Three years ago, the federal government set a series of targets to improve Americans’ overall health. Among the dozens of goals laid out in the plan, called

That, in turn, would enable more people to catch cervical cancer early, .����

New research from the ����Ӱ�Ӵ�ý and the (KPWHRI) found that the simplest solution may also be the most effective: mailing test kits directly to patients’ homes. In a study, researchers report that mailing test kits significantly increased cervical cancer screening rates, both in populations overdue for screening and those who had previously kept up to date. ��

The home test kits detect the presence of the human papillomavirus (HPV), which causes most cervical cancers. And a negative HPV test counts as a negative cervical cancer screening, allowing most people to avoid a clinic visit altogether. Currently, more than half of all cervical cancers diagnosed in the United States are in people who are overdue for screening or have never been screened. The team behind this study believes at-home testing can help close the gap.��

“This is an alternative, patient-centered way to get people screened for cervical cancer, because patients tend to prefer testing at home and not having to come into the clinic,” said , a UW professor of epidemiology who led the research. “This is a strategy that other countries are already using, and there’s overwhelming evidence that an HPV test on a patient-collected sample is to an HPV test on a sample collected by a clinician. So there’s really no reason why this shouldn’t be available in the U.S.” ��

In partnership with Kaiser Permanente Washington, researchers enrolled more than 31,000 female patients between the ages of 30-64 who were either due or overdue for screening, or whose screening history was unknown. Depending on their screening history, patients were randomly sorted into four groups: One group had HPV test kits mailed directly to participants’ homes, another received information on how to request a test kit, and another received an educational brochure on cervical cancer screening. The fourth group received only a standard reminder that participants were due for screening.

Over the next six months, 62% of people who were due for screening and 36% of people who were overdue were screened for cervical cancer after being directly mailed a kit. Those percentages fell to 48% and 19%, respectively, among patients who received only the educational brochure. Sending information on requesting a kit minimally increased screening.����

The results, Winer said, indicate that healthcare systems should prioritize mailing HPV test kits directly to patients to maximize cervical cancer screening participation.����

“We just think this should be an option for all patients,” Winer said. “It’s convenient, preferred by most patients and an accurate way to screen for cervical cancer. So why not have it as an option?”��

This study builds on previous research conducted by Winer and her colleagues, which found that mailing HPV test kits to under–screened patients increased screening rates, though most people remained untested. That study took place before the cervical cancer screening guidelines were updated to include HPV testing alone, so the test kit did not count as a regular screen.������

Self-testing is already an option for other routine screenings, most notably for colorectal cancer. The most recent guidelines encourage home test kits as a primary screening option, suggesting that annual stool samples may be taken in place of a routine colonoscopy, which many patients find uncomfortable. Home test kits are now so commonplace that Saturday Night Live has parodied the ubiquitous TV commercials for one prominent manufacturer.����

Colorectal screening rates have in recent years. ��

There are still significant barriers to overcome before HPV self-sampling can become widely available, Winer said. Chief among them is approval by the Food and Drug Administration, which is expected to come in the next few months.��

Once HPV self-sampling receives FDA approval for use as a cervical cancer screening tool, healthcare systems that want to implement self-screening need to procure test kits, review their policies and educate both patients and providers. Algorithms used to track patients’ care have to be updated. Health centers serving low-income and marginalized communities may not have the staff or financial resources to distribute test kits. Patients without a primary care physician may slip through the cracks

“HPV self-sampling is a tool certainly designed to increase access and reduce disparities,” Winer said. “But sometimes when a new intervention is introduced, it can further widen disparities if there isn’t attention taken to how to best implement it, or how to specifically make sure that it reaches people who need it the most.”��

This research was co-led by , a senior investigator at KPWHRI. Other authors include John Lin, research coordinator in the UW Department of Epidemiology; Melissa Anderson and Kristina Hansen from KPWHRI; Jasmin Tiro and Hongyuan Gao from the University of Chicago; Richard Meenan from the Kaiser Permanente Center for Health Research; Angela Sparks from UnitedHealthcare; and Diana Buist of GRAIL LLC in Menlo Park, Calif. This research was funded by the National Cancer Institute.��

For more information, contact Winer at rlw@uw.edu.����

Nanoparticles are a promising type of drug delivery system. Also known as nanocarriers, these tiny particles can bind to drugs and protect them from degradation until they enter tumor cells. But their effectiveness as drug carriers and drug protectors, as well as potential toxicity in patients, depends significantly on their size, composition and chemical properties. Balancing these competing factors is a delicate process. Although researchers have made significant advances in nanomedicine in the last decade, it remained a formidable challenge to design and synthesize small, stable nanoparticles that could deliver sufficient drugs to treat solid tumors.

Earlier this year scientists at the ����Ӱ�Ӵ�ý announced that they have achieved such a balancing act with a nanoparticle-based drug delivery system that can ferry a potent anti-cancer drug through the bloodstream safely. As they report in a published in May in Materials Today, their nanoparticle is derived from , a natural and organic polymer that, among other things, makes up the outer shells of shrimp.

