UC Riverside-led research describes mechanism by which some people may be more susceptible to colon cancer.

Karthikeyani Chellappa (left) and Frances Sladek, UC Riverside

An international research team led by cell biologists at the University of California, Riverside, has uncovered a new insight into colon cancer, the third leading cause of cancer-related deaths in the United States.  The research provides potential new avenues for diagnosing and treating the disease.

Led by Frances Sladek at UC Riverside and Graham Robertson at the University of Sydney, Australia, the team analyzed about 450 human colon cancer specimens and found that in nearly 80 percent of them the variants of a gene, HNF4A, are out of balance.

Human beings express several variants of the HNF4A gene, classified as P1 and P2 variants. Some tissues, like liver, have just one type of variant but the colon has both P1 and P2 variants.  The P1 variant is found in the nuclei of cells in the normal colon but in the human colon cancer samples this variant is frequently either absent or located outside of the nucleus and, presumably, no longer functional.

Using human colon cancer cell lines and in vitro assays, the researchers found that the imbalance observed in the human tumor tissues seemed to be the result of a complex, multi-step process by an enzyme, Src kinase. Src kinase has been known to be activated in colon cancer but, until now, it was not known to act on the HNF4a protein (HNF4A is the gene, a stretch of DNA; HNF4a is the protein encoded by HNF4A). The UCR group found that activated Src modifies the P1 but not the P2 variant. The net result is loss of the P1 variant in the nuclei of cells in the colon.

Study results appeared online last week in the Proceedings of the National Academy of Sciences.

“Loss of nuclear P1 HNF4a protein in the colon may be an early sign of colon cancer,” explained Sladek, a professor of cell biology and toxicologist. “A healthy colon has a good but delicate balance of the two HNF4a variants. If you could prevent the loss of the P1 variant via drugs, you might be able to maintain a normal colon and prevent colon cancer.”

The researchers found another factor that increases a person’s susceptibility to the disease:  certain “single nucleotide polymorphisms” or SNPs located in the HNF4A gene.  An SNP is a DNA sequence variation — a minor change in the genomic sequence that accounts for the variations we see between individuals.  SNPs are the most common type of genetic variation among people.

“Individuals with certain SNPs may be more susceptible to colon cancer,” said Karthikeyani Chellappa, a postdoctoral researcher in Sladek’s lab and the first author of the research paper.  “That’s because these SNPs result in a greater amount of modification and a faster degradation of HNF4a by Src, at least in cell-based assays. It still needs to be investigated, though, whether individuals carrying these SNPs are indeed more susceptible to colon cancer.”

Sladek noted that drugs are already available for inhibiting the activity of Src kinase.

“Some of these drugs are in clinical trials for colon cancer,” she said. “It would be exciting to determine whether these drugs can maintain the P1 HNF4a protein levels, as well as inhibit the Src kinase activity.”

A multifactorial disease influenced by genetics and the environment, colon cancer starts as a small polyp in the large intestine (colon) or the rectum (end of the colon). While most of the polyps are benign, some do turn cancerous.  With proper screening, the disease can be detected early, when it is most curable.

Sladek, Chellappa and Robertson were joined in the research by Songqin Pan and Jake M. Schnabl at UCR; Lucy Jankova, Caroline L-S. Fung, Charles Chan, Owen F. Dent and Stephen J. Clarke at the University of Sydney, Australia; and Yann Brelivet of the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.  Robertson and the Australian members of the team performed all the analysis of the human tumor samples.

The research was supported in part by a National Institutes of Health grant to Sladek.

Tax contributions fight breast cancer.

Supporting cancer research is easy, especially if you’re about to complete your California tax form.

Simply check box number 405 (California Breast Cancer Research Fund) and/or box number 413 (California Cancer Research Fund).

Both funds are administered by the University of California Office of the President. Even small donations are welcome and can make a large impact in cancer research. Ninety-five percent of contributions to those two programs via the tax check-off go directly to cancer research or community-based education.

Tax-deductible donations from box/code 405 of the tax form go to the California Breast Cancer Research Program. In recent years, those donations have supported critical research including:

• Identifying environmental factors that potentially cause breast cancer.
• Developing targeted therapies to block breast cancer from spreading to other organs.
• Improving support networks to empower patients as they maneuver the health care system
• Addressing the needs of underserved families.

Donations from box/code 413 of the tax form go to the California Cancer Research Fund, which is helping to providing prevention and awareness programs in communities disproportionately affected by cancer. A major research grant is increasing the understanding of the impact of tobacco use and cancer on vulnerable populations. The research could lead to increased tobacco control and cancer awareness and prevention programs.

