TAG: "Cancer"

UCSF to study benefits of personal approach to breast cancer screening


Five-year study will be a UC Health systemwide effort involving all five UC medical centers.

Breast cancer researcher Laura Esserman consults with a patient at UCSF. Esserman is leading a new study that will compare a personalized approach to breast cancer screening with annual mammograms. (Photo by Susan Merrell, UC San Francisco)

By Elizabeth Fernandez, UC San Francisco

A research team at UC San Francisco has won a five-year award of $14.1 million from the Patient-Centered Outcomes Research Institute (PCORI) to investigate whether a personalized approach to breast cancer screening is as safe and effective as annual mammograms.

The project, called the WISDOM study, will be led by breast cancer researcher Laura Esserman, M.D., M.B.A., professor of surgery and director of the Carol Franc Buck Breast Care Center at the UCSF Helen Diller Family Comprehensive Cancer Center.

“The controversy surrounding breast cancer screening has left women and their providers frustrated and confused,” said Esserman. “The time has come to put the controversy to rest.”

The five-year study – a UC Health systemwide effort with participation from all five UC medical centers – will involve approximately 100,000 women 40 to 80 years old. It will test a more targeted approach to breast cancer screening: Those at higher risk are screened more often and those at lower risk are screened less often. Annual screening will be weighed against a personalized schedule of screening based on each woman’s individual risk.

“This pragmatic trial will allow us to learn who is at risk for what type of breast cancer, and to continue to refine our approach to screening, potentially leading to less screening for those at very low risk and more for those at greater risk,” Esserman said. “It will enable us to focus on prevention as well. If our study is successful, fewer women will suffer from the anxiety of false-positive mammograms and unnecessary biopsies, and more women will gain a realistic understanding of their personal risk of breast cancer, which may reduce general worry about breast cancer.”

Women will be invited to be randomized (assigned by chance) to either the personalized or the annual screening arm. The two strategies will be compared to determine whether personalized screening is as safe as annual screening and whether it will reduce false-positive results and over-diagnosis.

Investigators also will determine whether women will readily accept personalized screening and whether knowledge of their own risks — and the reasons for their personalized screening regimen — will reduce, or at least not increase, anxiety about breast cancer. Additionally, the researchers will determine whether the personalized approach will lead to more of the highest-risk women deciding to use strategies that may prevent breast cancer.

Participants in the personalized screening arm will receive a risk assessment that will evaluate family and medical history, breast density, and tests for genes linked to the development of breast cancer.

Those with the highest personal risk of developing breast cancer or cancers that grow more quickly will receive recommendations to begin screening at an earlier age, receive mammograms more often, and continue screening until they are older. Those with the lowest personal risk will begin screening later, screen less frequently, and stop screening earlier. No woman will be screened less often than is recommended by the U.S. Preventive Services Task Force guidelines.

“We will learn from each woman who participates, and each woman will be equipped equally with more informed options to better personalize her medical care,” said Alan Ashworth, Ph.D., FRS, president of the UCSF Helen Diller Family Comprehensive Cancer Center and senior vice president for cancer services of UCSF Health. “This is a significant rethinking of breast cancer risk assessment and is a great example of how the UCSF cancer center is working to fully integrate cancer care with research for patient benefit.”

Participants in the breast cancer study will be drawn from the Athena Breast Health Network, a collaboration of the five University of California medical centers to drive innovation in breast cancer prevention, screening and treatment.

All eligible women from participating health plans who receive breast cancer screening at a UC medical center will be able to participate. The first health plan to participate is UC Care, a self-insured PPO plan for UC employees and retirees that offers care provided by UC’s medical centers. The first insurer to participate is Blue Shield of California, which has created a policy that will allow reimbursement for study-related services for members who are enrolled in the WISDOM trial while data are still being gathered about the safety and efficacy of personalized breast cancer screening. Discussions are underway with additional health plans and insurers.

“Blue Shield of California is pleased to support this important work to improve breast cancer screening and prevention,” said Marcus Thygeson, M.D., M.P.H., chief health officer at Blue Shield of California. “The current ‘one size fits all’ screening approach doesn’t do enough to reduce breast cancer deaths while also causing women to undergo unnecessary testing and treatment that harms their quality of life. This study promises to help find a better approach to breast cancer prevent and treatment, which will benefit our entire community.”

UC’s systemwide Center for Health Quality and Innovation will partner with Athena on the project to help provide value-based care.

“This project is a paradigm shift for preventive screening, harnessing UC’s systemwide strengths to advance care for Californians,” said John Stobo, M.D., executive vice president of UC Health. “We’re thrilled to be able to offer this screening trial to UC employees and the broader public.”

The breast cancer study is one of five projects selected for PCORI funding totaling $64.1 million. The award was approved pending completion of a business and programmatic review by PCORI staff and issuance of a formal award contract to UCSF.

“This project was selected for PCORI funding not only for its scientific merit and commitment to engaging patients and other health care stakeholders in a major study conducted in real-world settings, but also for its potential to answer an important question about breast cancer screening and fill a crucial evidence gap,” said PCORI Executive Director Joe Selby, M.D., M.P.H. “We look forward to following the study’s progress and working with UCSF to share its results.”

PCORI is an independent non-profit research institution. Its mission is to fund research that will provide patients, their caregivers, and clinicians with the evidence-based information needed to make better-informed healthcare decisions. For more information about PCORI’s funding awards, visit the Research and Results page on www.pcori.org.

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Curing cancer, one tax return at a time


Check a box and fund two UC-administered cancer research projects.

California taxpayers fund a number of health programs — some administered by UC — by designating a portion of their tax refund.

By Kate Rix, UC Newsroom

Those contribution lines on your 540 State Income Tax Return where you can fill in donation amounts for nearly 30 different California-based funds? Those are just nickel-and-dime funds without much impact, right?

Wrong.

