UC Irvine’s Janellen Smith warns against health risks from sun exposure.

Janellen Smith, UC Irvine

As a specialist in skin disorders and cancers, Janellen Smith, M.D., sees firsthand what too much sun can do. Sunburns and accelerated skin aging are common results, but excessive sun exposure also can be deadly.

Each year, more than 1 million Americans are diagnosed with skin cancer, the most common of all cancers. About 50,000 of these cases involve melanoma, the most serious form of skin cancer. If not treated promptly, it can spread to other parts of the body and prove fatal. Smith, a UC Irvine dermatology professor affiliated with the Chao Family Comprehensive Cancer Center, stresses that people – especially those in sun-worshipping Southern California – should be aware of the health risks associated with prolonged sun exposure and take proper precautions.

Q: Who should be most concerned about excessive sun exposure?

A: The sun is harmful to all skin types, but people with lighter skin that freckles easily are the most at risk. Another big risk factor is a family history of skin cancer. People with darker skin, especially Latinos, are developing skin cancers at an increased rate. Asians and African Americans are not immune to melanoma either, and when it does appear, it’s often on the palms, on the soles of the feet or under the fingernails.

Q: Why should people be concerned about getting too much sun?

A: The three most important reasons are the development of skin cancer, faster aging and the interaction the sun can have with certain medications. When I talk to patients, I often emphasize the ravages of aging, because they never think they’ll get cancer.

Q: What types of cancer can people get from sun exposure?

A: There are three main types of skin cancer: basal cell carcinoma, squamous cell carcinoma and melanoma. Basal cells are the most common, but melanomas are the most deadly.

Q: How can excess sun lead to melanoma?

A: Chronic sun exposure leads to the development of nonmelanoma skin cancers, and sporadic, high-intensity sun exposure leads to the development of melanomas. There is some crossover, but this is often the case. Damage is done to the skin that overwhelms the body’s repair mechanisms.

Q: What can be done for sun-damaged skin?

A: The sooner you get out of the habit of excess sun exposure the better. It sometimes seems as if this does no good, as some of the damage previously incurred is still developing. But eventually you will reap the benefits. UC Irvine Medical Center dermatologists have many methods for helping you. There are creams, lasers and fillers that go a long way in returning your skin to its peak condition.

Q: What products help protect the skin, and which ones should be avoided?

A: Sunscreens that contain avobenzone, titanium dioxide, zinc oxide or mexoryl are the best at protecting the skin from all wavelengths of damaging light. Tightly woven clothing is also protective, and some companies make clothing with sun protection factor (SPF) ratings. Do not use baby oil in the sun; it is not protective.

Q: What do you recommend people do this summer to maximize good skin health?

A: Avoid the sun during the peak hours of 10 a.m. to 4 p.m., and use sunscreen and sun-protective clothing. Sometimes it’s best to think of your day upside down: If you normally go to the beach in the afternoon and the movies at night, think about making a switch. There is nothing quite so fine as walking along the beach as the sun goes down, and movie theaters are much less crowded in the afternoon.

Attendees of June 10 event will attempt to form record-breaking line of surfboards.

The beach of La Jolla Shores will be home to a possible record-breaking line of surfboards on June 10, as hundreds of cancer survivors, caregivers, friends and surfers gather together in solidarity in the fight to wipe out cancer. As part of UC San Diego Moores Cancer Center’s 6th annual Survivor Beach, attendees will line surfboards along the shore, nose-to-tail, from Scripps Pier down La Jolla Shores, in a stunning visual display. Last year, the line reached more than five football field lengths. Sponsored by biotechnology company Genentech, Survivor Beach is free and open to the public. The event will take place from 8 a.m. to 10 a.m.

Jessica Yingling, Ph.D., established Survivor Beach six years ago to bring the community together in honor of all individuals who have fought against cancer and to show support for the research that will help make more cancer patients survivors.

“Survivor Beach offers a unique and meaningful way for anyone who has been touched by cancer to gather and receive support and inspiration,” said Yingling, chair of Survivor Beach. The event precedes the Luau and Longboard Invitational in August, which will raise funds for research, patient care, and outreach and educational programs at UC San Diego Moores Cancer Center, the region’s only Comprehensive Cancer Center, designated by the National Cancer Center Institute.

“The line of surfboards conveys the ‘aloha spirit’ felt at both Survivor Beach and the Luau and Longboard Invitational. It is a visual reminder of the saying, ‘many hands make light work,’” Yingling continued. “Fighting cancer takes many hands: the strength of the patient, the attentiveness of the doctors and medical staff, the persistence of the researchers and the support of family, friends and the community. The line reminds us that together we are stronger than one.  Together we can fight this disease and win.”

“Survivor Beach provides a stunning visual representation of San Diego’s support in the quest for a cure for cancer,” said Scott Lippman, M.D., director of the UC San Diego Moores Cancer Center. “Generous support from our community and corporate partners helps our physicians and scientists find ways to defeat cancer and continue to provide the most compassionate care possible to patients and families.”

In addition to the record-breaking attempt, speakers will share their inspirational stories about fighting cancer, local musician Rob Mehl will sing original, surf-inspired songs and Heali’i’s Polynesian Revue will perform authentic dances. The person or group to bring the most surfboards for the Survivor Beach line-up will receive a special prize. Participants will also have the chance to win a pair of tickets to the annual UC San Diego Moores Cancer Center Luau and Longboard Invitational, which will take place Sunday, Aug. 19.

Celebrating 19 years of surfing for a cure, the Luau and Longboard Invitational has raised more than $5 million to fund groundbreaking cancer research at UC San Diego Moores Cancer Center.  For more information about sponsorship opportunities, team entries and tickets for the Luau and Longboard Invitational, contact UC San Diego Moores Cancer Center at (858) 534-6797 or visit longboardluau.org.

