Early Detection Critical In Treating Pediatric Thyroid Cancer

Daily Science Journal (Feb. 6, 2008) — Efforts to treat pediatric papillary thyroid cancer are greatly improved by detecting the disease as early as possible, making the patient's age the most important factor in determining a prognosis, according to new research published in the February 2008 issue of the journal Otolaryngology -- Head and Neck Surgery.

The study, authored by Italian researchers, evaluated 2,709 patients who underwent a total thyroidectomy to treat papillary thyroid carcinoma (PTC). Among the group's pediatric patients (younger than 18 years old), the cancer was observed to be much more aggressive than that in adult patients. However, despite the aggressive course of the disease, this did not influence the patient's survival rate, since cases of pediatric cancer have a better prognosis than that in adults. As a result, the authors concluded that age of detection is the single most important factor to consider when issuing a prognosis.

Thyroid cancer is the third most common tumor malignancy in children. It is one of the few cancers that has increased in incidence rates over the past several years, with an estimated 11 percent increase from 2006 to 2007. Papillary thyroid cancer occurs in cells that produce thyroid hormones containing iodine. This type, the most common form of thyroid cancer in children, grows very slowly.

The study also confirms that PTC is more prevalent in younger patients, compared with other age groups; these patients also had significantly larger tumors. However, the study's authors concluded that the size of the tumor, which is considered a significant factor in determining prognosis in adult patients, does not play a significant role in a child's prognosis.

The study also suggests a longer period for follow-ups is in order to more accurately measure the success of treatment.

Adapted from materials provided by American Academy of Otolaryngology, Head and Neck Surgery, via EurekAlert!, a service of AAAS.

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New Nanotube Findings Give Boost To Potential Biomedical Applications

Daily Science Journal (Feb. 4, 2008) — Carbon nanotubes-cylinders so tiny that it takes 50,000 lying side by side to equal the width of a human hair-are packed with the potential to be highly accurate vehicles for administering medicines and other therapeutic agents to patients. But a dearth of data about what happens to the tubes after they discharge their medical payloads has been a major stumbling block to progress.

A representation of a carbon nanotube accessorized with a coating of branched PEG. (Credit: Courtesy of Hongjie Dai)

Now, Stanford researchers, who spent months tracking the tiny tubes inside mice, have found some answers.

Studies in mice already had shown that most nanomaterials tend to accumulate in organs such as the liver and spleen, which was a concern because no one knew how long they could linger. But fears that the tiny tubes might be piling up in vital organs, like discarded refrigerators at the bottom of a rural ravine, can now be put to rest, said Hongjie Dai, the J. G. Jackson and C. J. Wood Professor of Chemistry at Stanford, whose research team has demonstrated that the nanotubes exit the organs.

Dai and his group found that the carbon nanotubes leave the body primarily through the feces, with some by way of the urine. ''That's nice to know,'' Dai said. ''This now proves that they do get out of the system.''

The full extent of the news, which is scheduled to be published the week of Jan. 28 in Proceedings of the National Academy of Sciences Online Early Edition (PNAS), is even better than that: The three-month-long study also allays worries that the nanotubes, by simply remaining in the organs for a long time, would prove toxic to the mouse.

''None of the mice died or showed any anomaly in the blood chemistry or in the main organs,'' said Dai, senior author on the PNAS paper. ''They appear very healthy, and they are gaining weight, just like normal mice. There's no obvious toxicity observed.'' The lack of toxicity of nanotubes in mice is consistent with a previous pilot study done by Sanjiv Gambhir, a professor of radiology at Stanford, and his research group in collaboration with Dai's group.

''This is the first time anyone has done a systematic circulation and excretion study like this for nanotubes, and data on other nano particles is also scarce,'' Dai said. ''The excretion pathway may apply to other nano materials and may need to be looked at closely like this also.''

Previous research published by Dai's group has demonstrated the potential for using nanotubes in treating cancerous cells and targeting tumors in mice.