Last year California taxpayers contributed more than $4 million to an inspiring range of worthy health, environmental and educational funds. Among the funds that get an important boost around tax time are the California Breast Cancer Research Program and the California Cancer Research Fund. Both funds are administered by the University of California, which distributes the money as direct grants to California researchers working on the cutting edge.

In other words, those contributions have a tangible impact in the fight against cancer, supporting work that ranges from personalized support for young cancer survivors to new low-radiation screening tools.

Protecting fertility for young cancer survivors

As treatments for breast cancer improve, the number of young women surviving the disease has grown. Of the 2.8 million cancer survivors in the U.S., 10 percent are under 45 at diagnosis. After enduring cancer therapies and one of the most frightening experiences of their lives, survivors often find themselves faced with a variety of worrisome long-term health issues.

During chemotherapy, menstrual periods often stop, and it is not uncommon for women — even very young women — to experience the symptoms of menopause, including hot flashes and vaginal dryness. Cancer fears become compounded by worries that they may never be able to have children and that their bodies will never be the same.

“Young breast cancer survivors and their health care providers want to learn about how to manage reproductive health after cancer,” said Dr. Irene Su, an assistant professor in the Division of Reproductive Endocrinology and Infertility at the UC San Diego School of Medicine.

Closing the knowledge gap

“There hasn’t been an emphasis on providing reproductive health information to young survivors,” Su said. Also, because many health care providers may not see that many young women with cancer, they may face knowledge gaps on providing reproductive health care for this population.

“Right now, there is a dearth of resources for disseminating reproductive health care information to patients and providers.”

Su is leading a project, funded by the California Breast Cancer Research Program, to help women and their medical providers — no matter where they are located — have access to up-to-date, evidence-based information to treat estrogen deprivation symptoms, improve sexual function and monitor fertility potential after cancer. CBCRP received nearly $400,000 through the tax check-off program last year.

With a grant of more than $750,000 over three years, the project will generate the Reproductive Survivorship Care Plan (SCP-R), a Web-based tool that offers the best current research on managing hot flashes, sexual problems, fertility concerns and contraception to young breast cancer patients and their providers. Information can be tailored to the patient, and focuses on specific issues. The SCP-R will be tested in a randomized controlled trial that launches this summer.

The resource is being developed with the participation of patients and caregivers recruited across the country and with the oversight of a stakeholder panel of clinicians, researchers and breast cancer survivors.

Young women who survive breast cancer often have questions about fertility. It isn’t unusual, for example, for a young woman’s periods to stop when she undergoes chemotherapy. Women who have not completed their families may worry that not menstruating means that they are infertile. “The SCP-R will provide relevant information on the natural course of ovarian recovery, when survivors usually get their periods back, types of blood tests that can help monitor ovarian function, and, equally importantly, what tests are not recommended and what we still don’t know,” Su said.

Women who have completed their families will need to consider effective contraception. In the United States, birth control pills are the most common reversible form of contraception. For a cancer survivor, however, it is crucial to keep estrogen levels low.

“The copper IUD is a great form of reversible birth control, because it is non-hormonal and highly effective,” said Su. “It would be great if a family practice physician or oncology provider had knowledge of how effective different birth controls are and what are recommended methods for breast cancer survivors.”

Lung cancer screenings as safe as chest X-rays

Lung cancer is the most deadly form of cancer in the U.S. While patients with other forms of cancer are living longer than before, the five-year survival rate for lung cancers hasn’t improved much in recent decades. More people die from lung cancer than from the next four cancers combined (including breast and prostate cancer). And while smoking is a leading cause of lung cancer, up to 15 percent of lung cancers have no relation to smoking; even smokers who quit smoking up to 15 years previously are still at risk of lung cancer.

One obstacle has been the lack of any screening test to detect lung cancer at an early stage. While imaging technology held some promise, it was unproven and there were some risks associated with being screened. But just a few years ago, a national lung screening trial found that at-risk patients who were screened using low-dose CT scanning technology had a 15-20 percent lower chance of dying of lung cancer than those who received a standard chest X-ray.

These results showed promise for a new tool, with dramatically reduced radiation, to detect the most deadly form of cancer.

With funding from the California Cancer Research Fund (administered by UC’s Tobacco-Related Disease Research Program), a team at UCLA is working to bring the level of radiation in an ultra-low-dose CT scan even lower. The TRDRP received nearly $445,000 through the tax check-off program last year.

“We know how to do the screening and the technology is pretty good,” said Michael McNitt-Gray, a professor of radiology at the UCLA School of Medicine. “We want to push that dose even lower. We’d like to get the same level as a single chest X-ray.”

Shorter times, improved images

Several aspects of CT scanning technology have improved dramatically. While low-dose CT screenings have been possible for nearly 20 years, technical limits have made them difficult to use effectively.

For example, an accurate image used to take up to 60 seconds to capture. Patients had to hold their breath during that entire time, something that most smokers can’t do.

The improvements being made at UCLA make the process faster — the actual scan takes just 5 seconds — and can allow finer detail in the image, showing suspicious objects in the lung as small as 5 mm.

The timing of the UCLA project couldn’t be better. Last year, private insurers began covering the cost of ultra-low-dose CT scans. In February, Medicare announced that it also would cover the screening, making the early detection tool available to the elderly and disabled who may be at risk of developing lung cancer.

“The test itself is very quick,” says McNitt-Gray. “The patient lies down, puts their arms above their head, and does some practice breathing. Based upon a planning view, the scanner adjusts to the patient’s anatomy so that just enough of the radiation dose is used to provide the necessary image quality to detect anything suspicious in the lungs.”

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Nanotech platform shows promise for treating pancreatic cancer


Researchers create new method that may solve some problems of using chemotherapy.

Andre Nel, UCLA

By Shaun Mason, UCLA

Scientists at UCLA’s California NanoSystems Institute and Jonsson Comprehensive Cancer Center have combined their nanotechnology expertise to create a new treatment that may solve some of the problems of using chemotherapy to treat pancreatic cancer.

