Cancer Knowledge

Switch that might tame most aggressive of breast cancers

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The Sydney-based research team has found a gene that drives the aggressive disease, and hopes to find a way to ‘switch it off’.

The aggressive form of triple-negative breast cancer appears to arise from stem cells, while the more benign form appears to arise from specialised cells.

Stem cells have many of the same features as cancers. They are plastic and flexible, and have the ability to proliferate and spread into other tissues — deadly traits in cancers.

Previous studies have shown that breast stem cells are needed for breast growth and development during puberty and pregnancy, although how they evolve from stem cells into specialist cells has been unclear.

The new study has shown that a gene known as ‘inhibitor of differentiation 4’ (ID4) determines whether a stem cell remains a stem cell, or whether it differentiates into a specialist cell.

Notably, when the high levels of ID4 in a stem cell are ‘switched off’, other genes that drive cell specialisation are ‘switched on’.

Drs Alex Swarbrick and Simon Junankar from Sydney’s Garvan Institute of Medical Research spearheaded this large interdisciplinary study,2 which links the development of the mammary gland in mice with human breast cancer. Its main finding, that ID4 not only ‘marks’, but appears to control, the highly aggressive form of triple negative breast cancer is published online today in Nature Communications.

“We found that ID4 is produced at high levels in roughly half of all triple negative breast cancers, and that these cancers have a particularly poor prognosis,” said project leader Dr Alex Swarbrick.

“We also showed that if you block the ID4 gene in experimental models of triple negative breast cancer, the tumour cells stop dividing.”

It is interesting to note that blocking ID4 switches on the oestrogen receptor3 and several other genes expressed by the best-prognosis breast cancer.

“Oestrogen receptor-positive breast cancers have a relatively good prognosis because the drug Tamoxifen is very effective at blocking the oestrogen receptor and hence their growth” noted Swarbrick.

“We speculate, therefore, that by blocking ID4 it might be possible to turn stem-cell-like breast cancers into less aggressive breast cancers that may even respond to tamoxifen. If we are correct, that would be remarkable.”

The next step for Dr Swarbrick and his team will be to study the biochemistry of ID4 in a cell — to determine how best to block it in people.

There are also plans to undertake therapeutic experiments in mice to test whether or not switching off ID4 sensitises a tumour to tamoxifen.

“We don’t know yet whether we are seeing a real oestrogen-dependent cancer after ID4 is blocked — one with an effective oestrogen receptor — or just a caricature of one.

“We’re very fortunate that our collaborator in Cambridge UK is a world expert on oestrogen receptor function.

“We also have technologies that allow us to study processes on a genome-wide scale — so we can map the interactions of ID4 comprehensively.”

source : http://www.sciencedaily.com/releases/2015/03/150327091004.htm

Women with ovarian cancer gain extra months with addition of drug to standard chemotherapy

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The preliminary findings were reported here at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.

The phase III, randomized, controlled trial included women with platinum-sensitive recurrent ovarian cancer. A total of 374 women received the standard chemotherapy treatment of paclitaxel and carboplatin. Another 374 received the chemotherapy drugs paclitaxel and carboplatin, plus bevacizumab. Both arms received paclitaxel and carboplatin for six cycles and the study arm patients continued with bevacizumab maintenance. Unlike previous ovarian clinical trials of bevacizumab, this study’s primary endpoint was overall survival.

Median overall survival for woman in the chemotherapy plus bevacizumab treatment was 42.2 months, compared with 37.3 for those receiving chemotherapy alone. The period of time before ovarian cancer recurred (called progression-free survival) improved by nearly 3.5 months with the additional drug (13.8 months compared with 10.4 months for the woman on chemotherapy alone). The risk reduction for progression and death were 39% and 17%, respectively.

“Most women whose ovarian cancer is recurring want every edge to extend their lives,” said lead author Robert L. Coleman, MD, of The University of Texas MD Anderson Cancer Center in Houston. “This trial, while not completely definitive, builds on previous data, offering hope that we can hone in on treatments to achieve that goal.”

Some expected side effects, including gastrointestinal damage and joint pain, were observed but none that suggested a significant safety concern. The ongoing study will assess quality of life for women receiving the additional drug and the role of secondary surgery before chemotherapy.