The team, led by , a UW professor of materials science and engineering and of neurological surgery, demonstrated that their chitin-derived system can successfully ferry , a potent anti-cancer drug that is also known as paclitaxel, through the bloodstream and inhibit tumor growth and spread, also known as metastasis, in mice. The nanoparticles showed no adverse side effects, likely since they are derived in part from naturally occurring polymer.

“This could form the basis of a new class of nanoparticle delivery systems that can transport anti-cancer therapeutics through the body safely, with no toxic side effects from the nanoparticle material,” said Zhang, who is also a faculty researcher with the UW and the .

The nanoparticles, once loaded with Taxol, are about 20.6 nanometers in diameter. That’s about 1/4000th the width of a human hair, the U.S. National Nanotechnology Initiative. The particles are small enough to travel through blood vessels and get to potentially compact tumor sites.

Zhang’s team started by loading Taxol particles onto much longer strands of , a material derived from chitin. The nanofibers break down to form nanoparticles when exposed to serum, a blood protein, either in the lab or in the body. Researchers showed that drug-loaded nanofibers, when injected into mice, broke down rapidly into the tiny nanoparticles — thanks to serum proteins in the blood — and could circulate freely in the bloodstream, enter organs and reach tumor sites.

The team subjected Taxol-loaded nanoparticles to a barrage of experiments to see what they could do to tumors. In cell cultures of mouse mammary cancer cells, a majority of cancer cells showed signs of cell death 48 hours after treatment, indicating that nanoparticle-associated Taxol could enter cancer cells and impair cell growth at least as well as free-floating Taxol. In mice, Taxol-loaded nanofibers, which broke down into nanoparticles, showed 90% inhibition of mammary tumor growth compared to about 66% inhibition for Taxol injected in the clinical solution used widely today. The nanoparticles also inhibited melanoma tumor growth in mice by up to 75%. In separate experiments in mice, Taxol-loaded nanoparticles also prevented spread of mammary cancer to other parts of the body, unlike Taxol in a clinical solution.

In addition to these promising findings with tumors, the team found that the nanoparticles kept Taxol circulating in the bloodstream longer, giving the drug more time to reach the tumor site. In the bloodstream of mice, the half-life of Taxol-associated nanoparticles was nearly 25 hours, compared to less than 2 hours for Taxol injected in the clinical solution. Mice injected with the nanofibers showed no signs of toxic side effects, indicating that the nanoparticles themselves weren’t causing harm to tissues. In contrast, the clinical solution used widely today for Taxol can cause liver toxicity in mice, among other side effects.

Zhang believes that the chitosan-derived nanoparticles could form the basis of a non-toxic drug delivery system for cancer that keeps therapeutics in the body longer to inhibit tumor growth and metastasis.

“This is a very promising finding. Many drug delivery systems used today for anti-cancer drugs come with toxic side effects, and don’t protect the drug for very long in the patient’s body,” said Zhang. “The nanoparticles have all the characteristics you could hope for in getting the drug to into tumor cells. The small chitosan-based nanocarrier, made in situ, with unique biocompatibility and biodegradability, offers a new strategy for anti-cancer drug delivery and has great potential for rapid translation to the clinic.”

Co-authors on the paper are Qingxin Mu, Guanyou Lin, Zachary Stephen, Seokhwan Chung and Hui Wang in the UW Department of Materials Science & Engineering; Victoria Patton in the UW Department of Chemical Engineering; and Rachel Gebhart in the UW Department of Chemistry. The research was funded by the National Institutes of Health and the National Science Foundation.

For more information, contact Zhang at mzhang@uw.edu.

In patients with chronic lymphocytic leukemia (CLL), the rate of disease growth varies widely. In a new study from the Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, Massachusetts General Hospital and the ����Ӱ�Ӵ�ý, scientists report that CLL growth is apt to follow one of three trajectories: relentlessly upward, steadily level or something in between. The particular course the disease takes is tightly linked to the genetic makeup of the cancer cells, particularly the number of growth-spurring “driver” mutations they contain.

The , published online May 29 in the journal , contains a further insight: Genetic changes that occur very early in CLL development exert a powerful influence on the growth pattern the CLL cells will ultimately take. This raises the possibility that physicians may one day be able to predict the course of the disease by its molecular features at the time of diagnosis.

“Our findings provide a framework not only for understanding the differing patterns of CLL growth in patients but also for exploring the basic biological mechanisms that underlie these differences,” said Dr. of Dana-Farber, the Broad Institute and Brigham and Women’s Hospital, who is co-corresponding author with of the Broad Institute and Massachusetts General Hospital. “Ultimately, we’d like to be able to tie the genotype of the disease — the particular genetic abnormalities in a patient’s cancer cells — to its phenotype, or how the cancer actually behaves.”

CLL is a useful model for studying the pace of cancer growth because it progresses at widely different rates from one patient to another, said Wu. In many patients, it persists at a low level for many years before advancing to the point where treatment is necessary. In others, it progresses so rapidly that treatment is required shortly after diagnosis.

To see if there were different patterns of CLL growth among patients, researchers drew on data from 107 patients diagnosed with the disease. Beginning at diagnosis, each patient underwent periodic blood tests to track disease progress over the succeeding months and years, and continued until the disease reached a stage where treatment would begin. Each test consisted of a white blood cell count, which served as a proxy measure of CLL: the greater the number of white cells within a blood sample, the greater the burden of the disease. The tests were conducted over a period ranging from two years in one patient to 19 years in another.