Survivor Beach will also help kick off Moores Cancer Center’s Cancer Survivor Week 2012, which is a celebration designed to renew, recharge and rejuvenate those with experience in battling cancer. For more information on Cancer Survivor Week 2012, please visit cancer.ucsd.edu.

Survivor Beach will take place from 8 a.m. to 10 a.m. on June 10 on the beach by Scripps Pier. To register, please visit survivorbeach.eventbrite.com.

UCLA study quantifies learning curve for robotic-assisted surgery.

Jim Hu, UCLA

Prostate cancer is the most commonly diagnosed non-skin cancer in the U.S., and radical prostatectomy, the surgical removal of the prostate gland, remains the most popular therapeutic option, accounting for half of treatments.

The procedure, however, is not without possible side effects, primarily erectile dysfunction and incontinence. But a good nerve-sparing surgical technique can lessen the likelihood of these undesirable outcomes, as can the skill and experience of the surgeon, according to a new UCLA study that focused on robotic-assisted prostate surgery.

The study findings are published in the June 2012 print edition of the international peer-reviewed journal European Urology.

Based on their research, the study authors recommend that men undergoing robotic-assisted surgery for prostate cancer should look for a doctor who has performed at least 1,000 surgeries and who actively seeks to improve and enhance his surgical skills to help ensure a successful post-surgery recovery of erectile function.

The authors also found that new, refined techniques that prioritize the gentle handling of the delicate nerves around the prostate also make a difference in improved erectile function.

The study is one of the first to characterize a surgeons’ learning curve for improving erectile-potency outcomes and to demonstrate and quantify gentler handling techniques that involve minimizing stretch injury to the nerves around the prostate as the gland is removed, the researchers said.

“It would be helpful for men who seek a surgical cure for their prostate cancer to appreciate the nuances required by a surgeon to successfully protect erectile function,” said Dr. Jim Hu, director of minimally invasive surgery in the department of urology at the David Geffen School of Medicine at UCLA and lead author of the study. “Like improving a golf swing, a technique for nerve-sparing surgery has many subtleties that are influenced by training, talent, a desire to improve, and meticulous review of technique and outcomes.”

The research team developed a video demonstrating the new techniques so that robotic-assisted surgeons may achieve better outcomes more quickly and potentially shorten their learning curves. Hu noted that the anatomic concepts and techniques extend to traditional, non–robotic-assisted surgery as well.

For the study, the team looked at nerve-sparing techniques and maneuvers used in the operating room in 400 surgeries performed by Hu over a two-year period at Brigham and Women’s Hospital in Massachusetts. Hu tracked his patients’ erectile-potency recovery outcomes by groups of 50 up to one year after surgery.

While this is a single-surgeon study during robotic-assisted surgery, Hu used standardized questionnaires to quantify patient-reported recovery of erectile function, which is not often done by individual surgeons and which helped in assessing outcomes.

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Copper transporter carries anti-cancer drug into cancer cells to help kill them.

A team of University of California, San Diego, researchers has made new discoveries about a copper-transporting protein in the membranes of human cells that drug-discovery scientists can co-opt for the development of new anti-cancer drugs.

The findings, published May 9 as an online-first paper in Cell Biochemistry and Biophysics, describe how the copper transporter works as a biochemical pump to seize copper atoms outside of a cell and whisks the atoms through the otherwise impervious cell membrane into the cell cytoplasm. The same pump transports the platinum-containing drug cisplatin into cancer cells to help kill them. Igor Tsigelny, a research scientist at the university’s San Diego Supercomputer Center and Department of Neurosciences, is lead author of the paper.

The body needs only a tiny amount of copper, but the little that is needed acts as a key component of vital cellular enzymes, including superoxide dismutase, cytochrome c oxidase, lysyl oxidase and dopamine β-hydrolase.

Researchers have shown before that that human copper transporter 1 (hCTR1) protein also participates in transport of the platinum-containing cisplatin, one of the most widely used anti-cancer drugs. Once platinum-containing cisplatin molecules enter a tumor cell, the molecules interact with the cell’s DNA and kill it in a process that has been extensively studied by Stephen B. Howell, a professor of medicine at the UC San Diego Moores Cancer Center.

The way that hCTR1 works is a focus of research by Howell and other cancer researchers because cisplatin and similar drugs somehow lose their punch: they are effective anti-cancer drugs when first administered, but lose much of their effectiveness during cancer relapses. Some researchers theorize that the diminished effect of cisplatin could be due to a change in hCTR1 in cancer cells.

New insights derived by the UC San Diego team is leading to a better understanding of what happens to the protein transporter and that knowledge could possibly be used to design a better version of cisplatin or an entirely new drug to take advantage of the new information.

In addition to cancer researchers, the hCTR1 has been a mystery to cell biologists. Until recently, they didn’t know whether the transporter protein formed dimers, or trimers. In a 2006 breakthrough that was refined in 2009, scientists confirmed that the trimer is the predominant structure, which was confirmed by the pioneering work of Northwestern University professor Vincenz Unger.

Unger’s team identified the structure of the part of the hCTR1 transporter protein that spans the cell membrane. But they were not able to determine the structure of the part of the protein that extends to the outside of the membrane. Because of that gap in knowledge, they were not able to obtain a high-resolution 3-D map of the protein’s structure.

SDSC’s Tsigelny and his colleagues set out to create a complete, detailed 3-D model of the transporter. “There is no magic bullet in protein modeling, especially when we do not have a direct homologous template of another protein crystal structure,” Tsigelny said. “We predicted the structure of the protein on the level of information available at the current time, but this model needed to be checked with actual experimental results.”

Any model that Tsigelny’s team came up with would have to answer questions that had evaded scientists for years. For example, why is the extracellular end of the transporter so flexible? While the flexibility frustrated Unger’s ability to determine its 3-D structure, was the flexible tip of the protein stable enough to support its copper-transporting function?