This study, conducted by the Gynecologic Oncology Group, a cooperative group funded by the National Cancer Institute, was the second to test bevacizumab under these conditions (first chemotherapy for platinum-sensitive recurrence), a use for which bevacizumab is not currently approved by the Food and Drug Administration. Both this trial, also known as GOG 213, and the previous trial, known as OCEANS and published June 10, 2012, in the Journal of Clinical Oncology, showed a longer delay in time to the next recurrence when bevacizumab is added to standard chemotherapy. Neither study showed a significant improvement in long-term survival, though GOG 213 reported a strong trend towards improved overall survival. In 2014, the FDA approved bevacizumab with chemotherapies for the treatment of women with platinum-resistant, recurrent ovarian cancer.

source : http://www.sciencedaily.com/releases/2015/03/150328102416.htm

Stress granules ease the way for cancer metastasis

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When cells are under duress, they curtail almost all protein synthesis and stash their mRNAs in stress granules. These structures help healthy cells, but they also allow tumor cells to survive harsh conditions. A protein named YB-1, which is overexpressed in many types of tumors, accumulates in stress granules, but researchers don’t know how YB-1 affects these particles.

University of British Columbia scientist Poul Sorensen and his colleagues found that stressed-out cancer cells need YB-1 to assemble stress granules. Removing YB-1 decreased levels of one stress granule protein, G3BP1. The team discovered that YB-1 attaches to the mRNA encoding G3BP1 and stimulates the protein’s production.

To determine the effects of YB-1 in animals, the researchers implanted mice with cancer cells that either made or lacked the protein. A month later, cells in the control tumors carried more stress granules than did the tumor cells missing YB-1. Sorensen and colleagues then implanted mice with tumors that either produced or lacked G3BP1. The control tumors harbored more stress granules than did the G3BP1-deficient tumors, and only the control tumors metastasized.

Further research is needed to find out how the reduction in stress granules curbs metastatic spread, but the results suggest that inhibiting their formation might be a way to curb cancer metastasis.

source : http://www.sciencedaily.com/releases/2015/03/150323105247.htm


  • stress granules and cancer

Exercise linked to improved erectile, sexual function in men

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While past studies have highlighted the relationship between better erectile function and exercise, African-American men have been underrepresented in this literature.

“This study is the first to link the benefits of exercise in relation to improved erectile and sexual function in a racially diverse group of patients,” said Adriana Vidal, PhD, senior author of the study and investigator in the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute and Department of Surgery.

Nearly 300 study participants self-reported their activity levels, which researchers then categorized as sedentary, mildly active, moderately active or highly active. The subjects also self-reported their sexual function, including the ability to have erections, orgasms, the quality and frequency of erections and overall sexual function.

Results found that men who reported more frequent exercise, a total of 18 metabolic equivalents, or METS, per week, had higher sexual function scores, regardless of race. MET hours reflect both the total time of exercise and the intensity of exercise. A total of 18 METS can be achieved by combining exercises with different intensities, but is the equivalent of two hours of strenuous exercise, such as running or swimming, 3.5 hours of moderate exercise, or six hours of light exercise.

In contrast, men of any ethnicity who exercised less reported lower levels of sexual function. Additional contributors to low sexual function included diabetes, older age, past or current smoking and coronary artery disease.

Stephen Freedland, MD, co-author on the study and director of the Center for Integrated Research in Cancer and Lifestyle in the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, cautions that exercise should be tailored for each individual.

“When it comes to exercise, there is no one-size-fits-all approach,” said Freedland, who also serves as co-director of the Cancer Genetics and Prevention Program. “However, we are confident that even some degree of exercise, even if less intense, is better than no exercise at all.”

source : http://www.sciencedaily.com/releases/2015/03/150323091546.htm

Favorable 15-year survival outcomes for older prostate cancer patients with low-risk disease

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Previous research by the study’s lead author Grace Lu-Yao, PhD, MPH, cancer epidemiologist at the Cancer Institute of New Jersey and professor of medicine at Rutgers Robert Wood Johnson Medical School, and colleagues examined 10-year outcomes for this population (JAMA, Vol. 302, No. 11). The 2009 research showed men diagnosed with prostate cancer beginning in the early 1990’s had significantly improved survival compared with patients whose cancers were diagnosed in prior decades. Given the protracted nature of the disease and increasing longevity among elderly men, 10-year follow-up may not be sufficient to make informed treatment decisions. Dr. Lu-Yao notes this new study, which extends data examination by an additional five years, “helps provide a more complete picture of potential outcomes for patients who have a life expectancy greater than 10 years.”