The serial testing allowed researchers to calculate growth rates over time for CLL in each patient. They used a statistical model to determine if the rates were consistent with various patterns of cancer growth.

“We found that some cases of CLL show exponential growth, in which it expands without any apparent limit, while other cases show ‘logistic’ growth, in which it plateaus at a fairly consistent level,” said co-lead author , a UW assistant professor of applied mathematics.

Cases that didn’t fit either category were classified as indeterminate.

To explore whether genetic differences were at the root of these divergent growth patterns, the researchers performed whole-exome sequencing on several CLL samples collected from each patient prior to receiving therapy. Whole-exome sequencing provides a letter-by-letter readout of the regions of DNA that encode for cellular proteins.

They found that exponentially growing CLL typically carried a large number of driver mutations — those that confer a competitive advantage in growth — and quickly reached the stage where treatment was called for. In contrast, logistically growing CLL had fewer genetic alterations and fewer types of alterations and progressed relatively slowly toward the level that requires treatment. Seventy-five percent of patients with exponential growth eventually warranted treatment; by comparison, 21% of those with logistic growth and 67% of those with indeterminate growth eventually required treatment.

By analyzing patients’ serial blood samples collected over a period of time, researchers found that exponential CLL not only grows faster but also evolves faster, spinning off new subtypes of cancer cells, each with a particular set of genetic abnormalities. Whole-exome sequencing revealed that exponential CLL is marked by a great variety of tumor cell types and subtypes, while logistic CLL is marked by a relatively less diverse collection of tumor cells.

The information from whole-exome sequencing further enabled researchers to discover the growth rates of those subpopulations of cells within each patient’s leukemia that could be identified on the basis of a subset of mutations, some of them putative driver mutations. These measurements clearly revealed that many of the mutations, which were suspected to be centrally involved in CLL growth, did in fact provide subpopulations with preferential growth acceleration compared to populations lacking these putative drivers. Their results further indicate that the eventual course of CLL growth is inscribed in the genes of tumor cells early in the disease’s development.

“If the course of the disease isn’t altered by therapeutic treatment, the rate and pattern of CLL growth over time seems to ‘play out’ according to a predetermined set of genetic instructions,” said Wu.

“The discovery that CLL growth accelerates in the presence of large numbers of driver mutations is compelling evidence that these mutations do, in fact, confer a growth advantage to cells — that they truly do ‘drive’ the disease,” said co-lead author Dr. of Dana-Farber, the Broad Institute and the Medical University of Vienna.

Bozic and co-lead authors and at the Broad Institute developed methods to jointly model possible phylogenetic relationships of cancer cell subpopulations — which are a description of each subpopulation’s history and relationships to each other during the evolution of the cancer — as well as integrate growth rates with subclone-specific genetic information.

“Combining clinical data with computational and mathematical modeling, we show that the growth of many CLLs seems to follow specific mathematical equations — exponential and logistic — each associated with distinct underlying genetics and clinical outcomes,” said Bozic. “Integrating tumor burden and whole-exome sequencing data allowed us to quantify the growth rates of different tumor subpopulations in individual CLLs, methodology that could potentially inform personalized therapy in the future.”

Co-authors of the study are: Kristen Stevenson, Oriol Olive, Reaha Goyetche, Stacey M. Fernandes, Jing Sun, Wandi Zhang and Donna Neuberg of Dana-Farber; Dr. Jennifer R. Brown of Dana-Farber and Brigham and Women’s Hospital; Laura Rassenti and Dr. Thomas J. Kipps of the Moores Cancer Center at the University of California, San Diego; Daniel Rosebrock, Amaro Taylor-Weiner, Chip Stewart, Alicia Wong and Carrie Cibulskis of the Broad Institute; Johannes G. Reiter, Jeffrey M. Gerold and Martin A. Nowak of Harvard University; Dr. John G. Gribben of the Barts Cancer Institute at the University of London; Dr. Kanti R. Rai of Hofstra North Shore-LIJ School of Medicine; and Michael J. Keating of the MD Anderson Cancer Center.

The study funded by the National Cancer Institute; the CLL Global Research Foundation; the National Heart, Lung, and Blood Institute; the European Union; and the Leukemia and Lymphoma Society.

###

For more information, contact Bozic at ibozic@uw.edu.

Grant numbers: 5P01CA081534-14, 1R01CA155010-01A1, P01CA206978, U10CA180861, 1RO1HL103532-0, PIOF-2013-624924

Adapted from a by the Dana-Farber Cancer Institute.

Prepared by and with the ����Ӱ�Ӵ�ý and the Burke Museum of Natural History & Culture. ����Ӱ�Ӵ�ý press release .

Major findings

demonstrates that this type of tumor has existed for at least 255 million years and predates mammals.

Frequently Asked Questions

What are gorgonopsians?

• Gorgonopsians were a group of carnivorous, land-based vertebrates that lived between about 270 to 252 million years ago during the middle and late Permian Period. Their fossils are known from Africa and Russia.
• Gorgonopsians are distantly related to living mammals, but they lie “on the mammalian line,” meaning that they are more closely related to humans than to dinosaurs or other reptiles.
• Gorgonopsians ranged in body size from 2 to 10 feet long, from the length of a bobcat to that of a polar bear.
• Gorgonopsians are sometimes known as the “saber-tooths of the Permian,” for their enlarged canine teeth.