Would the positively charged metal ions be transported electrostatically? And how does the transporter initially corral metal ions at pick-up points on the cell exterior and drop them off inside?

Tsigelny’s team used a computationally rigorous approach to find the answers.

So-called molecular dynamics modeling studies showed that the path the metal ions take through the intra-membrane transporter channel is stable despite the innate flexibility of the protein. In addition, while electrostatic forces worked well to hold positively charged metal ions like magnets at the extracellular and intracellular ends of the transporter protein, the passage of the metal atoms through an interior channel in the protein must be caused by another means.

Searching the Protein Data Bank

To help to understand the metals’ interaction with protein, Tsigelny’s team invented a new programming tool called METBIND, which works like a chemistry search engine. The program tried to find the possible binding sites of copper and platinum (along with other metal ions) as they interact with the hCTR1 protein and then move along it.

They checked the validity of their METBIND program with all possible copper-protein binding arrangements reported in the 74,000 proteins in the Protein Data Bank.

To the Tsigelny team’s surprise, the METBIND program correctly predicted 80 percent of all known copper binding sites in all 636 copper-binding proteins in the Protein Data Bank. They then focused the METBIND search engine on hCTR1.

They looked for individual atoms in the protein that could be placed within 3.5 Angstrom units of a hypothetical copper ion. One Angstrom unit is equal to one hundred-millionth (10 -8) of a centimeter. They identified six histidine residues in the protein that bind copper (and probably platinum) as the first step in the metal transport process.

They identified nine negatively charged amino acids in the part of the hCTR1 protein that stick out into the extracellular medium waiting for oppositely charged copper or platinum ions to pass by. When the ions arrive, the hCTR1 protein grabs them firmly.

They also found that the hCTR1 trimer creates a neutral channel with a set of triads of methionine amino acids. The triads shepherd copper or platinum ions through the cell membrane into the interior cytoplasm. Each of the methionines is important: if one is lost, copper transport is inhibited. The same effect of methionines has been reported for yeast copper transporter (yCTR).

“Drug developers are interested in the selective transport of platinum and other metal ions into cells to invoke a desired effect, and this study provides a blue print for how they could search for drugs to enhance those effects,” Tsigelny said.

Tsigelny’s research team included Yuriy Sharikov, with SDSC and UC San Diego’s Department of Neurosciences; Jerry P. Greenberg, Mark A. Miller, Valentina L. Kouzentsova, Christopher A. Larson, all with SDSC; and Stephen B. Howell, a professor of medicine at the UC San Diego School of Medicine and associate director for clinical research at the UC San Diego Moores Cancer Center.

The research was funded by grant # W81XWH-08-1-0135 from the National Institutes of Health, as well as grants from the Department of Defense and the Clayton Medical Research Foundation. Computational resources were provided by SDSC and additional support was provided by the UC San Diego Neuroscience Microscopy Shared Facility and the UC San Diego Moores Cancer Center.

About SDSC
As an Organized Research Unit of UC San Diego, SDSC is considered a leader in data-intensive computing and all aspects of ‘big data’, which includes data integration, performance modeling, data mining, software development, workflow automation, and more. SDSC supports hundreds of multidisciplinary programs spanning a wide variety of domains, from earth sciences and biology to astrophysics, bioinformatics and health IT. With its two newest supercomputer systems, Trestles and Gordon, SDSC is a partner in XSEDE (Extreme Science and Engineering Discovery Environment), the most advanced collection of integrated digital resources and services in the world.

Studies in mice offer promise of new prevention strategy, treatment.

Neelima Mehta (left) and Brittany Greenberg, UC Davis

A vaccine that targets cancer cells in combination with the drug letrozole, a standard hormonal therapy against breast cancer, significantly increased survival when tested in mice, a team of UC Davis investigators has found.

The findings will be published today (May 15) in the journal Clinical Cancer Research.

“We found that the vaccine and the hormonal drug letrozole were more effective when given together,” said Michael DeGregorio, UC Davis professor of hematology and oncology and principal investigator of the study. “This adds critical evidence that immunotherapy with vaccines, which has traditionally been used to prevent infectious diseases, is also a promising new approach to combating cancer.”

The vaccine, known as L-BLP25 (Stimuvax), specifically targets Mucin1 glycoprotein (MUC1), an antigen that is expressed in an altered form on cancer cells. When introduced into the body, the vaccine generates an immune response by T-lymphocytes, which then recognize and destroy the tumor cells. Mice in the study were injected weekly with the vaccine — or a placebo — for eight weeks.

In addition to the vaccine or placebo, some mice were treated with either letrozole or tamoxifen, commonly used hormonal therapies against breast cancer. Both drugs work by blocking the effects of estrogen, which can slow or stop the growth of some types of breast cancer cells that need the hormone to grow. Although the drugs have similar actions, the benefits of the vaccine were greatest in the mice treated with letrozole; in contrast, vaccinated mice given tamoxifen actually fared worse than those given either the vaccine or tamoxifen alone.

“Hormonal drugs affect the immune system in different ways, and apparently the actions of tamoxifen prevent the vaccine from working effectively,” said DeGregorio. “This highlights the importance of rigorous testing of different combinations of therapies before using them in patients.”

The article, available online, is titled “L-BLP25 vaccine plus letrozole induces a TH1 immune response and has additive antitumor activity in MUC-1 expressing mammary tumors in mice.”

Breast cancer is the second-leading cause of cancer death in women in the United States, following lung cancer. Most cases of breast cancer are “estrogen-dependent” and respond to hormonal therapy. For tumors that are independent of hormonal influence, treatment options are limited and would especially benefit from a new treatment strategy such as a vaccine.

The vaccine was found to work best when the tumor burden – the amount of cancer present – was low, indicating that the vaccine may one day be best used as a preventative measure for women at high risk of developing breast cancer or for treatment of early disease.