The study, published online in the journal ACS Nano, describes successful experiments to combine two drugs within a specially designed mesoporous silica nanoparticle that looks like a glass bubble. The drugs work together to shrink human pancreas tumors in mice as successfully as the current standard treatment, but at one-twelfth the dosage. This lower dosage could reduce both the cost of treatment and the side effects that people suffer from the current method.

The study was led by Dr. Huan Meng, assistant adjunct professor of medicine, and Dr. Andre Nel, distinguished professor of medicine, both at the Jonsson Cancer Center.

Pancreatic cancer, a devastating disease with a five-year survival rate of 5 percent, is difficult to detect early and symptoms do not usually appear until the disease is advanced. As a result, many people are not diagnosed until their tumors are beyond the effective limits of surgery, leaving chemotherapy as the only viable treatment option. The chemotherapy drug most often used for pancreas cancer is gemcitabine, but its impact is often limited.

Recent research has found that combining gemcitabine with another drug called paclitaxel can improve the overall treatment effect. In the current method, Abraxane — a nano complex containing paclitaxel — and gemcitabine are given separately, which works to a degree, but because the drugs may stay in the body for different lengths of time, the combined beneficial effect is not fully synchronized.

“The beauty of the silica nanoparticle technology is that gemcitabine and paclitaxel are placed together in one special lipid-coated nanoparticle at the exact ratio that makes them synergistic with one another when co-delivered at the cancer site, giving us the best possible outcome by using a single drug carrier,” Meng said. “This enables us to reduce the dose and maintain the combinatorial effect.”

After the scientists constructed the silica nanoparticles, they suspended them in blood serum and injected them into mice that had human pancreas tumors growing under their skin. Other mice with tumors were given injections of saline solution (a placebo with no effect), gemcitabine (the treatment standard), and gemcitabine and Abraxane (an FDA-approved combination shown to improve pancreas cancer survival in humans).

In the mice that received the two drugs inside the nanoparticle, pancreas tumors shrank dramatically compared with those in the other mice.

Similar comparisons were made with mouse models, in which the human tumors were surgically implanted into the mice’s abdomens in order to more closely emulate the natural point of origin of pancreatic tumors and provide a better parallel to the tumors in humans. In these experiments, the tumors in the mice receiving silica nanoparticles shrank more than the comparative controls. Also, metastasis, or tumor spread, to nearby organs was eradicated in these mice.

“Instead of just a laboratory proof-of-principle study of any cancer, we specifically attacked pancreatic cancer with a custom-designed nanocarrier,” said Nel, who is also associate director for research of the California NanoSystems Institute. “In our platform, the drugs are truly synergistic because we have control over drug mixing, allowing us to incorporate optimal ratios in our particles, making the relevance of our models very high and our results very strong.”

Meng said the silica nanocarrier must still be refined for use in humans. The researchers hope to test the platform in human clinical trials within the next five years.

The research was supported by the U.S. Public Health Service and the National Science Foundation.

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Public health researchers go to church to promote hepatitis B screening


UCLA team held small group discussions in more than 50 L.A.-area Korean churches.

To reach a vulnerable population largely unaware of the health risks, a team from the Fielding School for Public Health held small group discussions in more than 50 Los Angeles-area Korean churches. (Photo by UCLA-Kaiser Permanente Center for Health Equity)

By Dan Gordon, UCLA

For the large Korean American-community in Los Angeles, chronic infection with the hepatitis B virus looms as a significant — and too often unspoken — health threat, associated with the highest rates of liver cancer for any ethnic group in Los Angeles. Knowing one’s hepatitis B status can be critical — it allows those who test HBV-negative to be immunized against the virus while pointing the way toward early treatment as well as more vigilant efforts to prevent transmission for those who are positive. But most adults in L.A.’s Korean-American community have never been screened and are unaware of whether they carry the virus.

In an effort to change that, a research team from the UCLA Fielding School for Public Health’s Kaiser Permanente Center for Health Equity and Center for Cancer Prevention and Control Research, working in partnership with leaders of Los Angeles’ Korean-American community, set out to increase HBV screening in the population through small group discussions led by trained community members. For their study testing the impact of this strategy, they chose unlikely venues: 52 Korean churches in Los Angeles.

“When we started, people questioned the feasibility of having discussions about a sexually transmitted virus at church,” said Roshan Bastani, the Fielding School professor with leadership roles in both centers who headed the study. “But if you want to target a general population of Koreans in Los Angeles, you have to go where they tend to gather. We learned that most Koreans go to church, and that it’s not just religious but also a social experience where non-religious services are delivered to members. In talking with church leaders and other members of the community, we were encouraged to pursue what they saw as an important project.”

If not treated, chronic HBV infection can lead to liver cirrhosis in as many as 1 in 4 carriers, which can ultimately progress to liver cancer. HBV is also highly infectious — spread not only via sexual contact and sharing needles, but also through household items such as razors or toothbrushes, or from an infected mother to her child during birth.

Because it is so common in many Asian countries, HBV disproportionately affects Asian Americans, particularly newer immigrants. The problem is particularly serious among Korean Americans. In Los Angeles, an estimated 12 percent of the Korean-American population is infected — and because the virus causes no symptoms until the liver damage becomes severe, the majority of them doesn’t know it. Although routine HBV vaccination of children has been implemented in the United States and much of Asia for two decades, most adults were born before childhood HBV vaccination became commonplace and can benefit from immunization only once they are tested and found to be HBV-negative. The potential for uninfected adults to get vaccinated, and for carriers to receive early treatment and monitoring while taking measures to prevent transmission to others, all point to the public health benefits of promoting HBV screening.

The Fielding School team relied heavily on the wisdom of its Korean-American community partners for both the design and implementation of an intervention aiming to increase screening. A seven-member community advisory committee included two church pastors, a pastor’s wife, a church elder, a church health leader, a physician and a representative of a Korean-American, nonprofit, faith-based organization. Fifty-one bilingual community members were hired as staff members for the study and trained to administer surveys and facilitate the small group discussion sessions with the churches — ensuring that the intervention could be sustained beyond the three-year study period.