UCSF study finds the new tax would create about 12,000 jobs, $2B in new economic activity.

Stanton Glantz, UC San Francisco

A new UC San Francisco analysis has found that a state ballot initiative to increase the cigarette tax would create about 12,000 jobs and nearly $2 billion in new economic activity in California.

The study found that the new tax would have a significant effect on the state’s overall economy because Californians would smoke less and spend their money in other ways.

The initiative, the California Cancer Research Act (CCRA), is on the statewide June 5 ballot. If the measure is approved, state cigarette taxes would rise by $1 a pack, generating an estimated $855 million a year for anti-smoking education programs, medical research, and tobacco law enforcement.

“The primary impact to the California economy, besides the effect on health care, is that people will smoke less and send less money out of state,’’ said study author Stanton A. Glantz, a professor of medicine at UCSF and director of the Center for Tobacco Control Research and Education based at UCSF.

Currently, approximately 80 percent of money spent on tobacco products is exported to out-of-state tobacco manufacturers and farmers. No tobacco is grown in California and no cigarettes are manufactured here.

Under the legislation, 60 percent of funds generated by the new tax would go to cancer research and to address other tobacco-related diseases, 20 percent toward tobacco cessation and prevention programs, and 15 percent toward facilities and equipment for health services and research. The remainder would go to law enforcement to reduce cigarette smuggling and tobacco tax evasion, and to administer the tax.

The state’s independent Legislative Analysts’ Office has calculated that the new tax could save more than 100,000 people from smoking-related deaths.

On Sept. 15, 2011, the UC Board of Regents endorsed the initiative. UC campuses are allowed to use their resources to objectively evaluate a ballot measure’s impact and to provide educational materials and information.

Glantz’ report of the analysis, which estimates both the direct and indirect effects of the initiative on employment and economic activity in California, uses standard estimates of jobs created and economic multipliers categorized by economic sector from the U.S. Department of Commerce. It is available online as part of the University of California’s eScholarship program at http://escholarship.org/uc/item/73g8m5j5.

If the new tax is approved, the study reports, it would cause some loss of retail jobs due to fewer retail sales — a loss that would be more than offset by a projected 12,000 new jobs in the California economy as a whole as well as in medical research, construction and other activities directly funded by the CCRA.

Altogether, the CCRA would generate a projected $1.9 billion in total economic activity.

A previous UCSF study co-authored by Glantz and James Lightwood, associate adjunct professor in the UCSF School of Pharmacy, estimated the ballot measure could save California up to $32 billion in health care costs over the next five years. Without the tax, the study concluded, the state’s tobacco control program would become less effective over time because inflation is eroding the five cents per pack currently allocated to tobacco control activities.

The new report notes that as a biomedical research center, UCSF conducts the type of research that the CCRA likely would fund.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Clinical trial sites, including one at UC San Diego, will employ procedure using electrical fields to disrupt cell division.

Santosh Kesari, UC San Diego

Jim Black is fighting the meanest, most aggressive, most common kind of brain tumor in the United States: recurrent glioblastoma multiforme (GBM). In the United States, each year, approximately 10,000 patients are affected by GBM. Now, a novel investigational device — available only at clinical trial sites — is offering new hope to these patients.

The non-invasive procedure — called Tumor Treating Fields (TTF) — is delivered using a portable device — called the NovoTTF-100A System made by Novocure. The TTF procedure uses alternating electrical fields to disrupt the rapid cell division exhibited by cancer cells.

“Patients with recurrent GBM present a significant treatment challenge,” said Santosh Kesari, M.D., Ph.D., director of neuro-oncology at UC San Diego Moores Cancer Center. “The initial clinical research for the approval trial demonstrated that, compared to patients who were treated with chemotherapy, patients treated with NovoTTF achieved comparable survival times, had fewer side effects and reported improved quality of life.”

On average, a patient with GBM survives less than 15 months with optimal treatment and only three to five months without additional effective treatment. The TTF procedure may provide physicians with a fourth treatment option in addition to surgery, radiation therapy and chemotherapy.

TTFs inhibit tumor growth by causing cancerous cells to die. The TTF procedure is delivered using non-invasive, insulated transducer arrays (electrodes) that are placed directly on the skin in the region of the tumor. The hat-like collection of electrodes connects to a portable device which is slightly thicker than a laptop and weighs about six pounds. The device sends a low intensity, alternating electric field into the tumor which prevents the cells from dividing and spreading and causes cancer cells to die.

The most commonly reported side effect from NovoTTF is a mild-to-moderate scalp rash, beneath the electrodes. The FDA-approved device is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.

