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The Academy

OBTN, May 2008, Volume 2, Issue 5

The Academy delivers the latest news on biotechand oncology research, providing a link between the clinical world of cancer care and the university researchers who are pushing the envelope of knowledge and discovery. In this issue: Jonsson Comprehensive Cancer Center, University of California, Los Angeles; Harvard Medical School, Boston; Dana-Farber Cancer Institute, Boston; Yale School of Medicine, New Haven; and Robert Wood Johnson Medical School,Piscataway, NJ.

Jonsson Comprehensive Cancer Center University of California, Los Angeles

Study Examines Impact of Sedentary Work On Prostate Cancer Risk

Cancer Causes Control

According to a new study from the University of California, Los Angeles’s (UCLA’s) Jonsson Comprehensive Cancer Center, the health hazards of a desk job may go beyond loss of fitness and carpal-tunnel syndrome. Findings presented by the researchers, published in a recent issue of , suggest that men with desk jobs may be more likely to develop prostate cancer than those who are physically active each day at work.

Investigators examined the medical and job histories of more than 2,100 men at a nuclear and rocket engine testing facility in California’s San Fernando Valley. According to the data compiled by the study team, men who got little exercise at work, such as managers, analysts, and engineers, were more likely to have prostate cancer than people like masons, welders, and janitors who engaged in active physical labor.

The study compared 362 men who were diagnosed with prostate cancer from January 1988 and December 1999 with 1,805 men of similar ages and backgrounds who were cancer free. All worked at Rocketdyne Propulsion & Power, which Boeing Co. sold to United Technologies Corp. in 2005 for $700 million. The facility, located north of Los Angeles, has been used to test rockets since 1948. Employees were exposed to radiation and other chemicals that may boost their risk of prostate cancer, the researchers said.

The case-control study nested within a larger cohort of more than 10,000 male subjects who worked at the nuclear and rocket-engine testing site from the 1950s to the early 1990s. The cases of prostate cancer were diagnosed between January 1988 and December 1999. Researchers obtained cancer incidence data for the workers from the California Cancer Registry and seven other cancer registries in neighboring states where workers may have moved after retirement.

Data from Rocketdyne company records was used to construct a job exposure matrix that ranked job descriptions by the amount of physical activity required and any harmful exposures the workers might have experienced.

Physical activity was separated into jobs with low, moderate and high amounts of exertion. Men with low-activity jobs were typically managers, supervisors, analysts, administrators, and senior engineers. Those with moderately active jobs included senior mechanics and technicians, inspectors, and engineers. Masons and bricklayers, metal fitters, welders, packers, painters, tool and die makers, truck drivers, lift operators, and janitors were considered highly active.

The study found that the men who developed prostate cancer were less likely to have held the more physically active jobs. In addition to the association made by researchers between prostate cancer risk and the performance of physically inactive work, study findings also indicated that men who got cancer had more contact with and exposure to chemicals such as hydrazine, benzene, trichloroethylene, and polycyclic aromatic hydrocarbons. They also were more often black and more likely to have a family history of the disease and get tested regularly.

The findings support previous studies, which have asserted that regular physical exertion is needed to keep prostate cancer at bay. It remains unclear as to exactly how exercise combats the disease, the most common cancer in men, though some experts hypothesize that activity influences hormone levels to reduce the risk.

“The message from this study for today is that if you’re more active, you may be able to prevent this cancer from happening,’’ said Beate Ritz, MD, PhD, senior author of the paper and an Associate Professor of Epidemiology at the UCLA School of Public Health. “If you have a desk job, do something physically active to counterbalance it,” advised Dr. Ritz.

According to researchers, a strength of the study was that personnel records, job description manuals, industrial hygiene reviews, and interviews with retired workers were employed to develop the job exposure matrix, avoiding problems with subject recall and interviewer bias. Researchers were also able to obtain cancer incidence data and did not have to rely on mortality data. Prostate cancer is largely non-fatal, so mortality rates would not have been good data to analyze, Dr. Ritz said.

The study was limited in that researchers were not able to account for other potential factors that might affect prostate cancer risk, such as recreational physical activity and diet, said Anusha Krishnadasan, PhD, epidemiologist at Olive View—UCLA Education and Research Institute and first author of the study.

