which women will respond to anti-estrogen therapy.

See Also:Health & MedicineBreast CancerCancerWomen's HealthLung CancerBrain TumorColon CancerReferenceBreast cancerMetastasisHormone replacement therapyMenopause

The research appears in the May 16 online issue of the Journal of Clinical Oncology.

Anti-estrogen drugs, most notably tamoxifen, are widely used in patients diagnosed with estrogen receptor-positive breast cancer. However, as many as a third of the women given tamoxifen fail to respond.

In this new study, the investigators found that women whose tumors retain the active form of the protein biomarker Stat5 have an increased likelihood of responding to tamoxifen. In contrast, women treated with tamoxifen whose tumors lacked active Stat5 had up to a 20-fold increased risk of dying from breast cancer after adjustment for effects of standard hormone receptor markers and other pathology data.

"Identification of predictive biomarkers present in breast cancer will lead to improved individualized therapies tailored specifically towards each woman's cancer," said Hallgeir Rui, M.D., Ph.D., professor of oncology, Kimmel Cancer Center at Thomas Jefferson University, and principal investigator of the study. "Absence of the active form of Stat5 could help identify a group of patients unlikely to respond to tamoxifen so they may be offered alternative and more aggressive treatments."

Stat5 protein is a DNA-binding factor that regulates expression of certain genes, many of which remain unknown. During pregnancy, Stat5 is activated by the hormone prolactin, and stimulates milk production in the breast. Active Stat5 is also detectable at lower levels in healthy breast tissue of non-pregnant women. This study further showed that active Stat5 was lost in the majority of more aggressive tumors and when those tumors metastasized to lymph nodes.

In 2004, Rui and colleagues reported that women with early stage breast cancer had higher survival rates when their tumors expressed active Stat5. Therefore, in two independent groups of breast cancer patients that were not treated with chemotherapy or anti-estrogen therapy, they further investigated the relationship between active Stat5 in the tumor and whether the patient had breast cancer recurrence or died of breast cancer over periods as long as 30 years. The team found consistent favorable breast cancer outcomes when tumors retained active Stat5.

The studies presented in this publication utilized a retrospective analysis of five large, independent breast cancer patient materials that included 1,000 patients, giving the studies a solid statistical basis. A benefit of optimizing a marker like Stat5 is that the assay for Stat5 is simple, inexpensive, and can be rapidly adapted to routine analysis in pathology laboratories using standard procedures.

"More work remains to be done, but we are optimistic about the utility of Stat5 as a biomarker," said Amy Peck, PhD, and lead author of the study. "The team is moving forward with plans for a randomized, prospective study with larger patient numbers to further evaluate the utility of Stat5 in managing and treating breast cancer."

Email or share this story:

Sun protects against childhood asthma

ScienceDaily (May 19, 2011) — Vitamin D, which is primarily absorbed from the sun, plays a role in protection against childhood asthma. Now, a new study led by Valencian researchers has shown that children who live in colder, wetter cities are at greater risk of suffering from this respiratory problem, since there are fewer hours of sunlight in such places.

See Also:Health & MedicineVitamin DAsthmaVitaminEarth & ClimateGeomagnetic StormsEnvironmental PolicyAtmosphereLiving WellReferenceUV indexHouse dust miteVitamin DRickets

"Prolonged exposure to the sun can cause cancer, but it's also dangerous to avoid it. There has to be a balance between the pros and cons," says Alberto Arnedo-Pena, an epidemiologist at the Public Health Centre in Castellón and lead author of the research, which is part of the International Study of Asthma and Allergies in Childhood (ISAAC), led by Luis García Marcos of the University of Murcia.

In fact, 90% of our vitamin D is synthesised through exposure to the sun. This vitamin, which can be found in various cell receptors, is usually found at lower levels in people with asthma. The study results show that there is a higher prevalence of this illness among children in wetter places with less sun (northern Spain).

The research, carried out on more than 45,000 children and teenagers from nine Spanish cities and published in the International Journal of Biometeorology, shows that climatic conditions, above all solar radiation, can in many cases explain the high geographical variation in the prevalence of asthma in Spain.

"Although we need more studies on this issue -- this hypothesis is not even five years old -- it is clear that an average level of sun exposure is important for the assimilation of vitamin D, a compound that is extremely important in preventing illnesses such as asthma, tuberculosis and other infectious diseases," stresses Arnedo-Pena.