The new research, which appears in the current online edition of European Urology (doi: 10.1016/j.eururo.2015.03.021), examined 33,137 Medicare patients aged 65 or older who were diagnosed with early-stage (T1 or T2) prostate cancer from 1992 through 2009 and received conservative management (no surgery, radiotherapy, cryotherapy or androgen deprivation therapy) within the first six months of diagnosis. The researchers utilized information from the Surveillance, Epidemiology and End Results (SEER) cancer registries and Medicare claims. All SEER registries hold the highest level of certification of data quality.

Investigators found that men aged 64 to 74 with a Gleason score (a grading system that indicates how likely a tumor will spread) of between five and seven had a lower risk (5.7 percent) of dying from prostate cancer over a 15-year period as compared to men 75 and older, whose risk was 10.1 percent. For men with the highest level Gleason scores (between eight and 10), 15-year prostate cancer mortality rates were 22 percent for men aged 65 to 74 and 27 percent for men 75 and older.

The authors also note mortality rates remained relatively stable from six to 16 years following diagnosis. The work also examined if these men had comorbid diseases and found that those who did have other health problems had a lower risk of dying from prostate cancer due to deaths from competing health issues.

“The proportion of men diagnosed with localized prostate cancer who choose to have conservative management is relatively small but, is on the rise. The information provided by this long-term study will help facilitate treatment decisions,” says Lu-Yao. “Our study, which includes data from the PSA testing era, is a more current representation of outlook survival for this population.”

Lu-Yao indicates the study could help change the conversation between patient and physician. “In weighing whether treatment benefits outweigh the risks, radical prostatectomy — for instance — is typically not recommended for older men with low-grade disease. But many elderly patients are treated with radiotherapy or hormonal therapy even if their cancer is indolent, so that they can feel like they are doing something,” she says. “By having additional data available to support conservative management, doctors can further educate their patients about survival outcomes and possibly help avoid treatments that may put the patient at risk.”

The authors note strengths of the study include the fact it is population based and broadly representative instead of focused on specific geographic areas or institutions. Lu-Yao also notes the study provided information on more than 10,000 men aged 75 or older — a population which is often omitted from studies. But they also caution that because the men in the study were older than 65, the data may not apply to younger patients.

source : http://www.sciencedaily.com/releases/2015/03/150323142801.htm

Experiments reveal key components of the body’s machinery for battling deadly tularemia

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The team, led by Thirumala-Devi Kanneganti, Ph.D., a member of the St. Jude Department of Immunology, found key receptors responsible for sensing DNA in cells infected by the tularemia-causing bacterium, Francisella. Tularemia is a highly infectious disease that kills more than 30 percent of those infected, if left untreated. It can be readily transmitted by air, insect bites or through contaminated food or water.

“Understanding the fundamental biology of how our immune system works will lead to the development of more effective drugs and vaccines,” said Kanneganti, corresponding author on the paper. The new findings also revealed how immune cells switch on genes that activate microbe-killing machinery called the AIM2 inflammasome.

The inflammasome is a complex of proteins that is a dedicated killing machine for bacteria and viruses. The inflammasome that attacks the tularemia bacterium is triggered by the sensor protein AIM2 that recognizes the tularemia DNA.

Previous studies indicate that both Francisella DNA and viral DNA activate AIM2 in the cell. The mystery was how different bacteria or viruses release their DNA into the infected cell to activate AIM2.

In the new studies, the researchers found that Francisella DNA is initially detected by a DNA sensor, cGAS, which specifically engages a gene-activating protein called IRF1 in the cell. Importantly, IRF1 triggers production of a group of proteins, called GBPs, that literally “mobs” the invading bacterium by surrounding and shredding it. The dying bacterium releases even more DNA and subsequently activates the DNA sensor AIM2 to further fuel the immune system, ultimately conquering the infection. Researchers still do not know whether GBPs directly kill bacteria or whether the GBPs require additional “help” to destroy them.

Studies with mice demonstrated the necessary role IRF1 plays in galvanizing the immune system to battle tularemia. Mice lacking IRF1 showed much higher levels of the bacteria when infected, and 100 percent succumbed to the infection, compared with only 25 percent of the mice that have IRF1. The new findings also showed that activation of the AIM2 inflammasome by the DNA virus cytomegalovirus does not involve IRF1, suggesting that the DNA of the invading microbes is presented to the cell in different ways.

According to the paper’s first author, Si Ming Man, Ph.D., a postdoctoral fellow in St. Jude Immunology, the findings could lead to new protective treatments against tularemia, including drugs that can enhance the ability of IRF1, GBP or AIM2 to cure infections more quickly and effectively. Vaccines could also be developed that would boost this immune machinery and protect against the disease.