Vaccine therapy is a promising new cancer-fighting strategy; the first therapeutic vaccine for prostate cancer was approved by the U.S. Food and Drug Administration in 2010. Trials with L-BLP25 vaccine are currently under way for lung and pancreatic cancers, whose cells also express altered MUC1, the same tumor-associated antigen found on breast cancer cells. The current study is the first known to the authors to demonstrate that a hormonal therapy combined with a vaccine provides additive antitumor activity and survival benefit.

“This was a true alliance between academics and industry,” added DeGregorio, who noted that trials such as this one are especially expensive because of the number of mice needed and the length of time — about three and a half years — required to establish their findings. The study had support from the pharmaceutical company, Merck KGaA Darmstadt Germany.

DeGregorio’s group will further test the vaccine with other conventional therapies and determine optimal dosing. Clinical trials in patients with breast cancer are in the planning stages.

Other UC Davis study authors were Neelima R. Mehta, Gregory T. Wurz, Rebekah A. Burich, Brittany E. Greenberg, Audrey Gutierrez and Jamie L. McCall, also of the Department of Internal Medicine, Division of Hematology and Oncology; Stephen Griffey of Veterinary Medicine’s Comparative Pathology Laboratory; and Katie E. Bell, of the Center of Comparative Medicine. Michael Wolf of Merck KGaA in Darmstadt, Germany, was also an author.

UC Davis Comprehensive 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 specialists provide compassionate, comprehensive care for more than 9,000 adults and children every year, and access to more than 150 clinical trials at any given time. Its innovative research program engages more than 280 scientists at UC Davis, Lawrence Livermore National Laboratory and Jackson Laboratory (JAX West), whose scientific partnerships advance discovery of new tools to diagnose and treat cancer. Through the Cancer Care Network, UC Davis collaborates with a number of hospitals and clinical centers throughout the Central Valley and Northern California regions to offer the latest cancer care. Its community-based outreach and education programs address disparities in cancer outcomes across diverse populations. For more information, visit cancer.ucdavis.edu.

Often-fatal form of cancer currently has no reliable method for early detection.

Jonathan Kelber, UC San Diego

Researchers at the University of California, San Diego, School of Medicine and Moores Cancer Center have identified a new biomarker and therapeutic target for pancreatic cancer, an often-fatal disease for which there is currently no reliable method for early detection or therapeutic intervention.  The paper will be published today (May 15) in Cancer Research.

Pancreatic ductal adenocarcinoma, or PDAC, is the fourth-leading cause of cancer-related death.  Newly diagnosed patients have a median survival of less than one year, and a 5-year survival rate of only 3 to 5 percent. Therefore, biomarkers that can identify early onset of PDAC and which could be viable drug targets are desperately needed.

“We found that a kinase called PEAK1 is turned on very early in pancreatic cancer,” said first author Jonathan Kelber, Ph.D., a postdoctoral researcher in the UCSD Department of Pathology and Moores Cancer Center.  “This protein was clearly detected in biopsies of malignant tumors from human patients – at the gene and the protein levels – as well as in mouse models.”

PEAK1 is a type of tyrosine kinase – an enzyme, or type of protein, that speeds up chemical reactions and acts as an “on” or “off” switch in many cellular functions.  The fact that PEAK1 expression is increased in human PDAC and that its catalytic activity is important for PDAC cell proliferation makes it an important candidate as a biomarker and therapeutic target for small molecule drug discovery.

In addition to showing that levels of PEAK1 are increased during PDAC progression, the scientists found that PEAK1 is necessary for the cancer to grow and metastasize.

“PEAK1 is a critical signaling hub, regulating cell migration and proliferation,” said Kelber. “We found that if you knock it out in PDAC cells, they form significantly smaller tumors in preclinical mouse models and fail to metastasize efficiently.”

The research team, led by principal investigator Richard Klemke, Ph.D., UCSD professor of pathology, studied a large, online data base of gene expression profiles to uncover the presence of PEAK1 in PDAC.  These findings were corroborated at the protein level in patient biopsy samples from co-investigator Michael Bouvet, M.D., and in mouse models developed by Andrew M. Lowy, M.D., both of the UCSD Department of Surgery at Moores Cancer Center.

While many proteins are upregulated in cancers of the pancreas, there has been limited success in identifying candidates that, when inhibited, have potential as clinically approved therapeutics. However, the researchers found that inhibition of PEAK1-dependent signaling sensitized PDAC cells to existing chemotherapies such as gemitabine, and immunotherapies such as trastuzumab.

“Survival rates for patients with pancreatic cancer remain low,” said Bouvet. “Therefore, earlier detection and novel treatment strategies are very important if we are going to make any progress against pancreatic cancer. Since current therapies are often ineffective, our hope is that the findings from this research will open up a new line of investigation to bring a PEAK1 inhibitor to the clinic.”

Additional contributors to the study include Theresa Reno, Sharmeela Kaushal, Cristina Metildi,Tracy Wright, Konstantin Stoletov, Jessica M. Weems, Frederick D. Park, Evangeline Mose, UC San Diego; Yingchun Wang, Chinese Academy of Science, Beijing; and Robert M. Hoffman, UC San Diego and AntiCancer Inc., San Diego.

The study was supported by the National Institutes of Health.

Researcher Karen Kelly named fellow of ELAM program.

Karen Kelly, UC Davis

Karen Kelly, associate director for clinical research at the UC Davis Comprehensive Cancer Center, has been selected as a fellow of the prestigious Hedwig van Ameringen Executive Leadership in Academic Medicine (ELAM) Program for Women at Drexel University College of Medicine.

Kelly, an internationally recognized medical oncologist who specializes in lung cancer, will be part of the 2012-2013 class of 54 women physicians and scientists from 48 different institutions around the country and beyond, including from Puerto Rico, Canada and Saudi Arabia.