“When all other options have been exhausted, patients are willing to do just about anything to keep the tumor at bay,” said Kesari. “This device gives them an opportunity to fight back, to feel like they are taking an active, hands-on role in their own treatment, and provides tremendous hope.”

“This is another, potentially highly efficacious way to block replication of hepatitis C.”

Samuel French, UCLA

Researchers from UCLA’s Jonsson Comprehensive Cancer Center have identified a cell-permeable peptide that inhibits a hepatitis C virus protein and blocks the viral replication that can lead to liver cancer and cirrhosis.

The finding by Dr. Samuel French, a UCLA assistant professor of pathology and senior author of the research, builds on previous work by French’s laboratory that identified two cellular proteins that are important factors in hepatitis C virus infection.

In that earlier research, French and his team set out to identify the cellular factors involved in hepatitis C replication. Using mass spectrometry, they found that heat-shock proteins (HSPs) 40 and 70 were important for viral infection. HSP 70 was previously known to be involved, but the study linked HSP 40 for the first time to hepatitis C infection. The researchers further showed that the natural compound quercetin, which inhibits the synthesis of these proteins, significantly inhibited viral infection in tissue culture.

In the current study, published Jan. 30 in the peer-reviewed journal Hepatology, French and his team demonstrated that the viral, non-structural protein 5A (NS5A) directly binds to HSP 70, and they mapped the site of the NS5A–HSP 70 complex on NS5A. While HSP 70 was previously shown to bind to NS5A in cells, a direct NS5A–HSP70 interaction and complex formation was established in this study. In an effort to stop this interaction, the researchers tested peptides that might inhibit HSP 70.

“This is important because we’ve developed a small peptide which binds to that site and blocks the interaction between the proteins that is important for viral replication,” French said. “This is another, potentially highly efficacious way to block replication of hepatitis C.”

An estimated 160 million people worldwide are infected with hepatitis C, and the conventional treatments — interferon and ribavirin — can have significant side effects. A new drug targeting cellular proteins rather than viral proteins would be a valuable addition to the treatment arsenal, French said.

“We were surprised that this peptide works this well,” he said. “While its mechanism is different, the activity of this peptide is comparable to other newly developed antivirals.”

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UCSF researchers say societal control of sugar needed, similar to alcohol, tobacco.

Sugar should be controlled like alcohol and tobacco to protect public health, according to a team of UCSF researchers, who maintain in a new report that sugar is fueling a global obesity pandemic, contributing to 35 million deaths annually worldwide from non-communicable diseases like diabetes, heart disease and cancer.

Non-communicable diseases now pose a greater health burden worldwide than infectious diseases, according to the United Nations. In the United States, 75 percent of health care dollars are spent treating these diseases and their associated disabilities.

In the Feb. 2 issue of Nature, Robert Lustig, M.D., Laura Schmidt, Ph.D., M.S.W., M.P.H., and Claire Brindis, D.P.H., colleagues at the University of California, San Francisco, argue that sugar’s potential for abuse, coupled with its toxicity and pervasiveness in the Western diet, make it a primary culprit of this worldwide health crisis.

This partnership of scientists trained in endocrinology, sociology and public health took a new look at the accumulating scientific evidence on sugar. Such interdisciplinary liaisons underscore the power of academic health sciences institutions like UCSF.

Sugar, they argue, is far from just “empty calories” that make people fat. At the levels consumed by most Americans, sugar changes metabolism, raises blood pressure, critically alters the signaling of hormones and causes significant damage to the liver — the least understood of sugar’s damages. These health hazards largely mirror the effects of drinking too much alcohol, which they point out in their commentary is the distillation of sugar.

Worldwide consumption of sugar has tripled during the past 50 years and is viewed as a key cause of the obesity epidemic. But obesity, Lustig, Schmidt and Brindis argue, may just be a marker for the damage caused by the toxic effects of too much sugar. This would help explain why 40 percent of people with metabolic syndrome — the key metabolic changes that lead to diabetes, heart disease and cancer — are not clinically obese.

“As long as the public thinks that sugar is just ‘empty calories,’ we have no chance in solving this,” said Lustig, a professor of pediatrics in the division of endocrinology at the UCSF Benioff Children’s Hospital and director of the Weight Assessment for Teen and Child Health (WATCH) Program at UCSF.

“There are good calories and bad calories, just as there are good fats and bad fats, good amino acids and bad amino acids, good carbohydrates and bad carbohydrates,” Lustig said. “But sugar is toxic beyond its calories.”