One member hired for the study team with deep roots in the Los Angeles Korean community, Hosung Kim, was assigned the task of inviting the participation of pastors and other church leaders. “My role was to convince them that our project could improve the lives of their members through health care awareness,” said Kim, who covered the activities of Korean churches as a reporter working for a Korean newspaper chain. “I explained that because the overwhelming majority of Korean immigrants participate in Sunday services, this would provide the best opportunity to recruit participants … Most of the responses were very positive.”

Of the 52 Korean churches that participated, half were randomly assigned to the study’s intervention arm, which featured small group discussions on hepatitis B among Korean adults who had either not previously been tested or couldn’t recall their results; the other half, which served as the control group, discussed nutrition and physical activity. The HBV discussions provided facts about hepatitis B and liver cancer, the risk for Koreans, and the rationale for testing. Through scripts and role-playing, participants were guided on how to bring up the topic with their doctors and encouraged to discuss HBV with family and friends. Testing and vaccination were framed within Korean medicine concepts of keeping the body healthy.

The project identified and addressed factors that prevent many Koreans from getting tested, even when they are aware of the HBV risk. Many participants expressed fear about the consequences of learning they were infected, or the potential for bringing shame to their family if they tested positive. There was also concern about the cost of the test — 57 percent of the study participants reported lacking health insurance. In an effort to overcome that barrier, the project staff provided a list of clinics offering low-cost or free HBV screening.

In the end, the discussions proved highly effective: Participants in the intervention group were three times more likely to get a hepatitis B test than those who were in one of the groups that discussed nutrition and physical activity.

“Few previous studies have attempted to identify effective strategies to promote hepatitis B screening among Koreans,” said Beth Glenn, associate professor of health policy and management and a member of the study team. “We were excited to see that a one-time, small-group discussion intervention produced a meaningful increase in hepatitis B screening in a population at high risk for hepatitis B and liver cancer.”

Any concerns the Fielding School team had about testing the intervention in Korean churches were quickly eased.

“For some of our projects, even when we are actively recruiting, it can be hard to find people to participate,” said Alison Hermann, project director for the study. “In this case we would simply go to the churches, set up a table with our banner, and people would come to us. Part of it had to do with the sense of community in the churches, where if something was going on, members wanted to know about it. But we also found that the interest in health-related issues was tremendous.”

This story originally appeared in the UCLA Fielding School of Public Health magazine’s Fall 2014 issue.

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UCSF team finds key to making neurors from stem cells


Pnky, noncoding RNA found in brain stem cells, may have range of clinical applications.

In this cluster of neurons, the greens cells have been infected with a virus to reduce levels of the RNA molecule called Pnky, resulting in increased production of neurons. Someday this finding could be important for regenerative medicine and cancer treatment.

By Steve Tokar

A research team at UC San Francisco has discovered an RNA molecule called Pnky that can be manipulated to increase the production of neurons from neural stem cells.

The research, led by neurosurgeon Daniel A. Lim, M.D., Ph.D., and published today (March 19) in Cell Stem Cell, has possible applications in regenerative medicine, including treatments of such disorders as Alzheimer’s disease, Parkinson’s disease and traumatic brain injury, and in cancer treatment.

Pnky is one of a number of newly discovered long noncoding RNAs (lncRNAs), which are stretches of 200 or more nucleotides in the human genome that do not code for proteins, yet seem to have a biological function.

The name, pronounced “Pinky,” was inspired by the popular American cartoon series Pinky and the Brain. “Pnky is encoded near a gene called ‘Brain,’ so it sort of suggested itself to the students in my laboratory,” said Lim. Pnky also appears only to be found in the brain, he noted.

Co-first authors Alex Ramos, Ph.D., and Rebecca Andersen, who are students in Lim’s laboratory, first studied Pnky in neural stem cells found in mouse brains, and also identified the molecule in neural stem cells of the developing human brain. They found that when Pnky was removed from stem cells in a process called knockdown, neuron production increased three to four times.

“It is remarkable that when you take Pnky away, the stem cells produce many more neurons,” said Lim, an assistant professor of neurological surgery and director of restorative surgery at UCSF. “These findings suggest that Pnky, and perhaps lncRNAs in general, could eventually have important applications in regenerative medicine and cancer treatment.”

Lim observed that Pnky has an intriguing possible connection with brain tumors.

Using an analytical technique called mass spectrometry, Ramos found that Pnky binds the protein PTBP1, which is also found in brain tumors and is known to be a driver of brain tumor growth. In neural stem cells, Pnky and PTBP1 appear to function together to suppress the production of neurons. “Take away one or the other and the stem cells differentiate, making more neurons,” said Lim. “It is also possible that Pnky can regulate brain tumor growth, which means we may have identified a target for the treatment of brain tumors.”

Lim said that the larger significance of the research is that it adds to a growing store of knowledge about lncRNAs, previously unknown sections of the genome that some biologists have referred to as the “dark matter” of the human genome.

“Recently, over 50,000 human lncRNAs have been discovered. Thus, there may be more human lncRNAs than there are genes that code for proteins,” said Lim. “It is possible that not all lncRNAs have important biological functions, but we are making a start toward learning which ones do, and if so, how they function. It’s a new world of experimental biology, and the students in my lab are right there on the frontier.”

Lim had particular praise for Ramos, an M.D.-Ph.D. student in the UCSF Medical Scientist Training Program, and Andersen, who has a fellowship from the prestigious National Science Foundation (NSF) Graduate Research Fellowship Program. “They have been a great collaborative team and an inspiration to others in my lab,” said Lim. “I think they represent the pioneering, investigative spirit of the UCSF student body.”

Co-authors of the study are Siyuan John Liu, Tomasz Jan Nowakowski, Sung Jun Hong, Caitlin Gertz, Ryan D. Salinas, Hosniya Zarabi and Arnold Kriegstein, M.D., Ph.D., all of UCSF.