ELAM is dedicated to preparing senior women faculty for positions of leadership at academic health centers, where they can play a role in helping the organizations become more inclusive of different perspectives and responsive to the needs and expectations of society.

“I am honored to have been chosen for this exciting program,” Kelly said. “With our cancer center’s new National Cancer Institute ‘comprehensive designation’ and expanding translational research programs, this fellowship will give me tools I can bring to our multidisciplinary efforts to discover better treatments and improve outcomes for all patients.”

As a fellow, Kelly will be required to develop an “Institutional Action Project” designed to address an institutional or departmental need or priority. The project is designed to help ELAM fellows understand the challenges facing academic health centers and the skills a leader needs to address them, while also helping to implement concrete changes within the health system. She will attend three week-long, in-residence sessions, beginning in September.

Since her recruitment to the cancer center from the University of Kansas in 2011, Kelly has enhanced the infrastructure of the clinical trials program and founded several clinical cancer innovation groups. As director of the Phase 1 Clinical Trials Unit, she is developing additional venues to evaluate new drugs, building relationships with industry partners and working to recruit more patients to trials.

Kelly has held many leadership roles in national cancer organizations, including the American Society of Clinical Oncology, the International Association for the Study of Lung Cancer and the National Cancer Institute. She has authored more than 150 papers, reviews and book chapters and frequently lectures on lung cancer topics worldwide.

About ELAM
ELAM is a core program of the Institute for Women’s Health and Leadership at Drexel University College of Medicine in Philadelphia, Pa. The Institute continues the legacy of advancing women in medicine that began in 1850 with the founding of the Female Medical College of Pennsylvania, the nation’s first women’s medical school and a predecessor of today’s Drexel University College of Medicine. For more information on the ELAM program curriculum, faculty and participants, visit 222.drexelmed.edu/elam.

UC Irvine doctor finds disparities in access to the top-quality care that boosts survival.

Robert Bristow, UC Irvine

Dr. Robert Bristow believes a decidedly low-tech approach could significantly enhance the survival rate for ovarian cancer, even though it’s the deadliest women’s reproductive cancer, claiming 15,000 lives each year; it has no reliable screening or prevention methods; and its research funding is about one-sixth the amount for breast cancer.

“We don’t have to redesign a molecule to improve the outcome for women with ovarian cancer,” says Bristow, the Philip J. DiSaia Chair in Gynecologic Oncology and director of UC Irvine’s Division of Gynecologic Oncology. “Recent research has shown that the most profound impact on survivorship occurs when women get proper care from surgeons trained in the latest techniques for treating ovarian cancer.”

In March, he presented to the Society of Gynecologic Oncology a study of 50,000 ovarian cancer patients finding that poor women and African Americans were less likely to receive the highest standards of care, leading to worse outcomes than for white and affluent patients.

[Related: UC Irvine study finds racial, economic disparities in ovarian cancer care, survival]

“Not all women are benefiting equally from improvements in ovarian cancer care,” Bristow says. “The reasons behind these disparities are not entirely clear, which is why we need additional research.”

The study’s goal was to quantify differences related to race and socioeconomic status among women being treated for epithelial ovarian carcinomas – cancer that forms on the surface of an ovary. It also aimed to determine whether their care adhered to National Comprehensive Cancer Network treatment guidelines.

Bristow and colleagues found that five-year survival rates varied significantly. (Improvement in ovarian cancer care is measured in length of survival after diagnosis rather than a “cure” rate.)

Among those whose care met NCCN standards, the rate for white women was 41.4 percent, compared with 33.3 percent for African American women. Among those whose care did not meet NCCN standards, the rate for white women was 37.8 percent, compared with 22.5 percent for African American women. Those on Medicaid or without insurance faced a 30 percent increased risk of death. Poor women – defined as having an annual household income of less than $35,000 – had worse survival rates regardless of race.

Bristow’s study was part of an effort by the Society of Gynecologic Oncology and colleagues at the Mayo Clinic and Washington University in St. Louis to assess the quality and outcomes of ovarian cancer care in the U.S.

In November, Bristow led a symposium at UC Irvine that attracted gynecologic surgeons from 10 countries – including Australia, Poland and Denmark – to learn the latest surgical and chemotherapy techniques for treating ovarian cancer.

“This is helping us understand the kind of advanced expertise we need to bring to women in Denmark,” said Dr. Pernille Jensen of Odense University Hospital. Her nation is planning to consolidate ovarian cancer treatment from five sites to one in order to concentrate surgical expertise and improve the level of care women receive.

“There is a great need to raise the education level of fellowship-trained surgeons,” Bristow says. “Under the best circumstances, treating ovarian cancer is challenging, because there’s no screening tool available to detect the disease in its early stages.”

Since only 20 to 30 percent of ovarian cancers are diagnosed while still confined to the primary site, it’s critical that surgeons can effectively treat it in advanced stages after the cancer has spread to areas such as the liver, the lungs and nearby lymph nodes.

Even women with late-stage ovarian cancer can see survival rates significantly higher than those treated with traditional approaches.

“For example, we’ve known for several years that the combination of intravenous chemotherapy and intraperitoneal chemo – in which the drugs are injected directly into the abdominal cavity – greatly improves survival,” Bristow says. “Yet too many cancer centers rely solely on IV chemo.”

He says the symposium will become an annual event, with UC Irvine and colleagues at Washington University in St. Louis hosting in alternate years.

UC Irvine has a legacy of leadership in treating reproductive cancers.

DiSaia, the founding director of the Division of Gynecologic Oncology and Bristow’s predecessor, is legendary, having written the first comprehensive book on treating gynecologic cancers. DiSaia recently published the eighth edition of Clinical Gynecologic Oncology. He is also chairman of the Gynecologic Oncology Group, a national collaboration of universities and cancer centers that directs studies funded by the National Cancer Institute.

UCSF is one of only two California institutions in Children’s Oncology Group Phase 1 Consortium.