Limiting the consumption of sugar has challenges beyond educating people about its potential toxicity. “We recognize that there are cultural and celebratory aspects of sugar,” said Brindis, director of UCSF’s Philip R. Lee Institute for Health Policy Studies (IHPS). “Changing these patterns is very complicated.”

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School of Medicine retreat focuses on applications in research, patient care and education.

(From left) Joseph DeRisi, Clay Johnston, Sam Hawgood, UC San Francisco

In the world of bioinformatics, the rush is on to extract gold from a data mine.

The amount of data that health care providers and scientists collect from patients and research participants is growing explosively. This information ranges from the genetic to laboratory tests and imaging exams, to medical histories and information about treatment and outcomes — and in some cases to survey data on large populations.

This deluge of data and the bioinformatics capabilities necessary to take advantage of it were the focus of this year’s daylong UC San Francisco School of Medicine leadership retreat on Jan. 20. In his welcome address, Dean Sam Hawgood, M.B.B.S., outlined his goal for the day — to engage campus leaders in the question of how to optimally develop, organize and integrate clinical-outcome data, research data, business intelligence, and population data so that information is accessible and usable to empower research and improve medical practice.

Making greater use of available data to improve care

Some have compared efforts to take advantage of the data to trying to drink from a fire hose. Consider DNA as an example. Our genetic variations contain clues to disease risk, disease prognosis and treatment response. The identification of such clues by scientists and their translation into medical practice is a major enterprise. Soon, expense will no longer be a major limitation to obtaining a readout of an individual’s entire genetic makeup. “A complete human genome assay will be an assay like any other, at least in terms of cost and time,” Hawgood said.

However, as vivid as the water hose analogy may be, it might be more apt to say that in many organizations data of many types dwells in various unconnected dammed reservoirs, with little of it flowing to potential users.

Much of the day’s discussions centered not only on identifying data to collect and on ways to use this data, but also on how best to “unlock the data” that already exists.

In introducing the day’s theme, Hawgood said that in his view, UCSF, despite the depth and range of clinical and research data being collected, must develop ways to make much greater use of available data in the day-to-day workflow to improve research and patient care.

UCSF’s leaders in informatics can learn from what others have already done. “We want to take enough time to make sure that we’re not repeating other people’s mistakes,” Hawgood said.

Already this year UCSF is completing implementation of a new electronic medical records system, called APeX, tailored to UCSF by EPIC Systems Corp. of Madison, Wis. The system features a single, comprehensive record for each patient.

Apart from being a boon to physicians and other care providers, information within the new clinical record can be “de-identified” to protect privacy and then made available to researchers.

The experience gained from the implementation and the system itself may be a good jumping off point for using data to advance research and education. But the true potential of APeX as a platform to support collaborative research is still being investigated. Taking full advantage of UCSF medical records for research — and enabling ways for new research findings to be used to better guide patient care — will require new innovations.

UCSF already has convened a task force, soliciting input from an external team of international leaders in the field, to explore strategies to bolster bioinformatics on campus, including the establishment of new academic programs and infrastructure through which computer sciences faculty and other bioinformatics experts could be recruited, new experts trained, and novel research collaborations launched. In addition, Hawgood noted, thanks to UCSF’s proximity to Silicon Valley, “We are in a spectacular region for partnerships.”

UCSF is exploring how to accomplish its bioinformatics goals within UCSF and its affiliates, as well as ways in which to access and use data in research networks that span institutions. In addition, there is a need to share information with other providers to provide the best care to patients who also obtain health care outside of UCSF, a theme discussed at last year’s School of Medicine retreat as well.

Using hospital systems as living laboratories

In his keynote address at this year’s retreat, “Aligning the Academic Health Care Enterprise for Acceleration of Precision Medicine,” Isaac Kohane, M.D., Ph.D., a renowned bioinformatics expert and a professor of pediatrics and health sciences and technology at Harvard Medical School, said that the expense of working with data from clinical records has historically been much more expensive than working with genetic and molecular laboratory data.

Kohane, who co-directs the Harvard Medical School Center for Biomedical Informatics, has led efforts to develop computer systems to allow cheaper use of clinical records data from multiple hospital data systems in the study of genes and disease, while maintaining privacy.

Kohane talked about the potential for “apps” to capture useful information related to health outside of the hospital or clinic — for instance a tool that tallies nutritional information on purchases from the cash register.

In his own research Kohane now combines clinical and genomic data to learn more about cancer and autism, but he also presented research showing that such systems — had they been in place earlier — could have called attention to serious side effects of Vioxx and other drugs much sooner.