What is an odontoma?

• The World Health Organization defines a compound odontoma as: “A malformation in which all the dental tissues are represented in a more orderly pattern than in the complex odontoma, so that the lesion consists of many tooth-like structures. Most of these structures do not morphologically resemble the teeth of the normal dentition, but in each one enamel, dentine, cementum and pulp are arranged as in the normal tooth.”
• Odontomas are one of the most common odontogenic tumors, constituting approximately 20 percent of odontogenic tumors. Ameloblastoma is the most common with 39.6 percent of odontogenic tumors.
• Odontomas are not cancer. They are considered benign tumors, though in humans they are often surgically removed.

Where was this specimen found?

• The gorgonopsian jaw with the odontoma was found in southern Tanzania in the Ruhuhu Valley in 2007.
• The specimen is about 255 million years old, based on dating of similar fossils in South Africa.

How did we find this pathology?

• There were no external indications of a pathology. We were thin-sectioning this specimen for an entirely different project —examining the tissues involved in tooth attachment.
• UW undergraduate researcher Larry Mose noticed a pathology along the root of the canine only after the specimen had been cut.

What is thin-sectioning?

• We make thin-sections of fossil bones and teeth so that we can study the fine, inner details of their hard tissues. These small details act as storybooks, preserving a lot of information about the biology of these animals while they were alive. As is easy to imagine, studying the biology of animals that lived millions of years ago can be challenging. We use the microstructure of fossil hard tissues to reveal aspects of their biology like growth rate, age and disease that otherwise would be inaccessible for us to study in these ancient animals.

Has an odontoma been found in the fossil record before?

• This is not the first time an odontoma has been reported in the fossil record. Previous instances include:
  • A Woolly mammoth from the Netherlands from the last glacial age, known as the Weichsel Glacial in Northern Europe, ca. 115,000-10,000 B.C.
  • Fossil red deer from France from 12,200-11,400 B.C.
  • Several recorded instances in archaeological material.
• All reported instances, however, are relatively recent in the history of life on earth —to within the last 1 million years or so.

Is this the oldest occurrence of tumors in the fossil record?

• There is a decisive case of cancer reported in a lower Carboniferous fish (300 million years ago), and a possible case of cancer in fossil fish from the Devonian (350 million years ago).
• But this is the oldest reported case of an odontoma. See above question.

How do teeth form?

• Teeth are derived from two major tissue layers, the outer epithelial layer that gives rise to enamel and an ectomesenchyme layer that gives rise to dentine and pulp.
• Odontomas arise when there are developmental anomalies involving both the epithelial and ectomesenchymal tissues. These anomalies give rise to tooth-like structures that have enamel, cementum, dentine and pulp in their normal anatomical relationships.

What did we learn? What are the implications?

• This is the oldest occurrence of odontoma in a mammal relative. Odontoma has remained relatively unchanged for 255 million years.
• Paleontology can contribute to medicine by shedding light on the history of disease.

Acknowledgements

• Laurent Nampunju and Anthony Tibaijuka (Antiquities Division, Ministry of Natural Resources and Tourism) for assistance with fieldwork in Tanzania.
• Field team for helping to collect the fossil (Ken Angielczyk, Sterling Nesbitt, Roger Smith, Linda Tsuji).
• Oral Biology group at the ����Ӱ�Ӵ�ý for helpful discussions.
• Royal Ontario Museum histology lab for use of thin section and imaging equipment.

Grant support

• National Geographic Society (NGS 7787-05) to C. Sidor (for fieldwork to collect fossils)
• National Science Foundation (DBI 0306158) to Ken Angielczyk, Field Museum of Natural History, Chicago (for fieldwork to collect fossils)
• National Science Foundation (EAR 1337569) to C. Sidor (for research and analysis)

For additional information, contact Christian Sidor at casidor@uw.edu and Megan Whitney at megwhit@uw.edu. ����Ӱ�Ӵ�ý press release .

When paleontologists at the ����Ӱ�Ӵ�ý cut into the fossilized jaw of a distant mammal relative, they got more than they bargained for —��more teeth, to be specific.

As they report in published Dec. 8 in the , the team discovered evidence that the extinct species harbored a benign tumor made up of miniature, tooth-like structures. Known as a , this type of tumor is common to mammals today. But this animal lived 255 million years ago, before mammals even existed.

“We think this is by far the oldest known instance of a compound odontoma,” said senior author , a UW professor of biology and curator of vertebrate paleontology at the . “It would indicate that this is an ancient type of tumor.”

Before this discovery, the earliest known evidence of odontomas came from Ice Age-era fossils.

“Until now, the earliest known occurrence of this tumor was about one million years ago, in fossil mammals,” said Judy Skog, program director in the ‘s , which funded the research.�� “These researchers have found an example in the ancestors of mammals that lived 255 million years ago.��The discovery suggests that the suspected cause of an odontoma isn’t tied solely to traits in modern species, as had been thought.”