(From left) Steven DuBois, Kate Matthay and Kate Mantis, UC San Francisco

It’s a real challenge to treat a patient with relapsed cancer, because the cancer has outsmarted initial treatment and has become more resistant, says Steven DuBois, M.D., assistant professor of pediatrics at UC San Francisco’s School of Medicine and a specialist in childhood cancers.

Now, DuBois and his colleagues at the UCSF Helen Diller Family Comprehensive Cancer Center have access to a vastly expanded array of potential resources in their battle against childhood cancers.

The extra firepower comes from UCSF’s recent acceptance into the Children’s Oncology Group (COG) Phase 1 Consortium, an elite National Cancer Institute consortium of institutions selected to lead Phase 1 studies of potential pediatric cancer drugs. UCSF is one of only two COG Phase 1 institutions in California, and one of only 21 centers in the United States and Canada.

Phase I testing, the first step in a drug’s translation from the laboratory to possible approval by the Food and Drug Administration (FDA), is designed to assess safety and appropriate dosage in a specific population — in this case, children.

As in adult Phase I trials, the patients recruited for pediatric Phase I studies have typically not responded well to initial treatment or have had a recurrence of their cancer. Many have been told that they have no other therapeutic alternatives.

Thanks to the variety of experimental treatments available through COG, says DuBois, “we are now able to offer these patients a wider array of novel agents across the spectrum of childhood cancers, from leukemia to brain tumors to other types of solid cancers.”

Most of the agents are targeted molecular therapies, which are designed to short-circuit the biological pathways that cancers depend upon to grow. “If you can find the right molecular target that is driving the growth of a cancer and then block it, you can control the cancer,” says DuBois. Others are oncolytic viruses, which infect and then dissolve tumors.

DuBois recently concluded a Phase I pediatric study for sunitinib, an oral drug that blocks angiogenesis, the process of new blood vessel growth that is integral to the development of solid cancers.

The study successfully identified the safest dose for children. In addition, since not all children can swallow pills, DuBois and his team developed and tested a more child-friendly formulation, where the drug powder is sprinkled onto yogurt or apple sauce.

Such studies are “quite intensive,” DuBois says. Patients are monitored not only for toxic reactions, but for pharmacokinetics — how the drugs are metabolized by the body. “There are frequent visits to the outpatient PCRC for blood draws, which have to be done in a really precise, standardized way.

“We couldn’t do this type of work without the infrastructure and personnel of the Pediatric Clinical Research Center,” a unit of the Clinical Research Services program managed by UCSF’s Clinical and Translational Science Institute (CTSI).

Such clinical studies call for nursing care that is “totally specialized,” says Katherine Matthay, M.D., professor of medicine and Mildred V. Strouss Endowed Chair in Translational Research in Pediatric Oncology at UCSF. For example, patients might need pharmacokinetics studies at very specific times after a drug is administered, as well as special lab studies for pharmacodynamics, “where we look at the effects of the drug on cancer cells and their molecular pathways,” Matthay says.

Blood samples are drawn by highly skilled nurses and rushed, sometimes in the middle of the night, to the CTSI core lab, where they are processed and stored. “These are not things that can be done on a regular pediatric oncology unit,” notes Matthay.

Side effects are a particular challenge. “Many of these inhibitors are oral medications, which don’t have the same obviously terrible side effects as intravenous chemotherapy, so we tend to think of them as benign,” says Matthay.

“But in Phase I therapy, we’re constantly running into unexpected or unusual side effects, and patients can die from them.” Parents, she says, “have to be willing to take that risk in enrolling their children in these trials. They usually are, because they have incurable cancers.”

“When we offer studies to patients, we’re offering them hope for more time,” says DuBois, who also notes that “some of the drugs that we’re testing now in children with relapsed cancer will become the future cornerstones of treatment for children with newly diagnosed cancer.”

“Ultimately, our participation in the COG Phase 1 Consortium will allow us to facilitate the translation of new drugs into the clinic from our rich pipeline of laboratories here at UCSF — and we can improve outcomes in pediatric oncology,” he says.

CTSI is a member of the National Institutes of Health-funded Clinical and Translational Science Awards network focusing on accelerating research to improve health. The institute provides services for researchers at every stage, and promotes online collaboration and networking through UCSF Profiles.

UCSF visualization shows why immune system fails to kill tumors in mice.

Matthew Krummel, UC San Francisco

A pioneering approach to imaging breast cancer in mice has revealed new clues about why the human immune system often fails to attack tumors and keep cancer in check. This observation, by scientists at the University of California, San Francisco, may help to reveal new approaches to cancer immunotherapy.

Instead, these immune cells are headed off at the pass. A completely separate set of healthy cells that are already in contact with the tumor effectively establish a defensive perimeter around it. There, like a thin red line between cancer and health, they head off the killer immune cells and keep them at bay outside the tumor. Published in the journal Cancer Cell last month, the work shows that the body’s natural defenses trip over themselves on their way to attacking a tumor. The activated immune cells, alerted to the threat of the tumor, should make their way to the site of the cancer and then attack and shrink the tumor.

“These cells are forming a last line of defense for the tumor against incoming cytotoxic cells,” said Matthew Krummel, Ph.D., an associate professor of pathology and a principal investigator in the UCSF Helen Diller Family Comprehensive Cancer Center.

The discovery adds a rich layer of understanding of how the immune system interacts with breast cancer, knowledge that may ultimately help researchers find better ways to treat the disease, said Krummel. Future immunotherapy cancer treatments could be made more effective on their own or in combination with other drugs, he said, if researchers can find a way to enhance the ability of T cells to make it through this tumor defense.

Cracking open a crashed airplane’s black box to parse its flight data and recreate its final few seconds is a powerful way of asking how improvements could be made to aviation safety. Biologists would like to do essentially the same thing with cancer: to liberate the data, see what went wrong and use that knowledge to find new ways to improve human health.