Kohane’s described workflows and systems that can better “unlock” clinical data to speed research discovery and its application in medical practice, while lowering the costs of using clinical data.

Imagining UCSF’s future in the Digital Age

Speakers at a morning panel titled “Imagining UCSF’s Future in the Age of Information Technology,” included Opinder Bawa, chief technology officer for the School of Medicine; Michael Blum, M.D., medical director of information technology for the UCSF Medical Center; Catherine Lucey, M.D., vice dean for education; Joe DeRisi, Ph.D., co-chair of the Department of Biochemistry and Biophysics; and moderator Clay Johnston, M.D., Ph.D., director of the Clinical and Translational Science Institute at UCSF and vice chancellor for research.

Not all bioinformatics applications are orchestrated institution-wide from the top down. Panelists and commenters from the audience highlighted a role for applications developed by smaller groups. For instance, as an educational tool, UCSF faculty from the Department of Emergency Medicine have spearheaded implementation of software used by physicians-in-training to respond to simulated clinical scenarios unfolding in real time.

The data collected during these exercises can be used to better understand how long it is likely to take for emergency room physicians to take critical actions — in the management of chest pain or in the ordering of pain medication, for example. In essence, the data can be used to learn more about how we learn, knowledge that can be incorporated into successive generations of teaching tools.

In the coming years, physicians will be trained to become increasingly comfortable using improved, data-driven, decision-making software tools, according to Lucey. “We will be able to teach students how to learn for themselves for 30 to 40 years, and we will free faculty up to teach in person what needs to be taught in person.”

DeRisi described how information on UCSF graduate school applicants is being used to identify factors associated with future success. In addition, he described how extensive data collection is being used to log graduate students’ progress and decision-making throughout their careers —  another way of identifying early career paths that bode well for future success. DeRisi also talked about an information-technology partnership that allows lab notebook entries made on pad devices to be immediately incorporated into a computerized database.

Developing more innovative research, clinical protocols

An afternoon panel — “The Future Is Now” — moderated by Robert Hiatt, M.D., Ph.D., co-chair of the Department of Epidemiology and Biostatistics and deputy director of the UCSF Helen Diller Family Comprehensive Cancer Center, focused on two large-scale collaborative research programs co-led by UCSF researchers in which molecular, clinical and demographic data already are being put to work to develop more innovative research and clinical protocols.

Laura van’t Veer, Ph.D., leader, and Laura Esserman, M.D., co-leader of the cancer center’s breast oncology program, described the ATHENA Breast Health Project, which unites UC academic medical centers in a state-wide collaboration. The project will initially involve 150,000 women throughout California who will be screened for breast cancer and followed for decades.

ATHENA project leaders aim to create common systems to integrate clinical research and care across the UC campuses to advance the science of prevention, screening, diagnosis, and treatment of breast cancer. The collaborators are creating a biospecimen repository that has broad racial and ethnic representation. A major goal is to marshal molecular and clinical data to better personalize breast care, tailoring treatment to the patient and avoiding overtreatment, and to use the information gained to drive innovation in prevention, diagnosis and treatment.

Neil Risch, Ph.D., co-chair of the Department of Epidemiology and Biostatistics at UCSF and director of the UCSF Institute for Human Genetics, along with Catherine Schaefer, Ph.D., director of the Kaiser Permanente Research Program on Genes Environment and Health, described progress to date in building the largest data base of its kind to focus on genetic variation and environmental exposures in an older population.

The average age of the hundreds of thousands of individuals whose genetic information will be genotyped for the project is 65. The project’s foundation is Kaiser’s electronic health record, which for many Kaiser Permanente members has information spanning decades — including information on clinical diagnosis and treatment as well as lab-test results and prescription information. UCSF expertise has allowed extraordinarily fast genotyping, as well as uniquely large-scale analysis of telomeres to quickly grow the molecular component of the data resource.

The afternoon panel provided a useful point of reference for break-out groups that met afterward, charged with identifying institutional priorities, problems and potential solutions in advancing the use of bioinformatics in research, clinical care and education.

For instance, the ATHENA collaborators have standardized protocols used at the different medical centers, including protocols for mammography screening. To make clinical data more useful for research, some breakout session panelists advocated more extensive standardization of clinical imaging and clinical lab protocols and reporting throughout UCSF clinical practices.

The Kaiser-UCSF collaboration highlights ways to combine strengths across organizations. While Kaiser is famous as a health maintenance organization, UCSF is perhaps best known as a tertiary care center. Some breakout session panelists raised the question — also raised at last year’s retreat — of whether or not the focus of UCSF research should more closely reflect the patient population seen at UCSF and its affiliated medical centers. UCSF specialists routinely gather extensive information on large numbers of patients with serious acute and chronic conditions, including many of the most difficult–to-treat cases. This extensive data is a potential gold mine for research aimed at identifying factors related to disease risk, prognosis and treatment outcomes.