In humans and other mammals, a compound odontoma is a mass of small “toothlets” amalgamated together along with tooth tissues like dentin and enamel. They grow within the gums or other soft tissues of the jaw and can cause pain and swelling, as well as disrupt the position of teeth and other tissues. Since odontomas do not metastasize and spread throughout the body, they are considered benign tumors. But given the disruptions they cause, surgeons often opt to remove them.

Surgery was not an option for the creature studied by Sidor’s team. It was a , a distant mammal relative and the apex predator during its pre-dinosaur era about 255 million years ago. Gorgonopsians are part of a larger group of animals called , which includes modern mammals as its only living member. Synapsids are sometimes called “mammal-like reptiles” because extinct synapsids possess some, but not all, of the features of mammals. The first mammals evolved over 100 million years ago.

“Most synapsids are extinct, and we —��that is, mammals —��are their only living descendants,” said , lead author and UW biology graduate student. “To understand when and how our mammalian features evolved, we have to study fossils of synapsids like the gorgonopsians.”

Paleontologists have categorized many “mammal-like” features of gorgonopsians. For example, like us, they have teeth differentiated for specialized purposes. But Whitney started studying gorgonopsian teeth to see if they had another mammalian feature.

“Most reptiles alive today fuse their teeth directly to the jawbone,” said Whitney. “But mammals do not: We use tough, but flexible, string-like tissues to hold teeth in their sockets. And I wanted to know if the same was true for gorgonopsians.”

A purely external examination of gorgonopsian fossils wouldn’t answer this question. Whitney had to take the risky and controversial approach of slicing into a fossilized gorgonopsian jaw: looking at thin sections of jaw and tooth under a microscope to see how the tooth was nestled within its socket. Since this technique would damage the fossil, Whitney and Larry Mose, a UW undergraduate student working with her, used a solitary or “orphan” gorgonopsian lower jaw that Sidor had collected in southern Tanzania.

Mose prepared multiple thin slices from the gorgonopsian jaw —��each only about as thick as a sheet of notebook paper —��and mounted them onto slides. He and Whitney immediately noticed something unexpected within the jaw: embedded next to the root of the canine were irregular clusters of up to eight tiny, round objects.

At higher magnification under a microscope, Whitney discovered that the objects within each cluster resembled small, poorly differentiated teeth, or toothlets. The toothlets even harbored distinct layers of dentin and enamel.

“At first we didn’t know what to make of it,” said Whitney. “But after some investigation we realized this gorgonopsian had what looks like a textbook compound odontoma.”

At 255 million years, this is by far the oldest reported evidence for an odontoma —��and possibly the first case in a non-mammal. According to Sidor, odontomas have been reported in archaeological specimens, as well as fossilized mammoths and deer. But those cases all date to within the last million years or so. Since this synapsid had an odontoma, it would indicate that this mammalian condition existed well before the first mammals had evolved.

“This discovery demonstrates how the fossil record can tell us a lot about our present-day lives —��even the diseases or pathologies that are part of our mammalian heritage,” said Sidor. “And you could never tell that this creature had it from the outside.”

The research was funded by the National Science Foundation and a ����Ӱ�Ӵ�ý Mary Gates Research Fellowship.

###

For more information, contact Sidor at casidor@uw.edu and Whitney at megwhit@uw.edu. Sidor and Whitney have also prepared answers to a list of frequently asked questions, which can be found , regarding gorgonopsians, tooth development, odontomas and more.

Grant number: NSF EAR-1337569.

But in published Sept. 27 in the journal , scientists at the ����Ӱ�Ӵ�ý describe a new system to encase chemotherapy drugs within tiny, synthetic “” packages, which could be injected into patients and disassembled at the tumor site to release their toxic cargo.

The group, led by UW professor of materials science and engineering , is not the first to work on nanocarriers. But the nanocarrier package developed by Zhang’s team is a hybrid of synthetic materials, which gives the nanocarrier the unique ability to ferry not just drugs, but also tiny fluorescent or magnetic particles to stain the tumor and make it visible to surgeons.

“Our nanocarrier system is really a hybrid addressing two needs — drug delivery and tumor imaging,” said Zhang, who is senior author on the paper. “First, this nanocarrier can deliver chemotherapy drugs and release them in the tumor area, which spares healthy tissue from toxic side effects. Second, we load the nanocarrier with materials to help doctors visualize the tumor, either using a microscope or by MRI scan.”

Their hybrid nanocarrier builds on years of research into the types of synthetic materials that could package drugs for delivery into a specific part of a patient’s body. In previous attempts, scientists would often first try make an empty nanocarrier out of a synthetic material. Once assembled, they would load the nanocarrier with a therapeutic drug. But this approach was inefficient, and carried a high risk of damaging the fragile drugs and rendering them ineffective.

“Most chemotherapy drugs have complex structures — essentially, they’re very fragile — and they do no good if they are broken by the time they reach the tumor,” said Zhang.

Zhang’s team worked around this problem by designing a nanocarrier that could be assembled and loaded simultaneously. Their approach is akin to laying cargo within a shipping container even as the container’s walls, floor and roof are being assembled and bolted together.