His group used Raman spectroscopy, a method of applying light from a laser beam that effectively ''illuminates'' the presence of the target molecules in the organs of the mice.

Being hit with light from the beam causes a detectable change in the state of a molecule's energy. Carbon nanotubes, composed entirely of carbon atoms that are mostly arranged in linked hexagonal rings, give off a strong signal in response to the beam. This allowed the researchers to pinpoint the position of the chosen molecules, as well as ascertain their abundance in the blood or organs.

Previous detection methods that relied on attaching fluorescent labels or spectroscopic tags to the nanotubes had yielded unreliable results. The attachments tended to either come loose from the tubes or decay over time spans ranging from a few days to only a few hours-far too short to reveal the ultimate fate of the nanotubes.

While knowing the carbon nanotubes will move through the digestive system at a healthy pace is critical to future practical applications, it is also crucial that the nanotubes not enter the digestive system too soon after being injected; they need to spend enough time in the circulatory system to find their way to their target location.

The key to fine-tuning the carbon nanotubes' speed of circulation turns on how the basic, bare-bones floor model is chemically accessorized.

''You can make the nanotubes circulate a very long time in the blood, if the chemistry is done right,'' Dai said. The researchers found that coating their carbon nanotubes with polyethylene glycol (PEG), a common ingredient in cosmetics, worked best.

They used a form of PEG with three little limbs sprouting off a central trunk. ''Those provide better shielding to the nanotube than just a single branch. Therefore, they interact less with the biological molecules around them,'' Dai said.

The team stuffed the PEG liberally into the linked hexagonal rings that compose the nanotubes, prompting Dai to describe the end result as resembling rolled-up chicken wire with feathers sticking out all over.

Though they may sound less than gorgeous visually, the feathery nanotubes turned in a beautiful performance in practical terms, Dai said. The coating of PEG made the nanotubes highly water soluble, which helped them to stay in the blood instead of being absorbed.

''They circulate in the blood for about 10 hours or so in mice, which seems to be a good length of time,'' Dai said.

The right chemical coating on nanotubes also can help ease them out of the mouse in a timely fashion, and the three-branched PEG was effective there, too.

Dai's earlier research demonstrated that nanotubes have promise for treating cancer with two different approaches. Once they have zeroed in on the target cells, shining light on the nanotubes causes them to generate heat, which can kill cancer cells. The other method is to rig the nanotubes to accumulate at targeted sites, where they can deliver medication from within the tubes.

''[Carbon nanotubes] seem to be promising for biomedical applications and for potentially treating cancer, either using drugs or using the physical properties,'' Dai said. ''This is the reason we carried out the study of the fate of nanotubes in mice. I think this is really a very fundamental issue.''

The research was funded by the Cancer Center for Nanotechnology Excellence, which is funded by the National Institutes of Health and the National Cancer Institute. The first author of the PNAS paper is Zhuang Liu, graduate student in chemistry. The paper's other authors, all affiliated with Stanford University, are Xiaoyuan ''Shawn'' Chen, assistant professor in radiology; Dr. Corrine Davis of the Veterinary Service Center in the Department of Comparative Medicine; Weibo Cai, postdoctoral scholar in radiology; and Lina He, formerly a technician in Chen's research group.

Adapted from materials provided by Stanford University.

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Kidney Cancer Drug Attacks A Major Type Of Acute Myeloid Leukemia

Daily Science Journal (Feb. 1, 2008) — A drug used to treat kidney cancer also targets a genetic mutation active in about one third of patients with acute myeloid leukemia (AML), the most common and lethal form of adult leukemia, researchers at The University of Texas M. D. Anderson Cancer Center report in the Jan. 29 edition of the Journal of the National Cancer Institute.

In a Phase I clinical trial, the drug sorafenib reduced the median percentage of leukemia cells circulating in the blood from 81 percent to 7.5 percent and in the bone marrow from 75.5 percent to 34 percent among AML patients whose leukemia includes the FLT3-ITD mutation. Two patients had circulating leukemia cells, or blasts, drop to zero.