Moving toward a new taxonomy of disease

The retreat followed on the heels of a similarly themed report by the National Academy of Sciences (NAS), “Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease” [PDF] by a committee co-led by UCSF Chancellor Susan Desmond-Hellmann, M.D., M.P.H. The NAS committee advocated the creation of a “knowledge network” that could link researchers in collaborations that span the nation and globe.

The NAS panel envisioned a future in which there is much greater use of genomic and other molecular data to improve and refine the classification of diseases, but also recognized an opportunity to improve research by more extensively taking into account information about how patients fare in the clinic or hospital.

Instead of the current state of affairs, through which biological, pre-clinical and clinical research eventually lead to advances in medical practice, the new paradigm will be a virtuous cycle through which — with appropriate privacy protections — patient data also will feed back into research. In patient care increasing amounts of laboratory information will become available and interpretable more quickly to help teams of caregivers make more accurate and effective decisions and choices in diagnosis, prognosis and treatment for each individual patient.

Molecular test can predict likelihood of death from early-stage lung cancer more accurately than conventional methods.

In the two largest clinical studies ever conducted on the molecular genetics of lung cancer, an international team led by scientists at the University of California, San Francisco, has demonstrated that an available molecular test can predict the likelihood of death from early-stage lung cancer more accurately than conventional methods. The work may eventually help improve the odds of survival for hundreds of thousands of patients each year.

Reported this week in The Lancet, the two studies demonstrated how the test, which measures the activity of 14 genes in cancerous tissue, improves the accuracy of prognosis. This in turn could guide treatments for patients with the most common form of the disease, non-squamous non-small cell lung cancer.

The research exemplifies UCSF’s efforts to advance patient care toward precision medicine, in which an individual’s genetic makeup or specific molecular markers of their disease help to drive treatment decisions.

The two independent clinical trials included one blinded study involving the analysis of tissue samples from 433 people with early-stage lung cancer in northern California and another study involving 1,006 people with early-stage lung cancer in China. In both trials, the team showed that the test could accurately predict whether the odds of death within five years of surgery to remove a lung cancer were low, intermediate, or high.

“It’s quite exciting,” said David Jablons, M.D., the Ada Distinguished Professor in Thoracic Oncology and leader of the Thoracic Oncology Program at the Helen Diller Family Comprehensive Cancer Center at UCSF. “This has the potential to help hundreds of thousands of people every year survive longer.” Jablons co-led the study with Michael Mann, M.D., a UCSF associate professor of cardiothoracic surgery.

Today, doctors assess early-stage lung cancers by their size, location and microscopic appearance. This information, known as staging, is then used to guide the use of additional treatment following surgery. If doctors could more precisely gauge prognosis, more people who might benefit from additional therapy could receive it immediately after surgery, before any residual cancer has had a chance to grow.

Evidence from other studies suggests that chemotherapy given in early-stage lung cancer helps thwart recurrence when there is evidence of lymph node involvement. Such involvement increases the risk of other, undetectable metastasis.

The scientists plan to design a large clinical trial that would seek to confirm that using the algorithm to guide therapy helps people with lung cancer survive longer.

The study conducted in China is the first major clinical trial result to emerge from the China Clinical Trials Consortium (CCTC), a collaboration between hospitals and universities across mainland China that was founded with the help of leaders from the UCSF Thoracic Oncology Program to confront the epidemic of lung cancer in China.

“The CCTC represents a revolutionary new collaborative approach to clinical research among Chinese and Western experts,” said Mann. “It is fitting that this body’s first major effort may support a molecular personalization of lung cancer care, and yield one of the first examples that fundamental tumor biology reaches across ethnic lines and can be used to try to improve outcomes for a large percentage of patients.”

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More precise treatment for head, neck cancers has resulted in fewer long-term side effects.

Allen Chen, UC Davis

Patients with head and neck cancers who have been treated with newer, more sophisticated radiation therapy technology enjoy a better quality of life than those treated with older radiation therapy equipment, a study by UC Davis researchers has found.

The findings, presented today at the Multidisciplinary Head and Neck Cancer Symposium in Phoenix, is the first of its kind to measure long-term quality of life among cancer patients who have undergone radiation therapy for advanced cancers of the throat, tongue, vocal cords, and other structures in the head and neck.