Because biology has no flight recorders, modern researchers look broadly at the genetics of large populations, or tease apart the molecular markers within tumors or closely following the disease as it develops in laboratory models.

What they found was that the interaction between breast cancer and the immune system is marked by missed opportunities. Krummel and his colleagues developed a way to produce different fluorescent-colored dyes in breast cancer tumors and the various cells around them. They then used a special microscope to image and track immune cells as they moved in and out of breast cancer tumors that arise spontaneously in the mouse. “We can see each of them arise, see where they are in the tumor and watch their direct interaction with immune cells in real time,” he said.

Fighting cancer is one of the things the immune system is designed to do, in numerous ways. One of these is by unleashing a set of actors known as killer T cells, which can destroy tumors by attacking their cells en mass. The success of this mechanism can mean the difference between a tumor that withers away and one that continues to grow to more advanced stages.

But the scene Krummel and his colleagues watched unfold under their microscopes revealed a subset of specialized “dendritic” cells that they were then able to extensively study. With the fluoroscent labeling technique they devised, they were able to purify just these cells and observe how they dampen the killer T cell responses.

As Krummel and his colleagues showed, these cells deactivated approaching killer cells, stifling them before they could spring into action.

This set of experiments is critical for cancer immunobiologists, said Krummel, because the data is the first to positively identify a partner for the incoming killer T cells. The fact that the interaction dampens the potency of the killer cells makes the dendritic cells a valuable target for future therapeutics.

The article, “Marginating Dendritic Cells of the Tumor Microenvironment Cross-Present Tumor Antigens and Stably Engage Tumor-Specific T Cells” by John J. Engelhardt, Bijan Boldajipour, Peter Beemiller, Priya Pandurangi, Caitlin Sorensen, Zena Werb, Mikala Egeblad, and Matthew F. Krummel appears in the March 16, 2012 issue of the journal Cancer Cell.

This work was supported by the National Institutes of Health and the Cancer Research Institute. Additional support was provided through an EMBO fellowship and an NIH Training Grant fellowship.

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.

Cancer Genomics Hub will manage, analyze “big data” gathered by cancer researchers.

The emerging field of “personalized” or “precision” medicine holds great promise in the fight against cancer. If scientists can identify the genetic changes that drive each patient’s cancer cells, they can use that information to develop targeted treatments. But achieving this goal will require massive amounts of genomic and clinical data and a sophisticated infrastructure to manage and analyze the data.

David Haussler, UC Santa Cruz

The University of California, Santa Cruz, has now completed a first step in building this infrastructure, said UC Santa Cruz bioinformatics expert David Haussler. Haussler’s team has established the Cancer Genomics Hub (CGHub), a large-scale data repository and user portal for the National Cancer Institute’s cancer genome research programs. CGHub’s initial “beta” release is providing cancer researchers with efficient access to a large and rapidly growing store of valuable biomedical data. The project is funded by the National Cancer Institute (NCI) through a $10.3 million subcontract with SAIC-Frederick Inc., the prime contractor for the Frederick National Laboratory for Cancer Research.

In personalized care, doctors design treatments to target specific genetic changes found in a patient’s cancer cells. Researchers are trying to catalog all the genetic abnormalities found in different types of cancers and find connections between specific genetic changes and how patients respond to different treatments. The scale and complexity of the information being gathered creates a critical challenge in the area of data management.

Although recent studies using genetically targeted treatments have shown promising results, much more research is needed to enable their widespread use, Haussler said. “There won’t be one magic bullet, because cancer is not one disease, or even 100 diseases. Every instance of cancer is different. We have to improve our understanding of the molecular biology of cancer and develop computer algorithms so that we can analyze the genetic changes in each individual patient. It will take time. But with cancer genomics, we will eventually know our enemy completely.”

Haussler’s team assembled the first draft of the human genome sequence in 2000 and created and maintains the UCSC Genome Browser, a Web-based tool that is used extensively in biomedical research and serves as the platform for several large-scale genomics projects. His group’s contributions to cancer genomics research include creation of a Cancer Genomics Browser for analyzing data from large-scale cancer studies.

Haussler’s group built CGHub to support all three major NCI cancer genome sequencing programs: The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and the Cancer Genome Characterization Initiative (CGCI). TCGA is a collaborative effort led by NCI and the National Human Genome Research Institute to map the genomic changes that occur in at least 20 major types and subtypes of adult cancer. The TARGET program is a related effort focusing on the five most common childhood cancers, and the CGCI makes available genomic data from HIV-associated cancers and certain lymphoid and childhood cancers.

These programs are laying the foundation for personalized cancer care by creating a database that scientists around the world can use to connect specific genomic changes with clinical outcomes. Haussler’s group has been closely involved in data analysis for TCGA.

“TCGA is allowing us for the first time to look at cancer in full molecular detail,” Haussler said. “Cancer is a disease caused by disruption of DNA molecules within the cell. When life starts, every cell in the body has the same DNA. In the course of a person’s lifetime, however, some cells may accumulate changes in their DNA that cause them to go rogue and multiply without control, creating the disease we call cancer. For the first time now, we are able to look into an individual patient’s cancer cells and see all the genetic disruptions, among which are the molecular drivers of that person’s cancer.”

There are currently only a few situations in which doctors can prescribe a treatment plan based on the specific genetic mutations in a patient’s cancer cells. That is expected to change as projects like TCGA, TARGET and CGCI yield a comprehensive catalog that researchers can use to find new targets for medicines and discover clues to improve patient outcomes. But there is an urgent need for an efficient and user-friendly portal to give researchers access to the data. The NCI genome projects are producing staggering amounts of data.