"AML patients with this mutation have a particularly poor prognosis, so this highly targeted drug appears to be a significant step forward in leukemia therapy," says senior author Michael Andreeff, M.D., Ph.D., professor in M. D. Anderson's Department of Stem Cell Transplantation and Cellular Therapy and Department of Leukemia.

The JNCI paper reports the drug's effect in lab experiments, a mouse model of the disease, and in a Phase I study of 16 patients with relapsed or resistant AML known to have the FLT3-ITD mutation.

There have been no major side effects in the clinical trial to date, so no maximum tolerated dose has been reached, Andreeff notes. The drug has little effect on cells with normal versions of the gene and does not interfere with normal blood cell formation.

A Phase I/Phase II clinical trial for AML is open at M. D. Anderson that combines sorafenib with the standard of care chemotherapy combination for AML, idarubicin and cytosine arabinoside. Presently, the trial is open for relapsed patients and those newly diagnosed with high-risk disease, says study co-author Jorge Cortes, M.D., professor in M. D. Anderson's Department of Leukemia. As safety and dose escalation research progress, sorafenib will be made available to other patients and assume a role in frontline therapy.

About 14,000 new cases of AML are diagnosed annually in the United States and the disease kills about 9,000 people each year. AML is characterized by swift proliferation of immature white blood cells in the blood and bone marrow that crowds out normal cells, leaving patients exposed to infection, severe anemia, and bleeding.

While major progress has been made treating some forms of leukemia and lymphoma, acute myeloid leukemia has seen less improvement in recent years. Andreeff says that's because AML exploits multiple molecular pathways and that these pathways differ from one type of AML to the next.

Andreeff and colleagues have shown that molecular pathways subverted and used by AML collude with each other, so when one pathway is blocked, the others redouble their efforts to fuel the disease.

"Here we have a great response against an important mutation, but sorafenib alone will not cure patients," Andreeff notes. Combination therapy will be required. Andreeff and colleagues are planning to examine other sorafenib combinations against FLT3-mutant disease.

After in vitro tests showed that sorafenib inhibited the growth of FLT3 mutant leukemia cell colonies, the research team tested the medication in a mouse model of the disease. Sorafenib-treated mice had a median survival of 36.5 days compared with 20.5 days in untreated mice. Bioluminescence imaging showed widespread cancer growth in untreated mice and barely detectable disease in those that had received the drug.

Sorafenib, known commercially as Nexavar® and co-developed by Bayer AG and Onyx Pharmaceuticals, already is approved for advanced renal cell carcinoma and inoperable liver cancer by the U.S. Food and Drug Administration. It is being tested against other solid tumors.

The drug targets both tumor cell growth and angiogenesis - new blood vessels woven by cancer to sustain itself - by targeting two classes of kinases, which are enzymes that affect proteins by attaching phosphate groups to them.

Sorafenib's antileukemia effects appear to be superior to early results of new therapies under development that more narrowly target the FLT3 gene. Andreeff says the drug's ability to hit multiple kinases probably accounts for this, but the exact molecular mechanisms involved require further study.

Co-authors with Andreeff and Cortes are lead author Weiguo Zhang, M.D., Ph.D., who conducted most of the project's laboratory research, Marina Konopleva, M.D., Ph.D., Yue-xi Shi, Teresa McQueen, Xiaoyang Ling, Ph.D., all of the department of Stem Cell Transplantation and Cellular Therapy; David Harris, Zeev Estrov, M.D., and Alfonso Quintas-Cardama, M.D. all of the Department of Leukemia; and David Small, M.D. of Johns Hopkins University School of Medicine.

Research was funded by grants from the National Cancer Institute, a Leukemia SPORE Career Development Award, and the Cancer Therapy Evaluation Program.

Adapted from materials provided by University of Texas M. D. Anderson Cancer Center.