The study was supported by funds from the National Institutes of Health, U.S. Department of Veterans Affairs, NSF, UCSF, San Francisco State University and the Howard Hughes Medical Institute.

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UCLA researchers develop new combination therapy to fight melanoma


Triple combination therapy helps immune system attack cancerous tumors.

By Reggie Kumar, UCLA

UCLA cancer researchers have found that a new triple combination therapy shows promising signs of more effectively controlling advanced melanoma than previous treatments and also with fewer side effects.

An estimated 70,000 new cases of metastatic melanoma are diagnosed each year in the United States, and of those 8,000 people will die of the disease. About 50 percent of the total men and women diagnosed have a mutated protein called a BRAF mutation, which in most cases allows melanoma to eventually build up a resistance to many drug therapies.

In the new study led by UCLA Jonsson Comprehensive Cancer Center member Dr. Antoni Ribas and colleague Dr. Siwen Hu-Lieskovan, UCLA scientists combined targeted therapies utilizing the BRAF inhibitor drug dabrafenib and the MEK inhibitor drug trametinib, with immunotherapy, which is treatment that uses a person’s own immune system to help fight cancer.

Dabrafenib causes cancerous tumors to shrink in people whose metastatic melanoma has a BRAF gene change. Trametinib prevents the disturbance of the MAPK/ERK pathway that dabrafenib causes on cells without the BRAF mutation. That disturbance causes overactive cells to form a different type of skin cancer.

The combination of the three therapies, which was shown to be a more effective treatment, works by sensitizing a person’s own immune system to enhance immunotherapy, and reducing the probability of the melanoma eventually developing resistance.

This is a significant advance compared to previous drug combination findings, in which a combination of the BRAF inhibitor vemurafenib with an immunotherapy drug caused serious liver toxicity in some people, and the targeted therapies (BRAF and/or MEK inhibitors) became less effective and reactivated cancer cell growth.

“The two-drug combination of BRAF and MEK inhibitors works synergistically and decreases the side effects of the BRAF inhibitor on normal cells. We reasoned that this combo would allow us to synergize with immunotherapy without increasing toxicities,” said Ribas, a professor of hematology-oncology at UCLA. “We have made incredible progress in the last three years of treating advanced melanoma, with six new drug therapies approved by the FDA. Half are immunotherapies and the other half are BRAF or MEK inhibitors. The next step is to figure out how to combine them and merge their benefits in the clinic.”

The triple combination of targeted therapies dabrafinib and trametinib inhibitors with immunotherapy (tumor antigen-specific adoptive cell transfer or anti-PD1 antibody) makes immune therapy more effective at killing cancerous tumors and it causes less toxicity, said Hu-Lieskovan, a UCLA clinical instructor of hematology and oncology.

“We’re trying to take advantage of the high response rate of the targeted therapy and durability of the immune therapy to induce a response that lasts in the majority of patients,” Hu-Lieskovan said.

Ribas and Hu-Lieskovan have opened two clinical trials to test the effectiveness of the triple combination therapy in advanced melanoma patients. The first reported findings will be presented at the American Society of Clinical Oncology annual meeting in May.

The study is available online today (March 18) in the journal Science Translational Medicine.

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Study uncovers mechanisms of cancer-causing mutations


Computer modeling leads to more precise targeting of therapies.

By Jan Zverina, UC San Diego

Researchers at the San Diego Supercomputer Center (SDSC) and the Moores Cancer Center at UC San Diego have described for the first time the molecular mechanism of cancer development caused by well-known “resistance” mutations in the gene called epidermal growth factor receptor (EGFR).

While these mutations were known for quite a long time, the question as to why they cause cancer or make some drugs ineffective was still not answered.

The study, called “Molecular Determinants of Drug-Specific Sensitivity for Epidermal Growth Factor Receptor (EGFR) Exon 19 and 20 Mutants in Non-Small Cell Lung Cancer,” and published online in the journal Oncotarget, demonstrates how computer modeling of EGFR mutations found in lung cancer can elucidate their molecular mechanism of action and consequently optimize the selection of therapeutic agents to treat patients.

On the basis of structural analysis of this protein, scientists demonstrated that specific mutations within the EGFR gene increase electrostatic interactions between the two dimer subunits of EGFR, stabilizing it in an “active” state, leading to cancer. Such a finding suggested that the treatment of EGFR-related lung cancers with the usual small molecule inhibitory drugs would not be successful (patients harboring these mutations are typically resistant to these drugs), while antibodies that interfere with dimerization of EGFR would be effective.

“The mutations are substitutions of one amino acid to another, or a set of neighboring amino acids to a different set of them,” said lead author Igor F. Tsigelny, a research scientist with the SDSC as well as the UC San Diego Moores Cancer Center and the Department of Neurosciences. “The proteins have mechanisms of adaptations for possible mutations, and in many cases the proteins survive and can fulfill some of their function. At the same time, some important changes can happen. For example, the protein can became permanently active, and such activity would lead to overgrowth of cells and eventually to cancer.”

Tsigelny added: “The clinical treatments that do not take into consideration the specific mutations in genes, but rather treat all mutations within a specific gene such as EGFR as the same, are a ‘hit-or-miss’ game because they are based solely on observational data on how other patients previously have reacted to drug therapies.”

This study is also important because it explains why some new mutations in EGFR – which are acquired during the course of treatment of lung cancer with small molecule EGFR inhibitors such as erlotinib – lead to drug resistance and patient death.

“The body doesn’t recognize tumors as harmful, but instead treats them like normal organs that need protection,” said Tsigelny. “This drives the development of mutations that cause drug resistance.”

Ready-made treatments

Moreover, new drugs are being developed to treat the resistant mutations, but the specific ones studied in this paper have not been amenable to therapy with these new drugs. Instead, the study showed that an existing drug (an antibody that targets EGFR) could be used, indicating that there may be a ready-made treatment available.

The modeling predictions are consistent with the clinical results. Two patients with the specific resistance mutation analyzed achieved partial remissions when treated with a regimen that included the EGFR antibody cetuximab, as predicted by the computer-based structural modeling. One patient continues to do well more than 3.5 years later.

“These studies form a proof-of-principle demonstration of the ability of computer modeling to be used to choose therapy for individuals,” said Razelle Kurzrock, senior deputy director (clinical science) and director of the Center for Personalized Cancer Therapy at UCSD Moores Cancer Center, and senior author of this paper. “Further investigation in larger patient groups is needed.”

Both Tsigelny and Kurzrock agreed that this finding is an excellent example of the power of collaboration between SDSC and the Moores Cancer Center, and that such modeling needed to be studied across tumors and with multiple different genes involved in cancer.

In addition to Tsigelny and Kurzrock, researchers involved in the study include Valentina L. Kouznetsova from SDSC and the Moores Cancer Center; Jerry P. Greenberg from SDSC; Lyudmila Bazhenova from the Moores Cancer Center; Jennifer J. Wheler from M.D. Anderson Cancer Center; and David J. Stewart from the University of Ottawa.

Financial support for the study was provided in part by the Joan and Irwin Jacobs Fund.

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Study reveals treatment for breast cancer patients with cognitive difficulties


Mental training exercises developed at UCLA shown to help mitigate effects of ‘chemo brain.’

Patricia Ganz, UCLA

By Reggie Kumar, UCLA

UCLA researchers have developed a program that could improve the day-to-day lives of women with breast cancer by addressing post-treatment cognitive difficulties, sometimes known as “chemo brain,” which can affect up to 35 percent of women after their treatments.

An estimated 1 in 8 women will develop invasive breast cancer in their lifetimes, and following treatment, a mental fogginess can prevent them from being able to concentrate, staying organized and completing everyday activities, such as sticking to a schedule or planning a family gathering.

The new study, led by breast cancer research pioneer and UCLA Jonsson Comprehensive Cancer Center member Dr. Patricia Ganz, builds upon her earlier research that found a statistically significant association between neuropsychological test performance and memory complaints among women with early stage breast cancer following treatment.

“We invited the women to participate in a research study that assigned them to early or delayed treatment with a five-week, two-hour group training session, where a psychologist taught them strategies to help them with their memory and maintaining their ability to pay attention to things,” said Ganz, director of prevention and control research at the cancer center. “These are activities we call executive function and planning, or the things all of us do in order to organize our day.”

Dr. Linda Ercoli, an associate clinical professor of health sciences at the UCLA Semel Institute for Neuroscience and Human Behavior, was responsible for the development of the cognitive rehabilitation intervention program and either delivered the training or supervised other clinicians who provided the group training sessions.

“We gave women exercises on, for example, how to remember a ‘to-do’ list, remembering to buy items at the store, or planning a party and deciding what type of food should be served to guests,” said Ercoli, a co-author of the study. “Participants were given real-life tasks to complete that would use these types of strategies to improve cognitive function.”

The intervention program also included homework and practice activities that they would discuss at the weekly sessions. These exercises were designed to improve memory and cognitive function.

Women in the delayed group were offered the intervention after completion of their two-month follow-up testing and this occurred when the researchers had enough women to form a group to provide them the intervention.

All of the women who participated in the study, whether they received the intervention early or at a delayed time point, completed questions about their mood and mental functioning. The women also had detailed neurocognitive testing three times: before learning which group they would be in, immediately after the end of the five weeks of training and then again two months later. Most of the women also had resting EEG (brain wave) testing to see if this could measure changes in how the women fared throughout the study.

Ganz and Ercoli found that the 32 women in the early intervention group reported improvement in memory complaints and test functioning, while the 16 women in the delayed intervention control group did not improve in either their cognitive complaints or test performance. The intervention group participants showed continued improvement two months after completion of the rehabilitation program.

“The brain wave pattern in the intervention group actually normalized,” Ganz said. “We hope that this might be an effective biologic way to assess the cognitive effects of cancer treatment in the future.”

The next steps are for other researchers to test this cognitive rehabilitation program in larger numbers of patients, and potentially to develop strategies to provide intervention much earlier in the course of breast cancer treatment to either prevent difficulties or hasten recovery.

“This study will be added to the growing body of literature demonstrating the validity of patient complaints,” Ganz said. “Furthermore, the intervention results provided important encouragement that these complaints can improve with appropriate training.”

The study was funded by the Breast Cancer Research Foundation and the Jonsson Comprehensive Cancer Center Foundation.

The randomized clinical trial results are available online in the journal of Psycho-Oncology.

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400% variation found in cost of treatments for enlarged prostate


UCLA study also finds no proof that ‘one way is any better than the other.’

Alan Kaplan, UCLA

By Kim Irwin, UCLA

UCLA researchers found a 400 percent discrepancy between the least and most expensive ways to treat a common condition called benign prostate hyperplasia. Their study was the first to describe cost across the entire care process for the condition.

Dr. Alan Kaplan, the study’s first author and a resident physician in the UCLA Department of Urology, said the finding is important because there isn’t any proven difference in outcomes between the lower- and higher-cost treatments.

The study appears in the March issue of Healthcare: The Journal of Delivery Science and Innovation.

During the yearlong study, conducted at the UCLA Ronald Reagan Medical Center, the researchers used a technique called time-driven activity-based costing to determine how much it costs to treat BPH, also known as enlarged prostate, a disorder that affects about half of men over 50. BPH can be treated in many different ways.

“We felt that if we could tackle the cost of such a complex and common condition we could use the technique to really understand cost on a larger scale,” Kaplan said. “Most importantly, we found that within our own institution the cost of treating BPH varied about 400 percent and, as of yet, we have no proof that one way is any better than the other.”

The UCLA researchers will continue to collect and analyze data to determine the value of BPH treatments, including which tests are useful and which may be unnecessary.

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New tool predicts whether liver cancer will recur in transplant patients


UCLA researchers develop method to more accurately calculate risk of disease recurring.

Ronal Busuttil, UCLA

By Kim Irwin, UCLA

UCLA transplant researchers have developed a novel method to more accurately calculate the risk of disease recurring in people with liver cancer who have undergone a liver transplant. The approach gives physicians a new tool to help make treatment and surveillance decisions.

The study, led by Dr. Ronald Busuttil, the William P. Longmire, Jr. Chair in Surgery and director of the Pfleger Liver Institute and Dumont–UCLA Transplant and Liver Cancer Centers, was published by the peer-reviewed Journal of the American College of Surgeons.

The research team developed a predictive calculator called a nomogram after analyzing 30 years’ worth of data from liver transplants for people with liver cancer. The study drew from records of 865 patients at UCLA between 1984 and 2013, said Dr. Vatche Agopian, an assistant professor of surgery in UCLA’s division of liver transplantation and the study’s first author.

Prior to 1996, there were no criteria to guide which liver cancer patients might be good candidates for transplants. Patients with tumors of all sizes and numbers underwent transplants, and many of them suffered early recurrence of the disease. In 1996, guidelines known as the “Milan criteria” were introduced, recommending that transplants be limited to patients who had a single tumor measuring 5 centimeters or less and those who had up to three tumors, as long as no single tumor was larger than 3 centimeters.

Agopian said one shortcoming of the Milan criteria was that they didn’t take into account the aggressiveness of the tumor or other blood biomarkers that can help predict recurrence. UCLA’s nomogram uses three groups of factors to predict recurrence more accurately than the Milan criteria and the existing American Joint Committee on Cancer pathologic TNM staging system, giving transplant physicians and oncologists more information to help decide how often to monitor patients for recurrence and whether or not adjuvant treatment is necessary.

“This novel nomogram includes three important groups of information that proved to be very accurate in predicting recurrence in liver cancer patients — better than any other system out there,” Agopian said. “Physicians can use our nomogram and have a meaningful discussion with transplant recipients regarding their post-transplant risk of cancer recurrence. It can help them decide how closely to follow their patient — a patient with a low risk of recurrence may not need screening as often — or whether a patient with a high risk of recurrence might need treatment following the transplant.”

The three groups of factors that comprise the UCLA nomogram are:

  • Pre-transplant radiologic information, or the number and size of tumors on MRI and CT scans
  • Three pre-transplant blood biomarkers thought to be predictive for cancer recurrence
  • Pathological characteristics of the explanted liver. (The diseased liver is studied to determine the aggressiveness of the tumor and whether the cancer has invaded the liver’s blood vessels, factors that can’t be determined before transplant.)

Under the Milan criteria, for example, a patient with a 5 centimeter tumor might have qualified for a liver transplant, but the UCLA-developed criteria might discover that the tumor was very aggressive and likely to recur after transplant. The nomogram also might find that a patient with a larger tumor might have a very low grade cancer and have a lower risk for recurrence. Using specific details about each patient provides an individualized profile of predicted risks for cancer recurrence, Agopian said.

“The Milan criteria presented a major step in improving the outcomes of liver cancer patients undergoing transplant,” Agopian said. “However, there is now a growing consensus and body of evidence that these criteria are too conservative, and that incorporation of other factors may improve the ability to select for patients with favorable tumor biology, regardless of size, who stand to benefit from liver transplantation.”

About 32,000 Americans will be diagnosed with liver cancer this year. Of those, 23,000 will die of their disease. Liver cancer is the sixth most common cause of cancer worldwide, and the third most common cause of cancer-related death. In the U.S., the incidence of liver cancer has nearly doubled over the past two decades. For most patients who are diagnosed with liver cancer, the disease generally is too advanced to treat with surgery. For patients with underlying liver dysfunction who are unable to undergo surgery to remove the tumor, a liver transplant is the best way to treat the patient.

“In the largest single-institution experience with liver transplant for liver cancer, excellent long-term survival was achieved,” the study reports. “Incorporation of routine pre-transplant biomarkers to existing radiographic size criteria significantly improves the ability to predict post-transplant recurrence, and should be considered in recipient selection. A novel clinicopathologic prognostic nomogram accurately predicts liver cancer recurrence after liver transplant and may guide frequency of post-transplant surveillance and adjuvant therapy.”

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Film camp offers hope for pediatric cancer patients


UC Riverside senior, cancer survivor seeking support at April 2 screening to expand program.

Cassie Nguyen, a senior public policy major and brain cancer survivor, will introduce her Spotlight On Hope Film Camp to the community on April 2.

By Bettye Miller, UC Riverside

Brain cancer. Not the diagnosis Cassie Nguyen was expecting as a sophomore at Riverside’s Martin Luther King High School. Neither was the debilitating surgery that saved her life.

Today, Nguyen is an honor student and School of Public Policy ambassador at the University of California, Riverside, where she will graduate in June. She is a 10-year cancer survivor, American Cancer Society advocate, and the creator of Spotlight On Hope Film Camp, a free filmmaking program for pediatric cancer patients that until now has been held only in Los Angeles.

Nguyen hopes to bring the film camp to UC Riverside and the Inland Empire, and is screening short films written and produced by pediatric cancer patients in the program on Thursday, April 2, from 3:30 to 6:30 p.m. in Highlander Union Building 367. The event is free and open to the public. Parking is free in Lot 1; pick up parking permits at the Kiosk on West Campus Drive at the University Avenue entrance to the campus. Reservations are requested as seating is limited and may be made online. The screening is co-sponsored by University Honors and the Women’s Resource Center.

The Riverside resident said she hopes the screening will generate support to expand the program to the Inland Empire. She hopes eventually to establish a nonprofit foundation and offer film camps across the country.

Approximately 13,500 children are diagnosed with cancer each year in the U.S., and about 25 percent of them die, Nguyen said. Although Spotlight On Hope Film Camp does not reduce the death rate, it does provide a therapeutic outlet for pediatric cancer patients, she explained.

“I know how boring the hospital scene is,” Nguyen said, recalling the surgery to remove the tumor from her brain, a year of radiation and chemotherapy, and physical therapy to learn to write with her left hand and regain mobility to address ongoing balance and difficult vision issues. “I wanted to do something to help kids take their minds off what was happening to them and give them something to look forward to.”

Nguyen suggested the film camp for young cancer patients while working as an intern for Think Ten Media Group, a production company based in Castaic that aims to use the power of media to create change and spread awareness of key issues.

She raised $700 to cover production costs of the first camp, held in September 2013, by selling plastic cancer bracelets to UCR faculty and students, family and friends in her junior year. She dedicated the first film camp to a younger cousin who died of sarcoma cancer at age 14.

Think Ten Media Group co-founders and filmmakers Ramon Hamilton and Jennifer Fischer helped Nguyen develop the Spotlight On Hope Film Camp for pediatric cancer patients at Children’s Hospital Los Angeles as part of their company’s arts education program. The UCLA School of Theater, Film and Television hosts the camp in Los Angeles.

When the film camp proved to be successful, Nguyen applied for and won a $10,000 scholarship from the Donald A. Strauss Public Service Scholarship Foundation in 2014, which funded 10 more film camps at UCLA. The foundation awards $10,000 scholarships to as many as 15 California college juniors annually to support public-service projects that the students carry out during their senior year.

Spotlight On Hope Film Camp allows patients to explore the art of green screen and special effects film-making while working in groups to create a short, green screen and special effects film. The participants, who range in age from 8 to 22, also learn about story/character development, camera technique, video and FX editing during three days of weekend classes.

“Being a pediatric patient myself, I understand how valuable a creative therapeutic outlet can be in the midst of your long, dreadful and difficult journey battling cancer,” Nguyen explained. “Spotlight On Hope Film Camp can help children live in a fantasy world that allows them to get away from all their troubles and create lasting memories.”

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New clues about risk of cancer from low-dose radiation


Berkeley Lab research could lead to ways to ID people particularly susceptible to cancer.

By Dan Krotz, Berkeley Lab

Scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have uncovered new clues about the risk of cancer from low-dose radiation, which in this research they define as equivalent to 100 millisieverts or roughly the dose received from ten full-body CT scans.

They studied mice and found their risk of mammary cancer from low-dose radiation depends a great deal on their genetic makeup. They also learned key details about how genes and the cells immediately surrounding a tumor (also called the tumor microenvironment) affect cancer risk.

In mice that are susceptible to mammary cancer from low-dose radiation, the scientists identified more than a dozen regions in their genomes that contribute to an individual’s sensitivity to low-dose radiation. These genome-environment interactions only become significantly pronounced when the mouse is challenged by low-dose radiation.

The interactions also have a big impact at the cellular level. They change how the tumor microenvironment responds to cancer. Some of these changes can increase the risk of cancer development, the scientists found.

They report their research March 9 in the journal Scientific Reports.

Because mice and humans share many genes, the research could shed light on the effects of low-dose radiation on people. The current model for predicting cancer risk from ionizing radiation holds that risk is directly proportional to dose. But there’s a growing understanding that this linear relationship may not be appropriate at lower doses, since both beneficial and detrimental effects have been reported.

“Our research reinforces this view. We found that cancer susceptibility is related to the complex interplay between exposure to low-dose radiation, an individual mouse’s genes, and their tumor microenvironment,” says Jian-Hua Mao of Berkeley Lab’s Life Sciences Division.

Mao led the research in close collaboration with fellow Life Science Division researchers Gary Karpen, Eleanor Blakely, Mina Bissell and Antoine Snijders, and Mary Helen Barcellos-Hoff of New York University School of Medicine.

The identification of these genetic risk factors could help scientists determine whether some people have a higher cancer risk after exposure to low-dose radiation. It could lead to genetic screening tests that identify people who may be better served by non-radiation therapies and imaging methods.

The scientists used a comprehensive systems biology approach to explore the relationship between genes, low-dose radiation, and cancer. To start, Mao and colleagues developed a genetically diverse mouse population that mimics the diversity of people. They crossed a mouse strain that is highly resistant to cancer with a strain that is highly susceptible. This yielded 350 genetically unique mice. Some were resistant to cancer, some were susceptible, and many were in between.

Next, Mao and colleagues developed a way to study how genes and the tumor microenvironment influence cancer development. They removed epithelial cells from the fourth mammary gland of each mouse, leaving behind the stromal tissue. Half of the mice were then exposed to a single, whole-body, low dose of radiation. They then implanted genetically identical epithelial cells, which were prone to cancer, into the fourth mammary glands that were previously cleared of their epithelial cells.

“We have genetically different mice, but we implanted the same epithelial cells into all of them,” says Mao. “This enabled us to study how genes and the tumor microenvironment — not the tumor itself — affect tumor growth.”

The scientists then tracked each mouse for 18 months. They monitored their tumor development, the function of their immune systems, and the production of cell-signaling proteins called cytokines. The researchers also removed cancerous tissue and examined it under a microscope.

They found that low-dose radiation didn’t change the risk of cancer in most mice. A small minority of mice was actually protected from cancer development by low-dose radiation. And a small minority became more susceptible.

In this latter group, they found thirteen gene-environment interactions, also called “genetic loci,” which contribute to the tumor susceptibility when the mouse is exposed to low-dose radiation. How exactly these genetic loci affect the tumor microenvironment and cancer development is not yet entirely understood.

“In mice that were susceptible to cancer, we found that their genes strongly regulate the contribution of the tumor microenvironment to cancer development following exposure to low-dose radiation,” says Mao.

“If we can identify similar genetic loci in people, and if we could find biomarkers for these gene-environment interactions, then perhaps we could develop a simple blood test that identifies people who are at high risk of cancer from low-dose radiation,” says Mao.

The research was supported by the Department of Energy’s Office of Science.

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