The solar vitamin

In northern countries (where there are fewer hours of sunshine than in the Mediterranean), the advice is to spend 20 to 30 minutes' in the sun each day, although not at times within the highest risk period (from noon to 4pm). For now, no similar advice exists in Spain.

Once the benefits of sun exposure are understood, it can be seen that there is a problem in countries at latitudes higher than 40º north, where it is not possible to absorb enough vitamin D during the winter months. "People in these countries should take supplements to ensure they are not at risk," the researcher concludes.

Email or share this story:

New test targets Lynch syndrome, a risk factor for colon cancer

ScienceDaily (May 18, 2011) — Mayo Clinic has developed a screening procedure that could dramatically increase testing for Lynch syndrome, a hereditary genetic disorder that raises cancer risk, particularly for colorectal cancer. An estimated 3 percent of colon cancers can be attributed to Lynch syndrome. At least 80 percent of people with Lynch syndrome develop colorectal cancer, many of them before age 50.

See Also:Health & MedicineColon CancerPersonalized MedicineToday's HealthcareDiseases and ConditionsWounds and HealingBreast CancerReferenceColorectal cancerMammographyMetastasisBreast cancer

In the past, as few as 50 percent of patients who fit the profile for possible Lynch syndrome were tested before or after surgery. Now, a group of Mayo Clinic researchers has developed and tested a protocol that could raise the level of testing to nearly 90 percent, helping doctors make important decisions on the timing and delivery of care for patients with the disease. Their findings were presented at The American Society of Colon and Rectal Surgeons Annual Scientific Meeting, May 14-18, 2011 in Vancouver, British Columbia, Canada.

Mayo Clinic researchers in 2003 started testing all newly diagnosed colorectal cancers in patients under 50. Biopsies of the cancers were sent to pathologists, who conducted Microsatellite Instability (MSI) testing on them. MSI testing looks for certain mutations in genes that repair DNA by testing 10 different DNA markers for irregularities. Patients categorized in the "high" group for microsatellite instability were offered additional testing for Lynch syndrome and genetic counseling.

Over the five-year study, 210 of 258 newly diagnosed patients under age 50 who underwent colorectal cancer surgery at MCR had the MSI testing. Of those, 13 percent had MSI-H tumors. Overall, 88 percent of the high-risk group had tests, and the protocol caught 11 percent of MSI-H tumors that would have otherwise been missed.

"Probably the most significant result of this research is that it has stimulated our multidisciplinary team of geneticists, pathologists, gastroenterologists and surgeons to develop new clinical pathways that will direct patients at risk to providers experienced with management of Lynch Syndrome," says Eric Dozois, M.D. who has organized the multidisciplinary Young Onset Working Group and is the lead researcher on this project. This ensures appropriate evaluation and genetic and surgical counseling before critical treatment decisions are made, thus allowing patients and referring physicians to be fully informed regarding options for treatment, especially risks and benefits.

"The benefit of this testing to the patient and their family is huge," says research fellow Rajesh Pendlimari, M.B.B.S. "If they have Lynch syndrome and will, therefore, be more prone to getting cancer, they can get screened more regularly. Plus, with it being a hereditary condition, family members can also get tested." As a result of this testing, cancer may be caught earlier and physicians may be more proactive in treatment. The testing should be done before surgery, because a diagnosis may change the course of treatment. Testing after surgery also is beneficial; the knowledge gleaned can affect future care for patients and their families.

The study's other researchers are Noralane Lindor, M.D.; Stephen Thibodeau, Ph.D.; Thomas Smyrk, M.D.; David Larson, M.D.; Robert Cima, M.D.; Lisa Boardman, M.D.; Nancy You, M.D.; and Jennifer Wang, M.D.

Email or share this story:

Key to fighting drug-resistant leukemia discovered

ScienceDaily (May 18, 2011) — Doctors who treat children with the most common form of childhood cancer -- acute lymphoblastic leukemia -- are often baffled at how sometimes the cancer cells survive their best efforts and the most powerful modern cancer drugs.

See Also:Health & MedicineLeukemiaLung CancerCancerColon CancerLymphomaBreast CancerReferenceLeukemiaTumor suppressor geneMetastasisLymphoma

Now a team of scientists led by researchers at the University of California, San Francisco has uncovered the basis for this drug resistance: BCL6, a protein that leukemia cells use to stay alive. Targeting this protein may be the key to fighting drug-resistant leukemia, a discovery that may make cancer drugs more powerful and help doctors formulate powerful drug cocktails to cure more children of leukemia.