This “load during assembly” technique also let Zhang’s team incorporate multiple chemical components into the nanocarrier’s structure, which could help hold cargo in place and make the tumor easy to image in clinical settings.

Their nanocarrier sports a core of iron oxide, which provides structure but can also be used as an imaging agent in MRI scans. A shell of silica surrounds the core, and was designed to efficiently stack the chemotherapy drug . They also included space in the nanocarrier for carbon dots, tiny particles that can “stain” tissue and make it easier to see under a microscope, helping doctors resolve the boundaries between cancerous and healthy tissue for further treatment or surgery. The intensity of many imaging agents fades over time, but Zhang said this nanocarrier can provide sustained imaging for months.

Yet despite holding so much cargo, the fully loaded nanocarriers are less than the thickness of a sheet of flimsy notebook paper.

The silica shell keeps the nanocarriers watertight. In addition, they do not interfere with healthy tissue, as Zhang’s team showed by injecting healthy mice with empty nanocarriers or nanocarriers loaded with drug cargo. Five days after injection, they checked vital organs in the mice for evidence of toxicity and found none.

“This would indicate that the nanocarriers themselves do not trigger an adverse reaction in the body, and that the loaded nanocarriers are keeping their toxic cargo shielded from the body,” said Zhang.

The UW team also designed the nanocarriers to be easily disassembled once they reached a desired location. Gentle heating from low-level infrared light was sufficient to make the nanocarriers break apart and disgorge their cargo, which is something doctors could apply to the tumor site during treatment.

As their final test of the nanocarrier effectiveness, Zhang’s team turned to mice with a form of transmissible cancer. Mice that they injected with empty nanocarriers showed no reduction in tumor size. But tumors shrank significantly in mice injected with nanocarriers that were loaded with paclitaxel. They saw a similar affect on human cancer cells cultured and tested in the lab.

“These results show that the nanocarriers can deliver their cargo intact to the tumor site,” said Zhang. “And while we designed this nanocarrier specifically to accommodate paclitaxel, it is possible to adjust this technique for other drugs.”

There are still mountains to climb before this technology is proven safe and effective for humans. But Zhang hopes her team’s approach and promising results will accelerate the ascent.

Lead authors on the paper are Hui Wang and Kui Wang in the UW Department of Materials Science & Engineering. Co-authors are Bowei Tian in the UW Department of Applied Mathematics and Richard Revia, Qingxin Mu, Mike Jeon, Fei-Chien Chang — all in the Department of Materials Science & Engineering. The research was funded by the National Institutes of Health and the ����Ӱ�Ӵ�ý.

###

For more information, contact Zhang at mzhang@uw.edu or 206-616-9356.

Grant number: R01CA161953.

Building on this basic knowledge, the search is underway for cellular mechanisms that could serve as gateways for new therapies. These could lead to precise treatments for disease — targeting a specific cellular function or gene with fewer unintended side effects. Ideally, these effects would also be temporary, returning cells to normal operation once the underlying condition has been treated.

A team of researchers from the ����Ӱ�Ӵ�ý and the University of Trento in Italy announced findings that could pave the way for these therapies. In a paper July 18 in , they unveiled an engineered protein that they designed to repress a specific cancer-promoting message within cells.

And that approach to protein design could be modified to target other cellular messages and functions, said senior author and UW chemistry professor .

“What we show here is a proving ground — a process to determine how to make the correct changes to proteins,” he said.

For their approach, Varani and his team modified a human protein called Rbfox2, which occurs naturally in cells and binds to microRNAs. These aptly named small RNA molecules adjust gene expression levels in cells like a dimmer switch. Varani’s group sought to engineer Rbfox2 to bind itself to a specific microRNA called miR-21, which is present in high levels in many tumors, increases the expression of cancer-promoting genes and decreases cancer suppressors. If a protein like Rbfox2 could bind to miR-21, the researchers hypothesized, it could repress miR-21’s tumor growth effects.

But for this approach to be successful, the protein must bind to miR-21 and no other microRNA. Luckily, all RNA molecules, including microRNAs, have an inherent property that imbues them with specificity. They consist of a chain of chemical “letters,” each with a unique order or sequence. To date, no other research team had ever successfully altered a protein to bind to microRNAs.

“That is because our knowledge of protein structure is much better than our knowledge of RNA structure,” said Varani. “We historically lacked key information about how RNA folds up and how proteins bind RNA at the atomic level.”

UW researchers relied on high-quality data on Rbfox2’s structure to understand, down to single atoms, how it binds to the unique sequence of “letters” in its natural RNA targets. Then they predicted how Rbfox2’s sequence would have to change to make it bind to miR-21 instead. Elegantly, altering just four carefully selected amino acids made Rbfox2 shift its attachment preference to miR-21, preventing the microRNA from passing along its tumor-promoting message.

The UW team spent several years proving this, since they had to test each change individually and in combination. They also had to make sure that the modified Rbfox2 protein would bind strongly to miR-21 but not other microRNAs. Since microRNAs have many functions in cells, it would be counterproductive to repress miR-21 while disrupting other normal microRNA-mediated functions.

The researchers also engineered a second protein that should clear miR-21 from cells entirely. They did this by grafting the regions of Rbfox2 that bound to miR-21 onto a separate protein called Dicer. Dicer normally chops RNAs into small chunks and generates functional microRNAs. But the hybrid Rbfox2-Dicer protein displayed a specific affinity to slice miR-21 into oblivion.