“All we can say for sure is that aerospace workers that were highly active on a regular basis for many years while working at Rocketdyne were at a decreased risk of prostate cancer,” summed up Dr. Krishnadasan.

Harvard Medical School, Boston

Designer Gene Functions Differently in Different People

Researchers at Harvard Medical School, Boston, have discovered that, depending on a given person’s genetic make-up, a gene known as STAT3 can play completely different roles in glioblastoma. Investigators nicknamed STAT3 the “Jekyll and Hyde” gene because of the wide-ranging way it acts.

According to previous research, STAT3 is an oncogene—a gene whose normal functions are disrupted and, as a result, helps promote tumor development—in several types of glioblastoma. In such cases, blocking STAT3 would be a way of fighting these tumors.

Genes & Development

However, in this new study presented by a Harvard Medical School team and published in a recent on-line edition of , findings indicated that STAT3 is actually a tumor-suppressor gene in other types of glioblastoma, meaning that the gene keeps renegade cancer cells in check.

“In other words,” wrote Azad Bonni, PhD, MD, Associate Professor of Pathology, Harvard Medical School, in a prepared media statement, “the same gene in the same cancer can play a completely different role from one person to the next, depending on genetic nuances between individuals.”

“This discovery,” continued Dr. Bonni, “lays the foundation for a more tailored therapeutic intervention. And that’s really important. You can’t just go blindly treating people by inhibiting STAT3." Dr. Bonni, a neurologist and neuroscientist by training, decided to investigate the genetic etiology of glioblastoma by studying whether certain regulatory genes that control the generation of astrocytes during normal development also play a role in these tumors. Nearly all brain cancers occur in a class of brain cells called astrocytes (or in the neural stem cells that generate astrocytes) which function as support cells, involved with functions such as providing nutrients to nerve tissue and repairing scars.

Dr. Bonni explained, “The logic here is simple: since disease is often the breakdown of a normal biological process, the more we understand how cells get it right, the more we understand what can go wrong. And since STAT3 is a key gene that turns neural stem cells into astrocytes during normal development, what is its role in glioblastoma?”

Dr. Bonni and colleagues, in collaboration with investigators in the laboratory of Ronald DePinho at the Dana-Farber Cancer Institute, Boston, began by genetically manipulating mouse astrocytes, then placing them into a second group of mice whose immune systems had been compromised. The findings surprised them.

Taking advantage of previously published data, the researchers looked closely at how two genes, EGFR and PTEN—whose mutated forms are associated with glioblastoma—affect the function of STAT3 in astrocytes. Dr. Bonni’s group found when EGFR is mutated, STAT3 is an oncogene; with a PTEN mutation, STAT3 is a tumor suppressor.

“EGFR, in its normal state, is a transmembrane receptor, usually performing its functions at the cell surface,” explained Dr. Bonni, “However, when it’s mutated, we find it in the cell’s nucleus interacting with STAT3—and turning it into an oncogene. STAT3 itself is not mutated or damaged. It’s the process of regulating STAT3 that gets damaged.”

“With PTEN, it’s a completely different story,” reported Dr. Bonni, “PTEN is itself a tumor suppressor gene. When PTEN becomes disabled in astrocytes, these potential tumors still have STAT3 standing in their way. This is because STAT3 acts as a tumor suppressor normally in astrocytes. However, as more PTEN becomes disabled, a cascade of molecular events is set in motion with the express purpose of inhibiting STAT3 function and thus turning the tide in the cells toward tumor formation.”

The researchers confirmed these findings in human glioblastoma tumors as well.

“The belief that STAT3 can only be an oncogene has been a pretty entrenched dogma in the field,” says Dr. Bonni, “so we performed many, many experiments to make sure this was correct. It took some very persistent investigators in my lab to get the job done. As a result, we’re convinced of our data.”

While glioblastoma tends to be uncommon, STAT3 has also been implicated in prostate and breast cancers, so these results may translate to other types of tumors as well.

Glioblastoma tends to strike people in the prime of life and is almost always fatal. There are limited treatment options, which have changed little over decades. The finding may help improve treatment of people with the deadly disease.