"We believe this discovery is of immediate relevance to patient care," said Markus Müschen, MD, PhD, a professor of laboratory medicine at UCSF and the senior author on the study.

As described in the journal Nature this week, Müschen and his colleagues showed that mice with drug-resistant leukemia can be cured of the disease when given conventional cancer drugs in combination with a compound that disables the BCL6 protein. This compound was initially developed by Ari Melnick, a professor of pharmacology at the Weill Cornell College of Medicine in New York and a co-author of the study.

A Common Form Of Cancer In Children

Acute lymphoblastic leukemia is the most common form of cancer in children and accounts for about 23 percent of all cases of cancer in children under the age of 15, according to the National Cancer Institute.

In this form of cancer, leukemia cells in the bloodstream and bone marrow continuously multiply, crowding out other, healthy cells. The disease progresses rapidly, and the leukemia cells begin to infiltrate tissues in other parts of the body. Treatment is neither cheap nor easy -- but it can be miraculous. It usually involves a long course of drugs that can be physically and emotionally taxing for the children and their parents. Once finished, many enjoy complete remission and are able to live cancer-free, cured of the leukemia.

Still a large number of children are not cured and ultimately succumb to the disease. In those cases, some of the cancer cells resist the therapy and survive quietly in the body. When the cancer reemerges, it is no longer sensitive to the drugs.

In their new report, Müschen and his colleagues show that the key to this resistance is the protein BCL6, offering the first evidence of how the cancer cells managed to survive.

"It is something like an emergency mechanism whereby tumor cells try to evade drug-treatment," Müschen said.

One Among 22,000 Genes

The work started four years ago when Müschen wanted to figure out what happens to cancer cells during cancer treatments. He and his colleagues exposed leukemia cells in the petri dish to drugs and then looked at how they responded to the treatment. They analyzed how the expression of 22,000 different genes changed when different cancer cells were given different drugs, and they found that BCL6 levels always rocketed up following treatment.

The BCL6 protein was already known to cancer researchers because it is active in other forms of cancer. In lymphoma, for instance, BCL6 protects cancer cells from dying, and the protein has long been the target for research and drug design. But it had never been connected to leukemia.

Reasoning that blocking BCL6 would make leukemia cells more sensitive to chemotherapy, the scientists showed exactly that. Working with Melnick and colleagues at Weill-Cornell Medical College in New York City who had developed a biotech drug-like peptide that blocks BCL6, they showed that giving the peptide to mice along with anti-leukemia drugs increased the potency of conventional drugs and helped the mice survive the disease.

Now Müschen is looking for ways to do the same thing with small molecules, which are generally easier to formulate into an oral drug and cheaper to mass produce than biotech drugs like peptides.

Last year, he was awarded a $3.6 million grant from the California Institute for Regenerative Medicine (CIRM) to develop such a molecule.

The article was authored by Cihangir Duy, Christian Hurtz, Seyedmehdi Shojaee, Leandro Cerchietti, Huimin Geng, Srividya Swaminathan, Lars Klemm, Soo-mi Kweon, Rahul Nahar, Melanie Braig, Eugene Park, Yong-mi Kim, Wolf-Karsten Hofmann, Sebastian Herzog, Hassan Jumaa, H. Phillip Koeffler, J. Jessica Yu, Nora Heisterkamp, Thomas G. Graeber, Hong Wu, B. Hilda Ye, Ari Melnick and Markus Müschen.

In addition to scientists at UCSF and Weill Cornell Medical College in New York City, the team included researcher at the Children's Hospital Los Angeles and University of Southern California, Universitatsklinikum Hamburg-Eppendorf in Hamburg, Germany, Cedars Sinai Medical Center in Los Angeles, the Albert-Ludwigs-Universitat Freiburg and Max-Planck-Institute for Immunobiology in Freiburg, Germany, Universitat Heidelberg, Klinikum Mannheim, Mannheim, Germany, Albert Einstein College of Medicine in New York City, and the University of California, Los Angeles.

This work was supported by grants from the National Institutes of Health and the National Cancer Institute, grants from the Leukemia and Lymphoma Society, the California Institute for Regenerative Medicine, the William Laurence and BlancheHughes Foundation and a StandUp To Cancer-American Association for Cancer Research Innovative Research Grant. Markus Müschen and Ari Melnick are Scholars of the Leukemia and Lymphoma Society.