“Future studies will not only seek to further map the function of AIM2 in infectious diseases, but also to track its role in other disorders, including cancer,” Man said. Studies of AIM2 could also aid in understanding some autoimmune diseases and cancers. Overactivation of AIM2 has been linked to disorders including psoriasis, an abdominal aortic aneurysm and lupus. Furthermore, reduced AIM2 activity has been linked to colorectal and prostate cancers.

source : http://www.sciencedaily.com/releases/2015/03/150323162404.htm

New insights into survival outcomes of Asian Americans diagnosed with cancer

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“What we have found is that Asian Americans are an incredibly diverse group that cannot be indiscriminately combined together,” said Trinh, associate surgeon for the Division of Urology at BWH, faculty at the Center for Surgery and Public Health (CSPH) and lead author of the study. “With Asian Americans, there is important variation in socioeconomic status, cultural beliefs, and length of time since immigrating to the United States that researchers must take into account.”

Although Asian Americans represent only 5 percent of the entire United States population, they are the most rapidly growing racial group in the country. This is one of the first studies not just to focus on the cancer-specific survival of Asian Americans, but also to break down that population into eight specific subgroups (Chinese, Filipino, Hawaiian, Japanese, Korean, South-East Asian, Vietnamese and others) for further analysis.

Trinh and his colleagues used Surveillance, Epidemiology, and End Results Program (SEER) data to look at more than 2.5 million Asian American patients who were diagnosed with lung, breast, prostate or colorectal cancer (the three leading causes of cancer-related mortality within each gender) between 1991 and 2007.

The team found significant differences in cancer outcomes among the Asian subgroups. Specifically, the researchers report that the Japanese subgroup had substantially better survival rates than non-Hispanic whites (especially with regard to prostate, breast and colorectal cancers), as did those of Filipino and South Asian descent (for prostate and lung cancers, and lung and colorectal cancers, respectively), while the Hawaiian and Korean subgroups did not. In Chinese and Vietnamese patients, only those with lung cancer had better CSM rates relative to non-Hispanic whites. Overall, most Asian subgroups were less likely to die from cancer than non-Hispanic white patients.

“We found that CSM is statistically significantly lower for Asian Americans than for non-Hispanic whites overall, despite similarities in odds of receiving definitive therapy, and even after adjusting for socio-demographic factors, cancer stage and treatment,” said Trinh. “We’ve effectively ruled out a number of variables, suggesting instead that underlying genetic or biological differences and/or complex cultural influences may impact survival in Asian American cancer patients.”

This study opens the door for future research to better understand why Asian Americans have better CSM than non-Hispanic whites, and to determine whether and to what extent genetic and/or cultural factors are involved.

source : http://www.sciencedaily.com/releases/2015/03/150323182548.htm

Precision medicine for adrenal cancer, study suggests

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In a randomized phase 3 trial, adrenal cancer patients receiving the investigational drug linsitinib fared no better than patients receiving a placebo. But the researchers noticed a small subset of patients who had significant response and remained on the drug for an extended time.

“While it was only a small subset of patients who responded to linsitinib, this remains very promising in the era of precision medicine,” says co-principle investigator Gary D. Hammer, M.D., Ph.D., Millie Schembechler Professor of Adrenal Cancer at the University of Michigan Comprehensive Cancer Center. The other co-principle investigator is Martin Fassnacht, M.D., head of the division of endocrinology and member of the Comprehensive Cancer Center at the University of W�rzburg, Germany.

The study enrolled 139 patients from nine countries and randomized them to receive linsitinib or placebo. Linsitinib was given as a pill taken twice daily for 21-day cycles.

The study stemmed from laboratory studies and early stage clinical trials originated at the University of Michigan and other groups to understand the role of insulin growth factor 2 in adrenal cancer. Laboratory studies showed linsitinib blocks the insulin receptor pathway, which is known to play a role in how adrenal cancer develops.

The phase 3 study was unblinded because the researchers were seeing no difference in survival between the group receiving the drug and those receiving placebo. Overall survival was 323 days for the linsitinib group and 356 for the placebo group. The time till cancer started progressing was 44 days for linsitinib and 46 days for placebo.

But at the time the study was unblinded, four patients who were currently enrolled on the linsitinib arm chose to continue treatment with linsitinib. In this small subset, the cancer was kept in check for two to four years. Across the whole study, eight patients taking linsitinib had progression-free survival for at least 150 days. None from the placebo group did.