Yale School of Medicine, New Haven

Test Detects Early-Stage Ovarian Cancer

New Haven, Connecticut—based Yale School of Medicine researchers have announced the development of a blood test that they claim is refined enough to detect early-stage ovarian cancer at a 99% accuracy rate.

The new platform uses six protein biomarkers instead of four, building on the results of the same Yale research team’s effors in 2005 by increasing the specificity of the test from its previous accuracy level of 95% to its currrent reliability factor of 99.4%, reported leading investigator and study author Gil Mor, MD, PhD, Associate Professor of Obstetrics, Gynecology and Reproductive Sciences.

“This is the most sensitive and specific test currently available,” Dr. Mor said in a statement. “Previous tests recognized 15% to 20% of new tumors. Proteins from the tumors were the only biomarkers used to test for ovarian cancer. That is okay when you have big masses of tumors, but it is not applicable in very early phases of the tumor. Testing the proteins produced by the body in response to the presence of the tumor as well as the proteins the tumors produce, helped us to create a unique picture that can detect early ovarian cancer.”

Evidence of the test’s efficacy was established by a phase II clinical trial led by Dr. Mor which included 500 patients—350 healthy controls and 150 patients with ovarian cancer. Dr. Mor and colleagues validated the previous research, which showed 95% effectiveness, and used a new platform called multiplex technology to simplify the test into one single reaction using very small amounts of serum from the blood. The new platform uses six protein biomarkers. The team looked for the presence of those specific proteins and quantified the concentration of those proteins in the blood.

The Early Detection Research Network (EDRN) of the National Cancer Institute (NCI) Bethesda, Maryland, independently evaluated the results of the test.

Clinical Cancer Research

The findings were published in a recent issue of the journal .

Dr. Mor said that epithelial ovarian cancer is the leading cause of gynecologic cancer deaths in the United States, and is three times more lethal than breast cancer, but is often not diagnosed until its advanced stages.

“The ability to recognize almost 100% of new tumors will have a major impact on the high death rates of this cancer,” said Dr. Mor. “We hope this test will become the standard of care for women having routine examinations.”

Dr. Mor and colleagues have begun a phase III evaluation in a multicenter clinical trial. In collaboration with EDRN/NCI and Laboratories Corporation of America (LabCorp), they are testing close to 2,000 patients.

The test is available at Yale through the Discovery to Cure program. Yale has licensed the test to three companies: Lab Corp in the United States, Teva in Israel and SurExam in China.

Dana-Farber Cancer Institute, Boston

Mouse Molecule May Help Facilitate Cancer Research

According to a recent issue of the journal Nature, scientists at the Dana-Farber Cancer Institute, Boston, have discovered an alternative method to grow new blood vessels in body parts that are starved for circulation.

Mice may have provided researchers with a more direct means (than currently employed pharmacologically-based methods) of developing new blood vessels because a key metabolic regulatory molecule in the rodents senses dangerously low levels of oxygen and nutrients when circulation is cut off and then triggers the formation of new blood vessels to fill in the gap.

Bruce Spiegelman, PhD, Professor of Cell Biology and researcher with the Dana-Farber Cancer Institute, and his colleagues discovered that PGC-1 alpha is the specific molecule that senses low levels of oxygen and nutrients when circulation is cut off. PGC-1 alpha then triggers the formation of new blood vessels to resupply the oxygen-starved area.

A similar response to hypoxia, or oxygen deprivation, has been observed before. The response is regulated by a group of proteins known as Hypoxia Inducible Factors (HIF) that detect hypoxia and activate the production of VEGF (vascular endothelial growth factor). VEGF, in turn, stimulates angiogenesis.

The process known as angiogenesis already happens naturally by way of a group of proteins in the body. However the discovery of a previously unknown and uncharted new molecular pathway gives “an independent way” of getting to new blood vessel creation, Dana-Farber researcher and professor of cell biology at Harvard Medical School, Dr. Spiegelman said in a statement.

Along with lead author Zoltan Arany, MD, PhD, and colleagues, Dr. Spiegelman found that HIF was completely left out of the loop when PGC-1alpha accomplished the same feat in single cells and in live mice using a different regulator, known as ERR-alpha (estrogen-related receptor-alpha). When the scientists knocked out the activity of PGC-1 alpha (which was first identified in Dr. Spiegelman’s lab) in cells and live mice, the hypoxia-induced response and angiogenesis were sharply decreased.

