TAG: "Cancer"

Tobacco-smoking parents increase diabetes risk for children exposed in utero

“Smoking of parents is by itself a risk factor for diabetes, independent of obesity or birth weight.”

Credit: iStock

By Michele La Merrill and Kat Kerlin, UC Davis

Children exposed to tobacco smoke from their parents while in the womb are predisposed to developing diabetes as adults, according to a study from the University of California, Davis, and the Berkeley nonprofit Public Health Institute.

In the study, published today (Feb. 9) in the Journal of Developmental Origins of Health and Disease, women whose mothers smoked while pregnant were two to three times as likely to be diabetic as adults. Dads who smoked while their daughter was in utero also contributed to an increased diabetes risk for their child, but more research is needed to establish the extent of that risk.

“Our findings are consistent with the idea that gestational environmental chemical exposures can contribute to the development of health and disease,” said lead author Michele La Merrill, an assistant professor of environmental toxicology at UC Davis.

The study analyzed data from 1,800 daughters of women who had participated in the Child Health and Development Studies, an ongoing project of the Public Health Institute. The CHDS recruited women who sought obstetric care through Kaiser Permanente Foundation Health Plan in the San Francisco Bay Area between 1959 and 1967. The data was originally collected by PHI to study early risk of breast cancer, which is why sons were not considered in this current study.

In previous studies, fetal exposure to cigarette smoke has also been linked to higher rates of obesity and low birth weight. This study found that birth weight did not affect whether the daughters of smoking parents developed diabetes.

“We found that smoking of parents is by itself a risk factor for diabetes, independent of obesity or birth weight,” said La Merrill. “If a parent smokes, you’re not protected from diabetes just because you’re lean.”

The study was supported through funding from the National Institute of Environmental Health Sciences, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the California Breast Cancer Research Program Special Research Initiative.

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FDA approves new drug to treat estrogen-receptor-positive breast cancer

UCLA research played key role in development of Ibrance.

UCLA Drs. Dennis Slamon (left) and Richard Finn

By Reggie Kumar, UCLA

The U.S. Food and Drug Administration today (Feb. 3) approved a new drug to treat patients with advanced breast cancer, signaling a new strategy for arresting tumor growth and extending the time before cancer worsens in women with metastatic disease.

The drug, Ibrance (palbociclib), was studied in 165 post-menopausal women with advanced estrogen–receptor positive (ER+) and HER2–negative (HER2-) breast cancer who had received no prior systemic therapy for their metastatic disease. In 2013, after patients in a clinical study led by UCLA researchers showed a dramatic improvement, the FDA granted the drug “breakthrough therapy” status, allowing it to be fast-tracked for approval.

ER+/HER2- is the most common type of breast cancer; it is traditionally treated with therapies like tamoxifen or letrozole that target the hormone receptor pathway.

“Ibrance is the first drug in its class to be approved by the FDA,” said Dr. Richard Finn, the study’s principal investigator and a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “All of us at UCLA are very proud of the important role we played in bringing this new agent to patients.”

Developed by Pfizer, Ibrance targets proteins in cancer cells — cyclin D kinase 4 (CDK 4) and cyclin D kinase 6 (CDK 6) — preventing the cells from dividing. A multiyear phase two study found a significantly higher progression-free survival rate for patients with advanced ER+/HER2- breast cancer who were given palbociclib in addition to letrozole, a standard anti-estrogen treatment, compared with women who received letrozole alone.

“With the FDA approval, this study represents a potential practice-changing result,” said Dr. Dennis Slamon, director of the Revlon/UCLA Women’s Cancer Research Program and director of clinical and translational research at the Jonsson Cancer Center. “I believe palbociclib will now become a standard treatment approach for postmenopausal women with ER+/HER2- metastatic breast cancer.”

Developing Ibrance

The research originated in 2007, when Finn and Slamon met with Pfizer to discuss palbociclib and other experimental drugs in the company’s pipeline.

In preclinical trials, the drug showed encouraging results against human breast cancer cells in culture dishes — and specifically against ER+ cancer cells. This led to a clinical study collaboration with Pfizer led by Finn and Slamon built on work at the Jonsson Cancer Center’s Translational Oncology Research Laboratory.

A phase 2 study evaluated the drug in 165 post-menopausal women with advanced ER+/HER2- breast cancer who had not received prior systemic therapy for their metastatic disease. It showed progression-free survival was 20.2 months for patients who received palbociclib plus letrozole, compared with 10.2 months for those who received the letrozole alone. The results also indicated a 51 percent reduction in the risk of disease progression when palbociclib was used with letrozole.

“What is really remarkable is that we doubled the median progression-free survival,” Finn said. “That type of result is not often seen in cancer medicine.”

Over 80 percent of the women in the study with metastatic ER+ breast cancer received some benefit from the treatment. The drug’s safety profile is distinct from traditional chemotherapy, but it does result in a lowered white blood cell count, which is manageable.