“One of our patients is still controlling her disease with a remarkable partial response by taking linsitinib now for more than 4 1/2 years — which is really amazing in advanced adrenal cancer, which has usually a median survival of less than 15 months,” Fassnacht says.

“This was a real response for a small group of patients. If we can find a way to identify who is likely to be among the exceptional responders, we can potentially make a real difference for this group of patients. This paves the way toward individualized and improved therapeutic options in adrenal cancer,” Hammer says.

The study is published in Lancet Oncology.

The researchers were not immediately able to find any obvious factors that would predict a response to linsitinib. They plan to evaluate the DNA collected through the study to identify possible markers for response.

Adrenal cancer is extremely rare, affecting about two in every million people worldwide. Few treatment options exist, and it’s often difficult to conduct clinical trials because the number of patients diagnosed is small. Hammer and Fassnacht have forged relationships with adrenal cancer researchers around the world to foster an international collaborative effort to improve treatment for this disease.

source : http://www.sciencedaily.com/releases/2015/03/150318074052.htm

Early recall rates decline after second round of lung cancer screening

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In the United States the National Lung Cancer Screening Trial (NLST) showed that annual lung cancer screening of high-risk individuals with LDCT reduces lung cancer mortality by 20% and overall mortality by 7%. There are now multiple lung cancer screening trials ongoing throughout the world, but one concern is the high number of early repeat scans for suspicious findings that are in fact not lung cancer. This high number of false positives could make screening impractical due to cost, invasive follow-up procedures, and anxiety for the patients.

The LUSI is comparing no intervention (n=2023) to 5 annual screens of individuals’ aged 50-69 with a history of heavy tobacco smoking (n=2029). All the participants have been followed for at least 3 years but many have been followed for 5 years. The control arm is tracked with an annual questionnaire and query of cancer registries. The LUSI is ongoing but the current analyses compare the first screening round to subsequent rounds with regard to performance indicators, such as early recall rate, detection rate, and interval cancer rate.

The results published in the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer, show that there was a strong decline in the early recall rate from 20% in the first screening round to 3-4% in rounds 2-4 (p<0.0001). The detection of lung cancer was 1.1% in the first round but then declined to 0.5%, on average, for the subsequent rounds. The cumulative number of advanced lung cancers was almost identical between the control and intervention groups for the first two years but by year three the number of advanced cancers in the screening group began to decline. The same trend was observed for the overall mortality.

The authors conclude “our data indicate that the most prominent side effect “false positive alarm” cannot be controlled if the choice of doctor is at the screenee’s discretion at every annual screening visit. The early recall rates of rounds 2-4 would have been around 30%, instead of 3-4%, if the prior scans were not available. Thus, a potential lung cancer screening program must be organized such that all previous images and results are available.”

source : http://www.sciencedaily.com/releases/2015/03/150318084728.htm

Is too much artificial light at night making us sick?

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It’s an emerging topic in health, one that UConn Health (University of Connecticut, Farmington, Conn.) cancer epidemiologist Richard Stevens has been studying for three decades.

“It’s become clear that typical lighting is affecting our physiology,” Stevens says. “But lighting can be improved. We’re learning that better lighting can reduce these physiological effects. By that we mean dimmer and longer wavelengths in the evening, and avoiding the bright blue of e-readers, tablets and smart phones.”

Those devices emit enough blue light when used in the evening to suppress the sleep-inducing hormone melatonin and disrupt the body’s circadian rhythm, the biological mechanism that enables restful sleep.

Stevens and co-author Yong Zhu from Yale University explain the known short-term and suspected long-term impacts of circadian disruption in an invited article published in the British journal Philosophical Transactions of the Royal Society B.

“It’s a new analysis and synthesis of what we know up to now on the effect of lighting on our health,” Stevens says. “We don’t know for certain, but there’s growing evidence that the long-term implications of this have ties to breast cancer, obesity, diabetes, and depression, and possibly other cancers.”

As smartphones and tablets become more commonplace, Stevens recommends a general awareness of how the type of light emitted from these devices affects our biology. He says a recent study comparing people who used e-readers to those who read old-fashioned books in the evening showed a clear difference — the e-readers showed delayed melatonin onset.

“It’s about how much light you’re getting in the evening,” Stevens says. “It doesn’t mean you have to turn all the lights off at 8 every night, it just means if you have a choice between an e-reader and a book, the book is less disruptive to your body clock. At night, the better, more circadian-friendly light is dimmer and, believe it or not, redder, like an incandescent bulb.”

source : http://www.sciencedaily.com/releases/2015/03/150318153947.htm