Allen Chen, assistant professor and director of the residency and fellowship training program in the UC Davis Department of Radiation Oncology, reported that the use of intensity-modulated radiation therapy, or IMRT, was associated with fewer long-term side effects, which led to a better quality of life. Standard radiation therapy to the head and neck has been known to affect a patient’s ability to produce saliva, taste, and even chew food. These side effects historically have resulted in permanent disabilities.

“With the newer machines using IMRT, physicians are skillfully able to deliver higher doses of radiation to the tumor and lower doses to surrounding normal tissues than ever before,” Chen said. “I wanted to see if this theoretical advantage resulted in any tangible improvements in quality of life for patients.”

For the study, Chen used the University of Washington Quality of Life instrument, a standardized, previously validated questionnaire that patients complete after radiation therapy. The survey was administered prospectively to 155 patients at UC Davis Cancer Center diagnosed with head and neck cancers, 54 percent of whom were initially treated with IMRT and 46 percent of whom were treated with other radiation therapy technologies. All of the patients receiving IMRT also underwent image-guided radiotherapy (IGRT), which has been available at UC Davis since 2006 and is used to increase accuracy by taking a high-quality scan of the tumor daily.

Chen and his colleagues found that the early gains observed in quality of life became magnified over time for those who received IMRT treatment. For example, one year after treatment, 51 percent of the IMRT patients rated their quality of life as very good or outstanding, compared to 41 percent of non-IMRT patients. But two years after treatment, the percentages changed to 73 percent and 49 percent respectively.

John Torres and his wife, Sophia

John Torres of Sacramento was diagnosed in early 2010 with a large tumor at the base of his tongue on the right side of his throat. Fearing that surgery might result in the loss of his voice box, Torres opted for IMRT with IGRT and had 33 treatments.

Torres, now 73 and in remission, points out that the treatments were “no walk in the park,” but said he is faring much better than he expected. Although his mouth is often dry and he has lost some taste sensation, he is enjoying an active life.

“I golf a couple of time a week,” he said. “My wife and I like to socialize. We go out, and we dance. And we are planning to take a cruise through the Panama Canal in the next two or three months. Life has gotten back to pretty much exactly what it was.”

Chen acknowledged that quality of life is difficult to measure because of its subjective nature. Nonetheless, he said the findings support the more widespread use of IMRT in radiation clinics throughout the country.

“There has been some reluctance to utilize it because it is expensive, resource intensive, and takes on average 10 to 12 hours to prepare a single patient’s treatment,” he said. “I think this is further evidence that our investment in developing newer technologies is really paying off.”

Chen, whose findings will be highlighted at a symposium press briefing on Friday (Jan. 27), received no outside funding for the research. Other investigators who collaborated on the study were Gregory Farwell, Quang Luu, Esther Vazquez, Derick Lau, and James Purdy, all from the UC Davis Cancer Center.

UC Davis Cancer Center is the only National Cancer Institute- designated center serving the Central Valley and inland Northern California, a region of more than 6 million people. Its top specialists provide compassionate, comprehensive care for more than 9,000 adults and children every year, and offer patients access to more than 150 clinical trials at any given time. Its innovative research program includes more than 280 scientists at UC Davis and Lawrence Livermore National Laboratory. The unique partnership, the first between a major cancer center and national laboratory, has resulted in the discovery of new tools to diagnose and treat cancer. Through the Cancer Care Network, UC Davis is collaborating with a number of hospitals and clinical centers throughout the Central Valley and Northern California regions to offer the latest cancer-care services. For more information, visit cancer.ucdavis.edu.

DNA mutation found to disrupt cellular function in patients with acute myeloid leukemia.

Norbert Reich, UC Santa Barbara

Researchers at UC Santa Barbara have discovered a molecular pathway that may explain how a particularly deadly form of cancer develops. The discovery may lead to new cancer therapies that reprogram cells instead of killing them. The findings are published in a recent paper in the Journal of Biological Chemistry.

The UC Santa Barbara research team described how a certain mutation in DNA disrupts cellular function in patients with acute myeloid leukemia (AML). The researchers were prompted to study this process by another research team’s discovery that AML patients have a mutation in a certain enzyme, which was reported in the New England Journal of Medicine. The enzyme is a protein called DNMT3A, which leads to changes in how the DNA of AML patients is methylated, or “tagged.” Norbert Reich, professor in the Department of Chemistry and Biochemistry at UC Santa Barbara, was already studying that particular enzyme with his research group, so they began to study the disease process of AML at the cellular level.