A phase three international clinical trial of the drug conducted by Finn and Slamon with Pfizer in approximately 660 people with advanced ER+/HER2- breast cancer has been completely enrolled.

Survivor stories

Janet Klein was first diagnosed with stage 1 ER+ breast cancer in 2004, and she decided to undergo a double mastectomy. A few years later, doctors discovered that the breast cancer had returned as metastatic disease in her bones.

Dr. Sara Hurvitz, a UCLA oncologist and member of the Jonsson Cancer Center, told Klein about the clinical trial at UCLA. Klein enrolled and was prescribed Ibrance in combination with an anti-estrogen treatment. Nine months later, her scans showed no evidence of the cancer.

“I had a large party with a lot of champagne,” she said. “It was life-changing but in a good way.” said Klein.

Klein, now 59, said the FDA approval was cause for more celebration. “Sixty percent of all women diagnosed with this disease have my variety, and this drug having this sort of an impact, so fast and so effectively, is earth shattering.”

Gloria Zollar, 78, joined the phase two clinical trial in 2010 after her UCLA oncologist discovered that her advanced breast cancer had spread to her bones. She has been on treatment since that then.

But after only a year of treatment, doctors noticed that Zollar’s tumors had stopped progressing — allowing her to remain active and continue playing golf.

“I am now in remission, and every day I’m thankful to God that I’m alive and able to see my great-grandchildren and spend time with them,” Zollar said.

She also is excited that the drug is now available to other women. “I am very pleased that other women could have a second chance at life like many of us who participated in the trial,” Zollar said.

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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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Researchers produce first comprehensive genomic map of head, neck cancers

Effort is the product of The Cancer Genome Atlas.

By Scott LaFee, UC San Diego

A team that includes scores of researchers from across the country representing dozens of universities and medical institutions has produced the most comprehensive integrative analysis yet of head and neck squamous cell carcinomas (HNSCCs), a particularly malignant and deadly type of tumor that accounts for roughly 3 percent of all cancers in the United States.

The study, published in today’s (Jan. 29) issue of Nature, is the product of The Cancer Genome Atlas (TCGA), a federally funded project to identify and catalog errors in DNA that cause cells to grow uncontrollably, resulting in at least 200 forms of cancer and many more subtypes.

Scott M. Lippman, M.D., director of the UC San Diego Moores Cancer Center, and Ezra Cohen, M.D., professor and associate director for translational science at Moores Cancer Center, are members of the network.

The vast majority of head and neck cancers begin in the squamous cells that line the moist surfaces of the mouth, throat, larynx (voicebox), nasal cavities and salivary glands. Symptoms include lumps that do not disappear, a persistent sore throat, difficulty swallowing or a change in voice.

Men are more than twice as likely to develop a HNSCC as women. An estimated 52,000 Americans are diagnosed each year. Worldwide, HNSCCs affect more than 600,000 patients per year. Alcohol and tobacco use are considered the two most important risk factors. Smoking is implicated in the rise of HNSCCs in developing countries; the role of human papillomavirus (HPV) has emerged as an important risk factor affecting non-smokers.

HNSCCs are deadly. Despite surgery, radiation and chemotherapy, roughly half of all patients die of the disease, usually within two years of initial diagnosis. Except for HPV status, investigations of various molecular and clinical risk factors have produced limited clinical benefit.

Past genome-wide profiling of HNSCC cases has been limited in scope and detail. Researchers with TCGA sought to create a much more comprehensive picture of molecular alterations associated with the disease, one that could help direct future treatments.

“Treatment at a comprehensive cancer center would offer potential advantages, including the ability to detect molecular alteration with accuracy and availability of novel therapies in clinical trials that can be personalized to a person’s cancer but not yet approved,” said Cohen.

The scientists profiled 279 patients with HNSCCs (with the ultimate goal of characterizing 500 patients with tumors). They found that HPV-associated tumors were dominated by specific mutations and molecular alterations that differed from those linked to smoking-related HNSCCs. Other subgroups of tumors were connected to other specific mutations or losses of cellular function.

The findings have clinical import. In most of the HNSCCs studied, the researchers identified therapeutic candidate alterations. That is, by correcting targeted mutations, they said it might be possible to improve treatments of diverse HNSCCs or possibly prevent them altogether.

“The next steps are to understand more comprehensively which molecular alterations affect prognosis,” said Cohen, “and more importantly, how to best treat patients whose tumors harbor these mutations. These are challenges currently being addressed at Moores Cancer Center.”

Co-authors are all members or affiliates of The Cancer Genome Atlas.

Funding for this research came, in part, from the National Institutes of Health (grants P50CA097190, P50CA16672, U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025 and RO1 CA 095419), the Bobby F. Garrett Fund for Head and Neck Cancer Research and the National Institute on Deafness and other Communication Disorders (Intramural Projects ZIA-DC-000016, 73 and 74).

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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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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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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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