Varani and his team believe that Rbfox2 could be redesigned to bind to microRNA targets other than miR-21. There are thousands of microRNAs to choose from, and many have been implicated in diseases. The key to realizing this potential would be in streamlining and automating the painstaking methods the team used to model Rbfox2’s atomic-level interactions with RNA.

“This method relies on knowledge of high-quality structures,” said Varani. “That allowed us to see which alterations would change binding to the microRNA target.”

Not only would these be useful laboratory tools to study microRNA functions, but they could — in time — form the basis of new therapies to treat disease.

Lead author on the paper is former UW researcher Yu Chen, who is now at the Seattle Children’s Research Institute. Other UW chemistry co-authors were Fang Yang, Tom Pavelitz, Wen Yang, Katherine Godin, Matthew Walker and Suxin Zheng. Co-authors from the University of Trento include Lorena Zubovic and Paolo Macchi. The research was funded by the National Institutes of Health, the University of Trento and the government of Trento province.

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For more information, contact Varani at 206-543-7113 or varani@chem.washington.edu.

Grant number: R01-GM103834.

Sarah Lien was 24 when she was diagnosed with breast cancer, yet she was not unprepared for the news.

She had spent six years going from doctor to doctor to ask about being tested for cancer. They all told her she was too young to worry about it.

Lien suspected otherwise. Ever since she learned that her mother, UW School of Nursing alumna Barbara Hawkins, was first diagnosed with breast cancer at age 37, Lien wondered what her own chances were for getting cancer at a young age.

She found out in March 2010, after feeling a lump in her right breast during a self-exam. She received her first mammogram the next day, and shortly after was diagnosed with stage 3 breast cancer.

Lien learned at the that she has the BRCA2 breast cancer gene, inherited from her father’s side of the family. (Her mother and sister subsequently tested negative for the gene.) Several doctors she saw recommended a mastectomy, but were focused only on eradicating the cancer.

“Doctors told me that I couldn’t worry about my fertility or appearance, that I should only be concerned with longevity of life, but as a newly married woman who wants four children, I was concerned about those things,” Lien said. “I felt that no one knew what to do with a woman in her 20s asking about cancer.”

She became the patient of Dr. Kristine Calhoun, a surgeon and breast specialist, and Dr. David Mathes, a plastic surgeon At UW Medical Center and the . ��Calhoun is a UW associate professor of surgery in the Division of General Surgery, and Mathes is a UW associate professor of surgery, Division of Plastic Surgery.

After discussing treatment options with them at the SCCA , Lien opted for bilateral mastectomies, which is the removal of both breasts.

“The bilateral mastectomies made sense based on Sarah’s family history of breast cancer,” Calhoun said. “I supported her decision, and was struck by her desire to maintain her fertility. She was very, very upfront about her desire to have children. She wanted to do everything possible to beat her cancer so she could achieve that goal.”

Mathes likewise listened to Lien’s concerns about how her body would look after surgery. He told her he would do his best to rebuild her breasts the way she wanted.

“Honestly, I just wanted to look great in a bikini, and I wanted to feel comfortable with my body,” Lien said. “I’m extremely happy with the results.”

Lien remained optimistic throughout her experience. She said that she modeled her mother’s approach to overcoming the disease.

Their cancer journeys are interwoven. Hawkins was diagnosed with breast cancer again in 2008, and for a third time in 2010, after which she chose to have a double mastectomy. Last October, Hawkins was diagnosed with stage 4 bone disease.

Mother and daughter have taken turns supporting each other through diagnosis, radiation, chemotherapy, surgery, and recovery. When Hawkins went through radiation, Lien had a card waiting for her at the hospital five days a week for six weeks, the duration of her treatment.

“There is a special bond between Sarah and me because we have gone through cancer together,” Hawkins said. “We know what each other is thinking and feeling.”

Hawkins is receiving bone-strengthening treatment and takes oral chemotherapy, yet still works full-time as a critical-care nurse. Lien is in remission and pregnant with her first child, a girl whose middle name will be Elizabeth, after both her and Hawkins’ middle name. Her due date is Nov. 20, Hawkins’ birthday.

“Cancer affected every part of my life and my mother’s life, but blessings came out of our cancer journey: new friends, support from so many people, and my relationship with my mom has grown,” Lien said. “Cancer has devastated our lives, but the struggles are well worth the blessings and knowledge that resulted. I wouldn’t wish cancer on anybody, but I’m happy with how it turned out. There is life after cancer.”

Lien and Hawkins and the story of their family journey with breast cancer is scheduled for tonight, Friday, Oct. 18. In Seattle, the newscast appears at 6 p.m. on KING TV, channel 5, and is expected to be rebroadcast on KING-5 News.

The gene, PAX5, has long been known to be involved in acute lymphoblastic leukemia.�� The new study indicates a mutation in the gene alone is sufficient to eventually cause the disease, which affects nearly 3,000 children and teenagers in the United States each year.