“The scale of this is far beyond anything faced in medical research before,” Haussler said. “Each genome file, the DNA record from a tumor or normal tissue, is 300 billion bytes. And for every case there are two of these files, the cancer genome and the normal genome. Add to this RNA sequence data, and the prospect of deeper sequencing in the future, and we must plan for up to a terabyte (1,000 billion bytes) for each case.”

TCGA currently generates about 10 terabytes of data each month. For comparison, the Hubble Space Telescope amassed about 45 terabytes of data in its first 20 years of operation. TCGA’s output will increase tenfold or more over the next two years. Over the next four years, if the project produces a terabyte of DNA and RNA data from each of more than 10,000 patients, it will have produced 10 petabytes of data (a petabyte is 1,000 terabytes). And TCGA is just the beginning of the data deluge, Haussler said, noting that 10,000 cases is a small fraction of the 1.5 million new cancer cases diagnosed every year in the United States alone.

New data compression schemes are expected to reduce the total storage space needed, so the CGHub repository is designed initially to hold 5 petabytes and to allow further growth as needed. That is still a massive amount of data, and CGHub will need to accommodate transfers of extremely large data files.

Managed by the UCSC team, the CGHub computer system is located at the San Diego Supercomputer Center. It is connected by high-performance national research networks to major centers nationwide that are participating in these projects, including UCSC. Haussler’s team designed and oversees the storage and computing infrastructure for the repository, which has an automated query and download interface for large-scale, high-speed use. It will eventually also include an interactive web-based interface to allow researchers to browse and query the system and download custom datasets.

It may take years for cancer genomics research to bring about major changes in cancer care. The first step, and the focus of the NCI cancer genomics programs, is to determine which genomic changes are involved in each type of cancer and to understand the molecular and clinical effects of those changes. Then biomedical researchers must identify or develop treatments to block those effects.

“Right now, cancer research needs something on a very large scale, like the Large Hadron Collider in physics,” Haussler said. “Instead of bringing subatomic particles together in high-energy collisions and computing their behavior, we’re bringing cancer genomes together in a common database and computing the disease drivers.”

CGHub program director is Robert Zimmerman, and project team members include technical director Mark Diekhans; operations manager Linda Rosewood; hardware systems lead Erich Weiler; engineering lead Chris Wilks; engineering consultant Brian Craft; and networking consultants Brad Smith and Jim Warner. The core code, including GT software for downloading data, was licensed from Annai Systems. The cancer genomics group at UCSC also includes co-principal investigator Joshua Stuart, an associate professor of biomolecular engineering at UCSC; assistant research scientist Jing Zhu; engineers Kyle Ellrott, Teresa Swatloski and Singer Ma; user testing engineer Mary Goldman; postdoctoral scholars Adam Ewing, Benedict Paten and Daniel Zerbino; research associate Charlie Vaske; and graduate students Tracy Ballinger, Steve Benz, Daniel Carlin, James Durbin, Ted Goldstein, Mia Grifford, Sam Ng, Amie Radenbaugh,  Zack Sanborn and Chris Szeto.

The CGHub project is 100 percent funded by the National Institutes of Health, in the amount of $10.3 million using prime contract HHSN261200800001E, from the Frederick National Laboratory for Cancer Research.

Researchers recommend considering other illnesses, age, before starting treatment.

San Francisco VA Medical Center

In a study of patients 65 and older with non-small-cell lung cancer (NSCLC), younger patients were more likely to receive treatment than older patients, regardless of overall health and prognosis.

The study of more than 20,000 patients, led by a team of physicians at the San Francisco VA Medical Center (SFVAMC) and UCSF, found that, for all stages of cancer, treatment rates decreased more in association with advancing age than with the worsening of other illnesses.

Patients between the ages of 65 to 74 who were severely ill from other illnesses, and thus less likely to benefit and more likely to be harmed from cancer treatment, received treatment at roughly the same rate as patients in the same age range with no co-morbidities. They were more likely to receive treatment than patients between 75 and 84 with no co-morbidities and much better prognoses.

“It’s clear that as human beings and physicians, we fixate on age in deciding whether to pursue cancer treatments, including lung cancer treatments,” said lead author Sunny Wang, M.D., an SFVAMC physician and an assistant clinical professor of medicine at UCSF. “Instead, we should be looking at our patients’ overall state of health.”

The study was based on an analysis of the electronic health records of 20,511 patients age 65 and older who were in the VA Central Cancer Registry from 2003 to 2008. It was published on May 1 in the Journal of Clinical Oncology.

NSCLC is the most common form of lung cancer. The authors cited previous research indicating that older NSCLC patients who are otherwise healthy can benefit from treatment, while those with co-morbidities are more vulnerable to the toxicity of cancer treatments and less likely to complete a course of treatment. Significant co-morbidity can also limit life expectancy, thus undermining the potential survival benefit of treatment.

“The message here is, don’t base cancer treatment strictly on age,” said Wang. “Don’t write off an otherwise healthy 75-year-old, and don’t automatically decide to treat a really ill 65-year-old without carefully assessing the risks and benefits for that patient.”

Currently, Wang and her fellow researchers are conducting a follow-up study looking at survival outcomes among the same cohort of patients.

Co-authors of the study are Melisa L. Wong, M.D., of UCSF; Nathan Hamilton and J. Ben Davoren, M.D., Ph.D., of SFVAMC and UCSF; Thierry M. Jahan, M.D., of UCSF; and Louise C. Walter, M.D., of SFVAMC and UCSF.

The study was supported by funds from the Department of Veterans Affairs, UCSF, the National Cancer Institute and the National Institutes of Health. Some of the funds were administered by the Northern California Institute for Research and Education.

NCIRE – The Veterans Health Research Institute – is the largest research institute associated with a VA medical center. Its mission is to improve the health and well-being of veterans and the general public by supporting a world-class biomedical research program conducted by the UCSF faculty at SFVAMC.

SFVAMC has the largest medical research program in the national VA system, with more than 200 research scientists, all of whom are faculty members at UCSF.

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.