Reich explained that tagging is a way of reading DNA at the cellular level. This falls within an area of study called epigenetics, a process that occurs “on top” of genetics. Each person has approximately 200 types of cells, all with the same DNA, and these must be controlled in different ways. “There is an enzyme — a protein — that tags DNA and controls which of the genes in your cells, your DNA, gets turned on and off,” said Reich. “So you have 20,000 genes, and you have to control them differently in your brain than in your liver.”

Reich explained that there is current interest in this broader field of epigenetics as a direction for the treatment of cancer. “There’s definitely the idea that this may be a new way of developing therapeutics, because you don’t have to kill the cancer cell,” said Reich. “Almost every cancer therapy that’s out there works on the principle that a cancer cell needs to be killed.”

With epigenetics, instead of only having DNA sequence coding for certain genes, there is an epigenetic process, with another layer of information on top of the genetic process. In this case, that information is the tagging by the methyl groups.

“If you really think about it, this is part of the answer as to how your cells can be so different and yet they all have the same DNA,” said Reich. “You have the same genome in every one of your cells, but you do not have the same epigenome, which is basically the methylation pattern, the tagging pattern. That is different in every type of your cells. And the way this relates back to cancer, with leukemia, in those patients, the tagging is messed up. The patterns are not correct. Our big contribution to that is we’ve explained how the mutations in the enzyme could lead to that disruption of the tagging pattern.”

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UCLA researchers seek ways to address long-term effects of treatment.

Patricia Ganz, UCLA

Quality of life in younger patients treated for breast cancer is seriously compromised, and these women face more physical and mental health issues than women their age who haven’t had cancer and women over 50 who have, according to a study by researchers at UCLA’s Jonsson Comprehensive Cancer Center.

The study, published Jan. 20 in the peer-reviewed Journal of the National Cancer Institute, found that younger breast cancer survivors suffer from a slew of problems, including severe psychological distress, infertility, premature menopause, a decrease in physical activity and weight gain.

The study points to the need for oncologists to let these younger patients know from the beginning of their therapy what may happen to them after it’s finished, said the study’s lead author, Dr. Patricia Ganz, director of cancer prevention and control research at UCLA’s Jonsson Comprehensive Cancer Center.

“We know that educating and providing younger breast cancer patients with information about what they might experience once their treatment ends is very helpful,” said Ganz, who has been conducting research on quality of life after cancer treatment for 25 years. “If they know what to expect, their anxiety level will be greatly reduced. Up to now, oncologists have not done a good job of preparing these women for what will come.”

Reducing anxiety is crucial, Ganz said, as preclinical studies have shown that stress can promote cancer growth and spread in animal models. A study by Jonsson Cancer Center researchers published in 2010 in Cancer Research showed that chronic stress acted as a sort of fertilizer that fed breast cancer progression, significantly accelerating the spread of disease.

The need to prepare younger breast cancer survivors for any adverse effects they may experience and seek ways to address those problems is vital as more and more younger women are surviving their cancer due to improvements in early detection and treatment, Ganz said.

“A cancer diagnosis can challenge younger women with issues that don’t impact older patients,” she said. “A younger breast cancer patient may have young children and may be worried about living to raise them to adulthood. A younger breast cancer patient may not have had children yet and may be faced with infertility following her treatment or may return to the dating scene following treatment. We need to find ways to reduce the stress and anxiety that dealing with these issues may create.”

Ganz recently received a grant from the Centers for Disease Control and Prevention that will fund a leading-edge program that seeks to enhance outcomes for young breast cancer survivors in the Los Angeles region. The program is being done in collaboration with the Jonsson Cancer Center, the UCLA–LIVESTRONG Survivorship Center of Excellence and the Simms/Mann–UCLA Center for Integrative Oncology.

The three-year, $700,000 grant will focus on making life after breast cancer better for women aged 21 to 45 in Los Angeles County by funding a program designed to meet their unique needs, Ganz said. UCLA is one of seven organizations nationwide to receive funding for this focus on young breast cancer survivors. The resources and strategies developed in the diverse and populous Los Angeles region will serve as a model for other organizations across the country.

Services will be offered to these women through the UCLA Health System and with collaborators at Torrance Memorial Medical Center and the South Bay Cancer Survivorship Consortium, as well as the Olive View–UCLA Medical Center, a public hospital in northern Los Angeles County that treats mostly minority women who are underinsured or who have no insurance.

“These three health systems provide breast cancer services for a substantial number of ethnically diverse, newly diagnosed women with breast cancer under 45 years old. They see about 225 new cases annually,” Ganz said. “We estimate that there are hundreds of young breast cancer survivors who are being followed in these institutions who will directly benefit from the programs that we will develop.”

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