The discovery should make it possible to screen for the gene in families with a history of the disease and suggests new strategies for treating the disease, said Dr. Marshall Horwitz, professor of pathology and of medicine at the ����Ӱ�Ӵ�ý. He is a co-author of the new study.

He was joined in the study by researchers at St. Jude Children’s Research Hospital in Memphis, Tennessee led by Dr. Charles Mullighan; Memorial Sloan-Kettering Cancer Center in New York City led by Dr. Kenneth Offit, and others at the UW. The results were published Sept. 8 in the journal Nature Genetics.

The researchers looked at the genes from two unrelated families that had a high rate of��acute lymphoblastic leukemia and identified the same mutation of the PAX5 gene that ran in both the families.

This variant does not cause leukemia as long as it is paired with a normal version of the PAX5 gene, said Horwitz, but if the normal copy of the gene is lost and only the abnormal variant remains, some blood cells fail to become normally functioning white blood cells and, instead, turn into leukemia cells.

In the case of the families in the study, all the children who developed leukemia had damage to a chromosome in the affected blood cells. The damage, in which part of chromosome 9 was lost, removed the normal copy of the PAX5 gene. This left the abnormal gene unopposed.

PAX5 codes for a kind of protein, called a transcription factor, that plays a key role not only in blood cell maturation, but also in embryonic development.

“It was not a surprise that PAX5 turned out to be involved. It’s ��the most commonly mutated gene found in ALL cells,” said Horwitz. “But it has not been clear whether PAX5 mutations were just mutations that had to happen at some point in the transformation of a normal cell to a leukemic cell or whether PAX5 variants were driving the leukemia.”

He said the findings indicate that PAX5 variants alone are sufficient to eventually cause acute lymphoblastic leukemia.

The finding has another important implication, said Horwitz. The fact that PAX5 is sufficient to cause acute lymphoblastic leukemia supports the concept that mutations that affect differentiation of blood cells are the key drivers of leukemia. If that is the case, it may be possible to design treatments that block de-differentiation or induce leukemic cells to re-differentiate so that they would begin to behave like normal cells again.

Such treatments might be more effective and have far fewer side effects than chemotherapy, the current standard treatment for these cancers, said Horwitz.

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In June 2011 Dr. Alisa Hideg was a 42-year-old mother and family physician in the prime of her career practicing at Group Health in Spokane when she was diagnosed with estrogen and progesterone receptor negative/HER 2 positive breast cancer.

Breast cancer in young, premenopausal women is usually aggressive. So even after chemotherapy, a double mastectomy, and radiation, with her cancer in remission, Hideg wasn’t ready to take it easy. Both the type of breast cancer and the fact that it happened at a young age made her chances of relapse higher. This knowledge led her to experimental trials, and to the UW’s Tumor Vaccine Group.

Hideg found the UW Tumor Vaccine Group on the National Institutes of Health clinical trials website, ClinicalTrials.gov. She had heard about a trial at the University of Pennsylvania’s Perelmen School of Medicine, where the use of gene-transfer therapy converted the patients’ own immune cells into weapons aimed at cancerous tumors. All 12 patients had advanced stage leukemia; nine of the 12 responded positively to the treatment, and two of the first three patients treated have been in remission for two full years. ��The Perlelmen results encouraged her to seek out a UW study to see if she qualified.

The UW Tumor Vaccine Group currently offers clinical trials for patients with breast, ovarian or colon cancer. Hideg is in a very desirable , and being approved to participate wasn’t easy. The goal of the clinical trial is to allow the patient to make and keep enough antibodies to quash any future HER-2 expressing breast cancer.

Dr. Nora Disis, UW professor of medicine and principal investigator of the study, explains how the vaccine may work.

“The vaccine is designed to stimulate a particular cell of the immune system, the T cell, to recognize the HER2 protein (that causes cancer),” Disis said. “If effective immunity is generated, the T cell activated by the vaccine should be able to hunt out tumor cells wherever they may be and destroy them.�� This particular study is testing the use of an immune stimulator, ampligen, which may be able to activate the T cells more effectively than other agents we have used before.“

Last month, Hideg received a vaccine dose at UW Medical Center. The process is gentle — a series of four small injections that make a little grid of dots on the upper arm — but the body’s response can be angry. Hideg experienced flu-like symptoms after the first visit. The reaction ��may actually be a promising sign that her body is responding to the vaccine.

She’s positive and funny in the face of serious medicine. She tweets pictures of her experience to a network of fans and writes about her cancer in Spokane’s daily newspaper, the Spokesman-Review. In addition to being a doctor, patient and full-time mother, Hideg recently went through a series of intense interviews to add “teacher” to her resume. She has become a clinical faculty member to teach second-year UW medical students at the Spokane WWAMI site. ��WWAMI is a regionalized medical education program that covers Washington, Wyoming, Alaska, Montana and Idaho.

“Teaching has always been a part of my clinical practice,” Hideg said. “I have taught medical students, residents and others in my clinic since I finished my own training. This experience has reminded me how important teaching can be and how much I enjoy passing on what I have learned as a physician, a parent, and as a patient. Whether the vaccine is effective for me or not, I am grateful for the opportunity to participate in the trial and help move the science forward. I believe in the potential of vaccine therapy for cancer and perhaps for other diseases also and I want a future with more options for my daughter and for others.”

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