Email or share this story:

Researchers home in on genetic signature of esophageal cancer

ScienceDaily (May 20, 2011) — University of Rochester Medical Center researchers have pinpointed two genes that are amplified in the worst cases of esophageal cancer, providing data to support a new investigational treatment that targets those same genes.

See Also:Health & MedicineCancerBreast CancerBrain TumorLung CancerDiseases and ConditionsColon CancerReferenceTumor suppressor geneMetastasisTumorStomach cancer

The study, led by Tony Godfrey, Ph.D., a research associate professor of Surgery at the James P. Wilmot Cancer Center at URMC, was published by the journal Clinical Cancer Research. It explores the chromosomal abnormalities that influence poor survival rates of esophageal adenocarcinoma (EAC), the more common type of esophageal cancer which occurs at the junction of the stomach and esophagus.

Considered uncommon 20 years ago, the incidence of EAC has grown faster than any tumor type in the United States, Godfrey said. Health authorities believe high rates of obesity and gastroesophageal reflux disease (GERD) contribute to the rising numbers. And despite more awareness, early detection, and newer combinations of cancer therapies, overall survival of esophageal adenocarcinoma ranges from 70 percent to 80 percent for early-stage patients to only 5 percent to 20 percent for stage 3 or 4 patients. Since most cases are discovered when the cancer has already spread, EAC is often a devastating disease.

Until lately, the identification of gene targets for EAC had been limited by too few tissue samples and the inability of technology to provide a finely detailed map of gene mutations.

However, Godfrey's lab was able to collect tumors samples from 116 EAC patients, and then use modern molecular analysis tools -- microarray technology -- to investigate the DNA in the tissue. The goal was to study known chromosomal regions associated with EAC and look for subsets of genes involved in malignancy that might also be markers of poor survival.

A better understanding of genetic markers is important because many modern cancer drugs, known as "targeted therapies," are designed to chemically inhibit or block the effect of oncogenes.

Prior studies on EAC had shown an extra copy of a DNA sequence in the 7q21 chromosome region. However, Godfrey and colleagues believe they are the first to map the region with fine enough resolution to identify six genes within the core of the amplified region, and to compare them to patient outcomes.

They further honed in on two genes, CDK6 and CDK4, and through laboratory experiments proved that both genes are critical for the growth of esophageal cancer cells.

Amin Ismal, Ph.D., the postdoctoral scientist in Godfrey's lab who led the research, explained that the two molecules appear to do exactly the same thing, however CDK4 is located elsewhere, in the 12q13 chromosome region, and although it is less frequently amplified compared to CDK6, its high expression in EAC may be attributed to other genetic alterations.

Researchers explored the activity of CDK4 and CDK6 both independently and in combination. They paid special attention to CDK6, which also has been associated with poor survival in T-cell lymphoma and two common brain cancers, gliomas and medulloblastomas. CDK6 is a known regulator of the cell cycle, and thus researchers theorized that if they could shut down the CDK6 activity, the proliferation of cancer should also cease.

These experiments, Ismail said, led to the discovery that CDK6 is not acting completely alone, and that the combined over-expression of CDK6/4 was a more accurate marker of poor survival than the amplification of either gene alone.

Meanwhile, researchers knew that an experimental drug (known as PD-0332991) targeting CDK6/4 had been developed by Pfizer and Onyx, and was already being used in early clinical trials, showing promise against a range of cancers.

Therefore, the Wilmot research team tested PD-0332991 in the laboratory on esophageal cancer cells and discovered that, indeed, the drug halted CDK6/4 by inhibiting the entire cell-cycle process involved in malignancy.

"Our data provide direct evidence that CDK6 and CDK4 are strong predictors of poor survival, and that targeting those molecules is a viable treatment option," Godfrey said. "Although we still have more work to do, we are excited about the excellent progress in the effort to find better treatments for esophageal cancer."

The approach used by Godfrey and his team follows a classic example of another success story in cancer research. Decades ago scientists discovered that the protein HER-2 (human epidermal growth factor receptor 2) is frequently amplified in some breast cancers, causing them to become more aggressive. They reasoned that a drug was needed to effectively interfere with the HER-2 gene. That drug, known as Herceptin, was developed and then approved by the U.S. Food and Drug Administration in 1998 and is widely used today to boost the life expectancy of thousands of women. Interestingly, some patients with EAC also take Herceptin, due to recent studies showing that HER-2 also is over-expressed in a subset of esophageal tumors.

The National Institutes of Health funded the URMC study.

Email or share this story: