TAG: "Cancer"

Chemists find a way to unboil eggs


Ability to quickly restore molecular proteins could slash biotechnology costs.

Chemistry major Stephan Kudlacek and professor Greg Weiss have developed a way of unboiling a hen egg. (Photo by Steve Zylius, UC Irvine)

By Janet Wilson, UC Irvine

UC Irvine and Australian chemists have figured out how to unboil egg whites – an innovation that could dramatically reduce costs for cancer treatments, food production and other segments of the $160 billion global biotechnology industry, according to findings published today (Jan. 23) in the journal ChemBioChem.

“Yes, we have invented a way to unboil a hen egg,” said Gregory Weiss, UCI professor of chemistry and molecular biology & biochemistry. “In our paper, we describe a device for pulling apart tangled proteins and allowing them to refold. We start with egg whites boiled for 20 minutes at 90 degrees Celsius and return a key protein in the egg to working order.”

Like many researchers, he has struggled to efficiently produce or recycle valuable molecular proteins that have a wide range of applications but which frequently “misfold” into structurally incorrect shapes when they are formed, rendering them useless.

“It’s not so much that we’re interested in processing the eggs; that’s just demonstrating how powerful this process is,” Weiss said. “The real problem is there are lots of cases of gummy proteins that you spend way too much time scraping off your test tubes, and you want some means of recovering that material.”

But older methods are expensive and time-consuming: The equivalent of dialysis at the molecular level must be done for about four days. “The new process takes minutes,” Weiss noted. “It speeds things up by a factor of thousands.”

To re-create a clear protein known as lysozyme once an egg has been boiled, he and his colleagues add a urea substance that chews away at the whites, liquefying the solid material. That’s half the process; at the molecular level, protein bits are still balled up into unusable masses. The scientists then employ a vortex fluid device, a high-powered machine designed by Professor Colin Raston’s laboratory at South Australia’s Flinders University. Shear stress within thin, microfluidic films is applied to those tiny pieces, forcing them back into untangled, proper form.

“This method … could transform industrial and research production of proteins,” the researchers write in ChemBioChem.

For example, pharmaceutical companies currently create cancer antibodies in expensive hamster ovary cells that do not often misfold proteins. The ability to quickly and cheaply re-form common proteins from yeast or E. coli bacteria could potentially streamline protein manufacturing and make cancer treatments more affordable. Industrial cheese makers, farmers and others who use recombinant proteins could also achieve more bang for their buck.

UCI has filed for a patent on the work, and its Office of Technology Alliances is working with interested commercial partners.

Besides Weiss and Raston, the paper’s authors are Tom Yuan, Joshua Smith, Stephan Kudlacek, Mariam Iftikhar, Tivoli Olsen, William Brown, Kaitlin Pugliese and Sameeran Kunche of UCI, as well as Callum Ormonde of the University of Western Australia. The research was supported by the National Institute of General Medical Sciences (grant R01 GM100700-01) and the Australian Research Council (grants DP1092810 and DP130100066).

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UCSF receives $40M gift for new Medical Center at Mission Bay


Outpatient medical building to be named in honor of the Ron Conway family.

CSF Medical Center's new outpatient building, located on 16th Street, will be named the UCSF Ron Conway Family Gateway Medical Building in honor of the family $40 million gift. Some outpatient clinics will begin opening on Jan. 26. (Photo by Cindy Chew)

By Karin Rush-Monroe, UC San Francisco

UC San Francisco has received a $40 million gift from angel investor and philanthropist Ron Conway, his wife Gayle, and sons Ronny, Topher and Danny, to help fund the outpatient medical building at the new UCSF Medical Center at Mission Bay, which opens on Feb. 1 on UCSF’s world-renowned biomedical research campus. The outpatient medical building, a 207,500-square-foot facility that anchors the hospital complex, will house outpatient services for women, children and cancer patients.

In honor of the Conways’ generosity, UCSF will name the outpatient building the UCSF Ron Conway Family Gateway Medical Building.

UCSF Medical Center at Mission Bay, a result of more than 10 years of planning and construction, comprises UCSF Benioff Children’s Hospital San Francisco, UCSF Betty Irene Moore Women’s Hospital and UCSF Bakar Cancer Hospital. The new facilities include a 289-bed hospital complex, with children’s emergency and outpatient services that will integrate research and medical advancements with patient-focused, compassionate care.​

Ron Conway is the founder of SV Angel and has worked with hundreds of startups including Google, Facebook, Zappos, Square, Airbnb, Dropbox, Pinterest  and Twitter. He also is a board member of the Salesforce.com Foundation and actively supports the tech civic organization sf.citi, College Track, Sandy Hook Promise, Americans for Responsible Solutions, Teach for America, THORN and Donors Choose.

“Ron and Gayle have been true partners with UCSF for more than a decade, and we are extremely grateful for their ongoing support. This building is significant for the connection it provides between the high-quality medical care patients will receive at our three specialty hospitals as inpatients, and the groundbreaking continuing care they will receive as outpatients,” said Sam Hawgood, M.B.B.S., chancellor of UCSF.

Ron Conway is a member of the UCSF Medical Center Campaign Cabinet and served on the UCSF Foundation Board for several years. He has been a generous fundraiser for and philanthropist to UCSF and in particular, UCSF Benioff Children’s Hospital San Francisco.

He also has been an active supporter of neurodegenerative disease research and treatment, through the UCSF Neuroscience Initiative, which brings together under one roof outstanding scientists and clinicians from multiple disciplines – and the core technologies that they need to be successful.

“Ron is known as an ‘angel’ investor, and that description certainly holds true for his passion to better the lives of patients at UCSF,” said Mark R. Laret, CEO of UCSF Medical Center and UCSF Benioff Children’s Hospitals. “As a public medical center, we depend on the generosity of people like Ron and Gayle to continue serving the patients of San Francisco as well as Northern California and beyond. The Conways have been generous not just through financial gifts but with their time, introducing UCSF to their colleagues throughout the technology sector and Silicon Valley in order to advance our mission of care, research and education.”

The UCSF Ron Conway Family Gateway Medical Building is expected to draw more than 1,500 outpatient visits daily, as well as serve as a teaching facility for students. It includes a cancer clinic and women’s health clinic, and pediatric clinic. Some outpatient clinics will begin opening on Jan. 26.

The new medical center, strategically located on UCSF’s 60.2-acre Mission Bay research campus, will enhance UCSF’s ecosystem of innovation by putting physicians in close proximity to researchers and near biotechnology and pharmaceutical companies in Mission Bay and beyond. The new cancer hospital, for example, will sit near the UCSF Helen Diller Family Cancer Research Building, where every day leading scientists are seeking causes and cures for cancer.

UCSF Medical Center at Mission Bay also will feature the only operating hospital helipad in San Francisco to transport critically ill babies, children and pregnant women to the medical center from outlying hospitals.

“Gayle and I are proud to partner with UCSF to improve the health of the Bay Area. We have watched UCSF Medical Center at Mission Bay grow from a concept to a magnificent hospital complex, and can think of no better investment than supporting patients who are accessing needed outpatient medical services,” Ron Conway said. “We encourage others to get involved with the new medical center philanthropically, as well as other programs at this leading institution.”

The total $1.5 billion cost of the Mission Bay Hospitals Project has been funded by UCSF Medical Center financing and private philanthropy. Of the $600 million fundraising goal, UCSF has raised $550 million.

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UC San Diego, UCSF launch new Cancer Cell Map Initiative


Collaboration aims to determine how all of the components of a cancer cell interact.

Cultured HeLa cancer cells. (Image by Thomas Deerinck, National Center for Microscopy and Imaging Research, UC San Diego)

Researchers from the UC San Diego School of Medicine and UC San Francisco, with support from a diverse team of collaborators, have launched an ambitious new project – dubbed the Cancer Cell Map Initiative or CCMI – to determine how all of the components of a cancer cell interact.

“We’re going to draw the complete wiring diagram of a cancer cell,” said Nevan Krogan, Ph.D., director of the UC San Francisco division of QB3, a life science research institute and accelerator, an investigator at Gladstone Institutes and co-director of CCMI with Trey Ideker, Ph.D., chief of medical genetics in the UC San Diego Department of Medicine and founder of the UC San Diego Center for Computational Biology & Bioinformatics.

In recent years, progress in genome sequencing has made it possible to decipher hundreds of mutations found in a patient’s tumor. But in only a few cases do scientists understand how these mutations give rise to cancer or indicate what treatments to pursue.  More puzzling still, the mutations found in each patient are almost always different – even though they can lead to the same type of cancer.

It has long been thought that, while these mutations are unique to individuals, they hijack the same hallmark cancer pathways or genetic circuits. To interpret genomic data, researchers say the complete wiring diagram of the cell is needed, one that details all of the connections between normal and mutated genes and proteins.

“We have the genomic information already. The bottleneck is how to interpret the cancer genomes,” said Ideker.  A comprehensive map of cancer cells would help – and accelerate the development of personalized therapy, the central aim of “precision medicine.”

Krogan agreed: “The key to understanding genomic information is being able to place it into biological context. Mutations in tumor DNA that at first appear to be unrelated may in fact be clustered in specific pathways or multi-protein machines in the cell. The information, in context, will point to areas that we can target with specific therapies.”

The CCMI combines expertise at UC San Diego in extracting knowledge from big biomedical data sets with advances developed at UCSF for experimentally interrogating the structure and function of cells. It is a multimillion dollar collaboration between the UC San Diego Moores Cancer Center and the UCSF Helen Diller Family Comprehensive Cancer Center; funded by QB3 at UCSF, UC San Diego Health Sciences and support from Fred Luddy, founder of ServiceNow, a provider of enterprise service management software.

“The combination of medical research and high technology is our best opportunity to understand and rid the planet of insidious diseases like cancer,” said Luddy, who is a member of the Moores Cancer Center advisory board. “I am thrilled and flattered to have the opportunity to be able to support this great frontier.”

Scott Lippman, M.D., and Alan Ashworth, Ph.D., F.R.S., directors of the UC San Diego and UCSF comprehensive cancer centers, respectively, will provide access to tissue samples donated by patients being treated for cancer. The samples constitute a library of mutations associated with the disease.

“The CCMI is an example of the best kind of collaborative science,” said Lippman. “It draws together the strengths of multiple institutions and combines them in ways that are exponentially more powerful. And it is fundamentally driven by real people – actual patients with cancer. It is their stories, and the stories contained within their DNA, that will ultimately help us reveal cancer’s darkest and most difficult secrets.”

Added Ashworth: “Over the last few years, genome analysis has revealed many of the commonly occurring mutations in human cancer. Optimal exploitation of this will require a detailed understanding of how these genetic changes subvert normal cellular functions. The insights that this project will create will be critical in achieving this goal. I am tremendously excited to be involved in this initiative.”

The CCMI will provide key infrastructure for the recently announced alliance between UC San Diego Health Sciences and San Diego-based Human Longevity Inc., which plans to generate thousands of tumor genomes from UC San Diego cancer patients. It also will leverage resources and information from the National Cancer Institute (NCI), including large databases of cancer genomes and pathways that are being developed in collaboration with the San Diego Supercomputer Center and UC Santa Cruz.

David Haussler, director of QB3 at UC Santa Cruz and creator of the NCI Cancer Genomics Browser, said, “This is an exciting opportunity to utilize the unique NCI repository of 1.5 petabytes of cancer genomics data, combined with proteomic and functional data, to dive deeper into the molecular processes of cancer.”

Primary partners at UC San Diego are the Division of Genetics and the Department of Medicine in the UC San Diego School of Medicine and UC San Diego Moores Cancer Center. At UCSF: QB3, the Department of Cellular and Molecular Pharmacology and the Helen Diller Family Comprehensive Cancer Center.

Several other institutes, resources and biotechnology companies are also involved, including the Gladstone Institutes in San Francisco, the Clinical and Translational Research Institutes at both UC San Diego and UCSF and Thermo Fisher Scientific Inc., based in Massachusetts.

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California breast density law slow to have an impact


UC Davis research demonstrates need for more physician education.

Jonathan Hargreaves, UC Davis

By Dorsey Griffith, UC Davis

Ten months after California legislators enacted a controversial law mandating that radiologists notify women if they have dense breast tissue, UC Davis researchers have found that half of primary care physicians are still unfamiliar with the law and many don’t feel comfortable answering breast density-related questions from patients. The findings, to be published in the March print edition of Journal of the American College of Radiology, suggest that if the law is going to have any significant impact on patient care, primary care providers need more education about breast density and secondary imaging options.

“Overall, the impact of the breast density legislation probably is not significant if  primary care physicians are not educated or aware of it,” said lead author Kathleen Khong, a UC Davis radiologist and staff physician. “We should put some emphasis on educating the primary care physicians so that when they get questions from patients, they can be comfortable in addressing the issues.”

The California law, which took effect in April 2013, requires that patients whose breast density is defined as “heterogeneously dense” or “extremely dense” (about 50 percent of women), receive the following notification:

“Your mammogram shows that your breast tissue is dense. Dense breast tissue is common and is not abnormal. However, dense breast tissue can make it harder to evaluate the results of your mammogram and may also be associated with an increased risk of breast cancer. This information about the results of your mammogram is given to you to raise your awareness and to inform your conversations with your doctor. Together, you can decide which screening options are right for you. A report of your results was sent to your physician.”

The researchers point out that breast density has long been a required part of any radiological report following mammography, but unless a patient asks to see the report, the information is shared only with the patient’s providers. Led by patient advocates, the legislation is intended to increase awareness of dense breasts and encourage patients to discuss the clinical issues with their doctors. According to published research, 28 states have passed, rejected or considered dense-breast notification legislation since 2009.

But the UC Davis study demonstrated that while women and their doctors are receiving the notifications, many of those physicians are unclear about what to do with the information. As a consequence, the researchers said, it appears that relatively few patients with dense breasts are asking questions about their breast density and its implications.

The UC Davis study surveyed 77 physicians about the new law.  Roughly half (49 percent) reported no knowledge of the legislation and only 32 percent of respondents noted an increase in patient levels of concern about breast density compared to prior years. In addition, a majority of primary care physicians were only “somewhat comfortable” (55 percent) or “not comfortable” (12 percent) with breast-density questions from their patients.

Khong said their survey results were surprising, but acknowledged that many primary care physicians may not feel they have sufficient training to make a clinical recommendation for a particular type of secondary screening. In fact, the study also found that 75 percent of respondents would like more education about the breast-density law and its implications for primary care.

“They are eager to learn and want to help their patients and be part of something positive as a result of this,” Khong said.

Jonathan Hargreaves, assistant professor of clinical radiology and a study co-author, said, for example,  that if a patient has dense breasts she should have a risk assessment, which takes into account her family history of breast cancer, biopsy history and other factors to determine whether a supplemental screening is warranted. Once  complete, the physician should then discuss the potential benefits and risks of supplemental imaging in determining the most appropriate approach for the patient. The use of ancillary screening in addition to mammography is a complex subject and still the subject of considerable debate, explained Hargreaves.

Tomosynthesis, known as 3-D mammography, is one supplemental test that breast radiologists generally agree provides a slight benefit for women with dense breasts over a standard mammogram and can be scheduled for the next annual mammographic screening appointment after receiving a notification. Breast magnetic resonance imaging (MRI) is another secondary imaging option, Hargreaves said, but is generally only used for screening in women who have a very strong family history of breast cancer or have a known high-risk gene, such as BRCA.

“The law has raised a lot of awareness about breast density,” Hargreaves said. “That being said, mammography screening is the primary thing patients need to do, and beyond that, the real benefits of other screening techniques are still the subject of ongoing medical debate.”

Khong and Hargreaves hope to validate their findings by expanding their research to include primary care physicians from other major university health care systems in California.

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Q&A with Alan Ashworth


UCSF’s new cancer center director was key player on team that discovered BRCA2 gene.

Alan Ashworth

Alan Ashworth,  Ph.D., F.R.S., is one of the world’s pre-eminent cancer scientists. This January he assumed the role of the new director of the UCSF Helen Diller Family Comprehensive Cancer Center. Ashworth studies genes involved in cancer risk, and was a key player on the team discovered the gene BRCA2, which is linked to a heightened risk of breast, ovarian and other cancers. He went on to develop a treatment for BRCA1- and BRCA2–related cancers that was recently approved by the FDA. Before coming to UCSF this January, Ashworth was chief executive of The Institute of Cancer Research, London. He answered a few questions about his new position.

What brought you to UCSF?
I saw this as a fantastic opportunity to make a difference. UCSF has always been a place I’ve enjoyed visiting. I like the scale and breadth of it, the excellence, the feeling of entrepreneurship. The new hospital at Mission Bay was also one of the major drivers in my coming here – it will allow a totally seamless integration between clinical programs and research in a stunning new facility.

Additionally, there’s a lot of cutting-edge, emerging technologies being developed here in the Bay Area which I’m looking forward to tapping into. I believe partnership between academia and commercial outfits to be critical in developing the next generation of cancer therapies and diagnostic tools.

What’s your top priority for the UCSF Helen Diller Cancer Center as its new leader?
We’ve already started a strategic review of UCSF organizational structures and our strengths and weaknesses.

With the opening of the new UCSF Bakar Cancer Hospital at Mission Bay there will be huge new opportunities. This review will allow us to work out how we might be best configured to achieve our ultimate goal, that of delivering new advances to cancer patients in the most rapid fashion.

Where do you see the fight against cancer in 10 years? 20?
History proves that predicting exact timelines in this area is a tricky business.

Let’s say that in the coming decades we will first see much better and long-term disease control. A smorgasbord of therapies will be available – conventional, new targeted drugs and immune therapies – and these will be increasing used in rational sequential and combination strategies. This will initially result in the stabilization of advanced disease with more cures in early disease.

We should also eventually see cures of some currently lethal advanced cancers. Methods of early detection will become much more efficient.

Unfortunately, I fear the fight against tobacco use will still be ongoing around the world. Pinpointing cancer risk and cancer prevention of cancer will rightly be getting much more attention.

What advice do you have for young researchers?
I’ve been asked this question a number of times and generally my answer is “Don’t take advice from old f*rts like me.” If I have to answer I would say: Find your own path, everyone is different; get excited; take risks, don’t be boring; change the world.

What are you most excited about regarding living in SF?
The adventure.

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Enzymes believed to promote cancer actually suppress tumors


UC San Diego finding upends dogma and may lead to new activator-based drugs.

By Scott LaFee, UC San Diego

Upending decades-old dogma, a team of scientists at the UC San Diego School of Medicine say enzymes long categorized as promoting cancer are, in fact, tumor suppressors and that current clinical efforts to develop inhibitor-based drugs should instead focus on restoring the enzymes’ activities.

The findings are published in the Jan. 29 issue of Cell.

Protein Kinase C (PKC) is a group of enzymes that act as catalysts for a host of cellular functions, among which are cancer-relevant activities, such as cell survival, proliferation, apoptosis, and migration. The discovery that they are receptors for tumor-producing phorbol esters, plant-derived compounds that bind to and activate PKC, created a dogma that activation of PKCs by phorbol esters promoted carcinogen-induced tumorigenesis.

“For three decades, researchers have sought to find new cancer therapies based on the idea that inhibiting or blocking PKC signals would hinder or halt tumor development,” said Alexandra Newton, Ph.D., professor of pharmacology and the study’s principal investigator, “but PKCs have remained an elusive chemotherapeutic target.” The reason, suggest Newton and colleagues, is that contrary to conventional wisdom, PKCs do not promote cancer progression; rather, they act to suppress tumor growth.

Using live cell imaging, first author Corina Antal, a graduate student in the biomedical sciences program at UC San Diego, characterized 8 percent of the more than 550 PKC mutations identified in human cancers. This led to the unexpected discovery that the majority of mutations actually reduced or abolished PKC activity, and none were activating. The mutations impeded signal binding, prevented correct structuring of the enzyme, or impaired catalytic activity.

When the scientists corrected a loss-of-function PKC mutation in the genome of a colon cancer cell line, tumor growth in a mouse model was reduced, demonstrating that normal PKC activity inhibits cancer. One possible explanation, said the researchers, is that PKC typically represses signaling from certain oncogenes – genes that can cause normal cells to become cancerous. When PKC is lost, oncogenic signaling increases, fueling tumor growth.

“Inhibiting PKC has so far proved not only an unsuccessful strategy in a number of cancer clinical trials, but its addition to chemotherapy has resulted in decreased response rates in patients,” said Newton. “Given our results, this isn’t surprising. Our findings suggest therapeutic strategies need to go the other way and target ways to restore PKC activity, not inhibit it. This is contrary to the current dogma.”

How could this misconception of PKC promoting tumors have arisen?

Long-term activation of PKCs by phorbol esters results in their degradation, said first author Antal. In models of tumor promotion, a sub-threshold dose of a carcinogen is painted on mouse skin, followed by repeated applications of phorbol esters. “This repeated application of phorbol esters will lead to the loss of PKC. Thus, their tumor-promoting function may arise because a brake to oncogenic signaling has been removed.”

Co-authors include Emily Kang, UCSD; Andrew M. Hudson, Christopher Wirth, Crispin J. Miller, Natalie L. Stephenson, Eleanor W. Trotter and John Brognard, University of Manchester, U.K.; Ciro Zanca and Frank B. Furnari, Ludwig Cancer Research, UCSD; Lisa L. Gallegos, UCSD and Harvard Medical School; and Tony Hunter, Salk Institute.

Funding for this research comes, in part, from the National Institutes of Health (grants GM43154, NS080939, CA82683), the James S. McDonnell Foundation, UCSD Graduate Training Program in Cellular and Molecular Pharmacology, the National Science Foundation Graduate Research Fellowship and Cancer Research U.K.

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Melanoma study maps cancer drivers


UC Merced researchers analyze hundreds of genomes to find genetic drivers of melanoma.

By James Leonard, UC Merced

Researchers at the University of California, Merced, have completed a comprehensive map of the genetic makeup of melanoma, the deadliest form of skin cancer. By comparing the genomes of more than 300 melanomas, the researchers were able to identify mutational hotspots that give rise to cancer.

The research team, led by professor Fabian V. Filipp, was able to confirm preeminent drivers of melanoma and identify new melanoma genes. The study, “Cancer systems biology of TCGA SKCM: Efficient detection of genomic drivers in melanoma,” published today (Jan. 20) in Scientific Reports, an open access journal from the publishers of Nature.

“Now that we have the genomic landscape of melanoma, we can navigate it,” Filipp said. “We can provide the maps to make it easier to identify melanoma risks, develop new therapeutic targets and create better diagnostic readouts.”

The team employed a systems biology approach to the study — instead of examining a single DNA change and its role in cancer development, the researchers combed through billons of DNA base pairs. The result was a map showing a dense network of mutational hotspots — areas where a series of related genetic mutations occur. Such hotspots coordinate cell division and are anything but random.

The availability of big genomic data — a recent development in scientific research — challenged the researchers to study more melanoma genomes than anyone had before and promises to provide new methods by which scientists can learn about and understand cancer.

“Systems biology has a major impact on how we view cancer today,” Filipp said. “An important step was to employ a rigorous filter that separates millions of random molecular events from those events that drive cancer.”

The study found that in melanoma patients, the signaling pathway of proto-oncogene BRAF — a gene that causes cancer — is hyperactive, triggering uncontrolled cell division. Filipp and his team determined that BRAF mutations are bona fide drivers of melanoma, then looked for the mutation in other forms of cancer.

They found the mutation was also prominent in thyroid cancer, which was previously unknown, and their analysis could lay a foundation for future assessment and treatment of melanoma and other cancers.

The study was carried out within the framework of The Cancer Genome Atlas (TCGA), a big-data project exploring the universe of genomic changes involved in all types of human cancer.

Filipp’s research focuses on melanoma and cancer metabolism, and he recently was awarded the prestigious Thomas B. Fitzpatrick Medal, presented only once every three years by the International Federation of Pigment Cell Societies to a handful of researchers worldwide who have made outstanding contributions to the study of melanoma and pigment cells.

“Professor Filipp exemplifies the innovative ways in which UC Merced researchers approach issues of local, national and global significance,” said Vice Chancellor for Research and Economic Development Sam Traina. “We are proud to see that his outstanding work is being recognized.”

For the melanoma study, Filipp’s multidisciplinary team — which included Dr. Jian Guan and Ph.D. student Rohit Gupta — received an $800,000 grant from the National Cancer Institute at the National Institutes of Health. Filipp hopes to one day apply the same sort of analysis to melanoma patients in the Central Valley of California, to learn more about risk factors in the region.

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How melanoma resists new drug combination therapy


UCLA discovery paves way for development of more effective patient-tailored therapies.

Roger Lo, UCLA

By Reggie Kumar, UCLA

Researchers at the UCLA Jonsson Comprehensive Cancer Center have uncovered how melanoma becomes resistant to a new drug combination therapy consisting of BRAF+MEK inhibitor — chemical compounds used to fight cancer.

During the two-year study led by Dr. Roger Lo, the research team took 43 tumor samples from 15 patients before they were prescribed the new BRAF+MEK inhibitors and then after the patients relapsed after the melanoma developed resistance to the drug therapy. The participants had all benefited from the combo therapy initially, but after a timeframe of a few months to more than a year, the tumors that had initially regressed, started to grow again.

After obtaining biopsies of the tumors, the researchers extracted and analyzed the genetic material. This analysis provided leads for the investigators to study how melanoma cells grown in Lo’s laboratory rewired their growth circuitry to get around the combo inhibitors.

Lo’s team found that the melanoma cells resist the combo therapy of BRAF+MEK inhibitors by developing highly unusual changes in certain key cancer genes. These signature changes or configurations not only mark the presence of drug resistance melanoma cells but also indicate to researchers potential new ways to shut them off.

“We need to find ways to go beyond the BRAF+MEK drug combination, by possibly finding a third drug, or alter how we prescribe the combo of drugs,” said Lo, UCLA assistant professor of dermatology. “The idea is to eventual suppress melanoma drug resistance even before it arises.”

“In most cases, melanoma eventually becomes resistant,” said Dr. Antoni Ribas, JCCC member and professor of hematology and oncology, and a co-author of the study. “We now understand the molecular basis of the resistance mechanisms, which leads to the planning of new treatment approaches to disable these mechanisms.”

An estimated 70,000 new cases of melanoma are diagnosed each year in the United States. Of those with advanced stage or metastatic melanoma, about 8,000 people will die of the disease each year. About 50 percent of people with metastatic melanoma, have tumors that harbor a mutated protein called a mutated BRAF protein. The presence of this mutated BRAF protein is what makes a patient with metastatic melanoma appropriate for the BRAF+MEK combo inhibitor therapy.

Lo and Ribas previously collaborated on several seminal drug resistance studies investigating how melanoma resisted the then-experimental drug PLX4032, which is now known as Zelboraf (vemurafenib) and was approved by the FDA in 2011.

These studies have provided critical insights that led to development of the current combo therapy for melanoma using BRAF+MEK inhibitors and additional on-going clinical trials. Lo hopes this new study will also lead to more effective therapies for patients.

“If we understand how a disease fights your therapy, then we can start to design more effective treatment strategies,” Lo said.

The study is published online today in the journal Cancer Cell.

The research was funded by the National Institutes of Health (NIH), the Melanoma Research Alliance, and Stand Up To Cancer.

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‘NanoVelcro,’ temperature control used to extract tumor cells from blood


System could allow doctors to detect, analyze cancer to tailor treatment for individuals.

The device, developed at UCLA, enables scientists to control the blood’s temperature — the way coffeehouses would with an espresso machine — to capture and release the cancer cells in optimal conditions. (Credit: Tseng Lab, UCLA)

By Shaun Mason, UCLA

An international group led by scientists at UCLA’s California NanoSystems Institute has developed a new method for effectively extracting and analyzing cancer cells circulating in patients’ blood.

Circulating tumor cells are cancer cells that break away from tumors and travel in the blood, looking for places in the body to start growing new tumors called metastases. Capturing these rare cells would allow doctors to detect and analyze the cancer so they could tailor treatment for individual patients.

In his laboratory at the UCLA California NanoSystems Institute, Hsian-Rong Tseng, a professor of molecular and medical pharmacology, used a device he invented to capture circulating tumor cells from blood samples.

The device, called the NanoVelcro Chip, is a postage-stamp–sized chip with nanowires that are 1,000 times thinner than a human hair and are coated with antibodies that recognize circulating tumor cells. When 2 milliliters of blood are run through the chip, the tumor cells stick to the nanowires like Velcro.

Capturing the tumor cells was just part of the battle, though. To analyze them, Tseng’s team needed to be able to separate the cells from the chip without damaging them.

In earlier experiments with NanoVelcro, the scientists used a technique called laser capture microdissection that was effective in removing individual cells from the chip without damaging them, but the method was time-consuming and labor intensive, and it required highly specialized equipment.

Now Tseng and his colleagues have developed a thermoresponsive NanoVelcro purification system, which enables them to raise and lower the temperature of the blood sample to capture (at 37 degrees Celsius) and release (at 4 degrees Celsius) circulating tumor cells at their optimal purity. Polymer brushes on the NanoVelcro’s nanowires respond to the temperature changes by altering their physical properties, allowing them to capture or release the cells.

Because it could make extracting the cancer cells much more efficient and cost-effective at a time in a patient’s life when information is needed as quickly as possible, Tseng said it is conceivable that the new system will replace laser capture microdissection as the standard protocol.

“With our new system, we can control the blood’s temperature — the way coffeehouses would with an espresso machine — to capture and then release the cancer cells in great purity, ” said Tseng, who is also a member of UCLA’s Jonsson Comprehensive Cancer Center. “We combined the thermoresponsive system with downstream mutational analysis to successfully monitor the disease evolution of a lung cancer patient. This shows the translational value of our device in managing non–small-cell lung cancer with underlying mutations.”

The study, which was published online by the journal ACS Nano, brought together an interdisciplinary team from the U.S., China, Taiwan and Japan. The research was supported by the National Institutes of Health, RIKEN (Japan), Academia Sinica (Taiwan), Sun Yat-sen University (China) and the National Natural Science Foundation of China.

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Kids of melanoma survivors need better protection from sun’s harmful rays


UCLA study is first to include Latinos, whom have often been left out of skin cancer prevention research.

Credit: Sean Brenner, UCLA

By Reggie Kumar, UCLA

UCLA researchers have found that children of melanoma survivors are not comprehensively adhering to sun protection recommendations, despite them being at an increased risk for developing the disease as adults.

In the study led by Beth Glenn, associate director of the UCLA Jonsson Comprehensive Cancer Center’s Healthy and At-Risk Populations Research Program, researchers asked parents about their attitudes toward melanoma prevention, how at risk for melanoma they believed their child to be, and their current use of sun protection strategies for their child. They found that about three-quarters of parents relied on sunscreen to protect their child against sun exposure, but less than a third of parents reported that their child wore a hat or sunglasses or attempted to seek shade when exposed to the sun.

Additionally, Glenn said, 43 percent of parents surveyed reported that their child experienced a sunburn in the past year. This is concerning because sunburns are a major risk factor for melanoma.

The UCLA researchers used the California Cancer Registry (which tracks all cases of cancer across the state) to identify and survey 300 melanoma survivors with children ages 17 and younger during a three-year period. The study targeted both non-Latino white melanoma survivors and for the first time Latino melanoma survivors as well.

Latinos have often been left out of skin cancer prevention research due to a common misconception that sun protection is not important for this group.

“Sunburns were common among the children in our study despite their elevated risk for skin cancer. Also, children of Latino survivors were just as likely as children of non-Latino white survivors to have experienced a recent sunburn, which highlights the importance of including this group in our work,” said Glenn, associate professor of Health Policy and Management in the UCLA Fielding School of Public Health.

The survey results will be used to apply for additional funding to develop an intervention program that combines a text message reminder system with educational materials and activities for parents and children. The intervention program is designed to help melanoma survivors more effectively monitor and properly protect their child against UV radiation.

“Protecting kids against the sun’s harmful rays at an early age is vitally important. Our goal is to develop an intervention that will help parents protect their children today and help children develop sun safe habits that will reduce their risk for skin cancer in the future,” said Glenn.

The study will be published online Jan. 13 in the journal Cancer Epidemiology, Biomarkers & Prevention.

The research was supported in part by the National Cancer Institute.

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Novel imaging technique improves detection of prostate cancer


More accurate diagnoses could mean less invasive interventions, more surveillance.

By Scott LaFee, UC San Diego

In 2014, prostate cancer was the leading cause of newly diagnosed cancers in men and the second leading cause of cancer death in men. Writing in today’s (Jan. 6) issue of the journal Prostate Cancer and Prostatic Disease, a team of scientists and physicians from the UC San Diego School of Medicine, with counterparts at UCLA, describe a novel imaging technique that measurably improves upon current prostate imaging – and may have significant implications for how patients with prostate cancer are ultimately treated.

“This new approach is a more reliable imaging technique for localizing tumors. It provides a better target for biopsies, especially for smaller tumors,” said Rebecca Rakow-Penner, M.D., Ph.D., a research resident in the Department of Radiology and the study’s first author.

The technique is also valuable in surgical planning and image staging, said David S. Karow, M.D., Ph.D., assistant professor of radiology at UC San Diego and the study’s corresponding author. “Doctors at UC San Diego and UCLA now have a non-invasive imaging method to more accurately assess the local extent of the tumor and possibly predict the grade of the tumor, which can help them more precisely and effectively determine appropriate treatment.”

The current standard of care for detecting and diagnosing prostate cancer is contrast enhanced magnetic resonance imaging (MRI), which involves intravenously injecting patients with a contrast agent to highlight blood flow. Greater blood flow is often a requirement of growing cancer cells. When compared to surrounding healthy tissues, it’s hoped that contrast enhanced MRIs will reveal the shape and nature of any tumors present.

But many tumors do not significantly differ from surrounding healthy tissues with contrast enhanced MRI and so evade easy detection. An imaging technique called diffusion MRI measures the diffusion of water and has been a standard imaging technique in the brain and an emerging technique in the prostate. Cancer tissues are denser than healthy tissues and typically limit the amount and mobility of water within them. But diffusion MRI suffers from magnetic field artifacts that can distort the actual location of tumors by as much as 1.2 centimeters or roughly half an inch – a significant distance when surgeons are attempting, for example, to assess whether a tumor extends beyond the prostate and into adjacent nerve bundles.

The new approach described in today’s published paper is called restriction spectrum imaging-MRI or RSI-MRI. It corrects for magnetic field distortions and focuses upon water diffusion within tumor cells. By doing both, the ability of imaging to accurately plot a tumor’s location is increased and there is a more refined sense of the tumor’s extent, said Nathan White, Ph.D., assistant project scientist at UC San Diego, study co-author and co-inventor of the RSI-MRI technique.

In a related paper to be published in the journal Frontiers in Oncology, the same team of researchers reported that RSI-MRI appears to predict tumor grade. Higher grade tumors correlate with higher restricted water volume in the cancer cells’ large nuclei.

“Prostate cancer can often be an indolent disease, where a patient may only require surveillance rather than aggressive surgery,” noted co-author Christopher J. Kane, M.D., professor of urology at UC San Diego.

“If by imaging we could predict the tumor grade,” added Robert Reiter, M.D., professor of urology at UCLA, “we may be able to spare some patients from prostate resection and monitor their cancer with imaging.”

Co-authors include senior author Anders M. Dale, Hyung W. Choi, Joshua M. Kuperman, Natalie M. Schenker-Ahmed, Hauke Bartsch, Robert F. Mattrey and William G. Bradley, Department of Radiology, UCSD; J. Kellogg Parsons and Michael A. Liss, Department of Urology, UCSD; Ahmed Shabaik, Department of Pathology, UCSD; Jiaoti Huang, Department of Pathology, UCLA; Daniel J. Margolis and Steven S. Raman, Department of Radiology, UCLA; Leonard S. Marks, Department of Urology, UCLA.

Funding for this research was provided, in part, by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health, the Department of Defense, Prostate Cancer Research Program, the American Cancer Society and the UC San Diego Clinician Scientist Program.

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Sugar molecule links red meat consumption, elevated cancer risk in mice


Neu5Gc, found in red meat, promotes inflammation, cancer progression in rodents.

By Heather Buschman and Scott LaFee, UC San Diego

While people who eat a lot of red meat are known to be at higher risk for certain cancers, other carnivores are not, prompting researchers at the UC San Diego School of Medicine to investigate the possible tumor-forming role of a sugar called Neu5Gc, which is naturally found in most mammals but not in humans.

In a study published in today’s (Dec. 29) online early edition of the Proceedings of the National Academy of Sciences, the scientists found that feeding Neu5Gc to mice engineered to be deficient in the sugar (like humans) significantly promoted spontaneous cancers. The study did not involve exposure to carcinogens or artificially inducing cancers, further implicating Neu5Gc as a key link between red meat consumption and cancer.

“Until now, all of our evidence linking Neu5Gc to cancer was circumstantial or indirectly predicted from somewhat artificial experimental setups,” said principal investigator Ajit Varki, M.D., Distinguished Professor of Medicine and Cellular and Molecular Medicine and member of the UC San Diego Moores Cancer Center. “This is the first time we have directly shown that mimicking the exact situation in humans — feeding non-human Neu5Gc and inducing anti-Neu5Gc antibodies — increases spontaneous cancers in mice.”

Varki’s team first conducted a systematic survey of common foods. They found that red meats (beef, pork and lamb) are rich in Neu5Gc, affirming that foods of mammalian origin such as these are the primary sources of Neu5Gc in the human diet. The molecule was found to be bio-available, too, meaning it can be distributed to tissues throughout the body via the bloodstream.

The researchers had previously discovered that animal Neu5Gc can be absorbed into human tissues. In this study, they hypothesized that eating red meat could lead to inflammation if the body’s immune system is constantly generating antibodies against consumed animal Neu5Gc, a foreign molecule. Chronic inflammation is known to promote tumor formation.

To test this hypothesis, the team engineered mice to mimic humans in that they lacked their own Neu5Gc and produced antibodies against it. When these mice were fed Neu5Gc, they developed systemic inflammation. Spontaneous tumor formation increased fivefold and Neu5Gc accumulated in the tumors.

“The final proof in humans will be much harder to come by,” Varki said. “But on a more general note, this work may also help explain potential connections of red meat consumption to other diseases exacerbated by chronic inflammation, such as atherosclerosis and type 2 diabetes.

“Of course, moderate amounts of red meat can be a source of good nutrition for young people. We hope that our work will eventually lead the way to practical solutions for this catch-22.”

Study co-authors include Annie N. Samraj, Oliver M. T. Pearce, Heinz Läubli, Alyssa N. Crittenden, Anne K. Bergfeld, Kalyan Banda, Christopher J. Gregg, Andrea E. Bingman, Patrick Secrest, Sandra L. Diaz and Nissi M. Varki, all at the UC San Diego School of Medicine.

This research was funded, in part, by the Ellison Medical Foundation, the National Cancer Institute (grant R01CA38701), a Samuel and Ruth Engelberg Fellowship from the Cancer Research Institute, and a Swiss National Science Foundation Fellowship.

Disclosure: Ajit Varki and Nissi Varki are co-founders and have equity interest in SiaMab Therapeutics Inc., a biotech company with an interest in Neu5Gc and anti-Neu5Gc antibodies. In addition, Ajit Varki is a member of SiaMab Therapeutics Inc.’s Board of Directors and is a scientific advisor to the company. The terms of this arrangement have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies.

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