“We were surprised to find this novel mechanism,” commented Dr. Spiegelman. “It was apparently there all along,” added Dr. Arany. “That means there is now a second pathway that you need to know about if you are trying to activate or inhibit angiogenesis.”

As stated above, angiogenesis occurs in the normal development of the body. However, it’s also an “oncall service” when an injury or an artery blockage, the cause of heart attacks and strokes, leaves normal tissues starved for blood. Generating a new network of small vessels to nourish the area can protect against further injury. On the downside, cancer has evolved the ability to commandeer VEGF and other angiogenic factors to encourage blood vessel growth around tumors that have outgrown their oxygen supplies.

Some drugs already exist that help grow new blood vessels or in the case of cancer treatment, restrict them. However, scientists think the novel pathway they have found may be significant in that it could eventually help treat heart and blood vessels and cancer, broadening the potential therapies in both areas.

“We’re still far from having good drugs to modulate angiogenesis through the HIF pathway,” commented Dr. Arany. The discovery of a second, alternate pathway, involving PGC-1 alpha and ERR-alpha, leading to angiogenesis may offer new opportunities for therapy “in any situation where angiogenesis is a factor,” he added.

Robert Wood Johnson Medical School, Piscataway, NJ

Watchful Waiting Affirmed for Older Men with Early-Stage Prostate Cancer

A new study that examined data on more than 9,000 older men with localized prostate cancer who were not treated for the disease asserts that most older men with early-stage prostate cancer will not require treatment or will die of other causes before their cancer significantly progresses.

Commenting on data from the study, lead author Grace Lu-Yao, PhD, MPH, cancer epidemiologist at The Cancer Institute of New Jersey, Associate Professor at UMDNJ-Robert Wood Johnson Medical School and School of Public Health, Piscataway, New Jersey, stated, “Because prostate cancer therapies are associated with significant side effects, our data can help patients make better informed decisions about the most appropriate approach for them and potentially avoid treatment without adversely affecting their health.” Dr. Lu-Yao added that men who choose not to undergo treatment should be carefully monitored for rising prostate-specific antigent (PSA) and other signs of cancer growth.

This study, which, according to its authors represents one of the largest research initiatives to date to observe the course of early-stage prostate cancer in older men, is one of the first investigations to describe the natural history of prostate cancer that is not immediately treated, during the current era of common PSA testing. This is particularly relevant, explained investigators, because PSA tests can detect cancer six to 13 years earlier than traditional diagnostic methods, and researchers have found that PSA-diagnosed cancers can often differ in stage and biology.

Investigators examined Medicare claims data on 9,018 men from the U.S. Surveillance, Epidemiology and End Results (SEER) database who had been diagnosed with stage I or II prostate cancer between 1992 and 2002 and who did not initially receive local therapy (such as surgery or radiation therapy) or hormonal therapy within six months of diagnosis. The median age of the men at diagnosis was 77 (the age range of participating subjects was 66 to 104). Men with other cancers were excluded from the study.

Researchers discovered that prostate cancers in the study group were generally slow growing. Most of the men did not have any therapy (approximately two out of three died of other causes or did not experience cancer progression that resulted in the use of surgery or radiation therapy. During the study period, 6,523 (72%) of the study cohort died of competing causes of death or did not have documented cancer complications that required surgery or radiation. The corresponding statistics for low-, moderate-, and high-grade cancer are 87% (162/187), 73% (5,521/7,544), and 65% (840/1,287), respectively. Of the 2,675 men who did have some treatment (surgery, radiation, chemotherapy, or androgen deprivation), the median time between diagnosis and the start of cancer therapy was 10.6 years (127 mo).

As expected, men with less aggressive disease (low or moderate grade) fared better than those with high-grade cancers. Ten-year prostate cancer specific mortality was 6% (11/187), 3% (256/7,544), and 17% (215/1,287) for low-, moderate-, and high-grade cancer, respectively.

Dr. Lu-Yao noted that the clinical outcomes of this study population were also substantially more favorable than those observed in previous studies, perhaps because the use of PSA tests has resulted in earlier detection of prostate cancer.