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Pathway To Turn Off Immune System Cells Discovered

Daily Science Journal (Feb. 1, 2008) — University of Minnesota researchers have discovered a new way to turn genes off in human T cells, a type of white blood cell that helps the immune system fight infections.

Turning off genes, through a process known as mRNA decay, is important for regulating the body's immune response after fighting infection. This research could lead to development of new drugs that turn off the immune system in patients with autoimmune diseases -- such as rheumatoid arthritis and lupus. It could also prevent cancer cells from dividing.

Researchers used a novel approach that combines molecular biology and computational analysis to identify mRNA sequence responsible for turning off T cells.

"Although this study analyzed T cells, this pathway is present in all human cells," said Paul Bohjanen, M.D., Ph.D., co-director of the Center for Infectious Diseases and Microbiology Translational Research (CIDMTR) and principal investigator of the study. "Knowledge from this study can be applied to help researchers better understand other types of cells and how they function."

During an infection, T cells turn on and divide to help clear the infection from the body. After the infection is cleared, the cells need to turn off so the body can return to a stable condition. If the cells do not turn off, however, they can cause damage to the body and can potentially develop into cancer cells.

This research is important because to date, understanding the mechanisms that turn off cells has not been very well understood.

Researchers measured the rate of mRNA decay for each of the approximately 6,000 genes in human T cells. That information was then analyzed by George Karypis, Ph.D., associate professor of computer science, and his colleagues at the Minnesota Supercomputing Institute, using complex computer programs to identify a sequence present in mRNA that was destroyed rapidly in the cell. Bohjanen and his colleagues performed molecular biology experiments to confirm that this sequence targets mRNA for destruction and was responsible for turning off genes in activated T cells.

"This discovery would not have been possible without the interdisciplinary collaboration between molecular biologists and computer scientists," Bohjanen said. The collaboration between Bohjanen and Karypis was facilitated by Irina Vlasova, M.D., Ph.D., research associate in Bohjanen's molecular biology laboratory, who received training in computational biology through a Minnesota Supercomputing Institute fellowship.

The research is published in the February 1 issue of Molecular Cell. The research was conducted by researchers at CIDMTR, Department of Microbiology, Department of Medicine, Department of Computer Science, and Division of Biostatistics.

The research was funded by grants from the National Institutes of Health, the Minnesota Medical Foundation, the Minnesota Supercomputing Institute, the Lymphoma Research Foundation, and the Swedish Research Council.

Adapted from materials provided by University of Minnesota, via EurekAlert!, a service of AAAS.

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Nanotubes Help Advance Brain Tumor Research

Daily Science Journal (Jan. 30, 2008) — The potential of carbon nanotubes to diagnose and treat brain tumors is being explored through a partnership between NASA's Jet Propulsion Laboratory, Pasadena, Calif., and City of Hope, a leading cancer research and treatment center in Duarte, Calif.

Benham Badie, M.D., director of the Department of Neurosurgery and the Brain Tumor program at City of Hope, performs a minimally invasive procedure to surgically remove a pituitary tumor. Nanotube technology may help in the development of new treatments that would require only minimally invasive procedures no matter the location of the brain tumor. (Credit: City of Hope)

Nanotechnology may help revolutionize medicine in the future with its promise to play a role in selective cancer therapy. City of Hope researchers hope to boost the brain's own immune response against tumors by delivering cancer-fighting agents via nanotubes. A nanotube is about 50,000 times narrower than a human hair, but it length can extend up to several centimeters.

If nanotube technology can be effectively applied to brain tumors, it might also be used to treat stroke, trauma, neurodegenerative disorders and other disease processes in the brain, said Dr. Behnam Badie, City of Hope's director of neurosurgery and of its brain tumor program.

"I'm very optimistic of how this nanotechnology will work out," he said. "We are hoping to begin testing in humans in about five years, and we have ideas about where to go next."

The Nano and Micro Systems Group at JPL, which has been researching nanotubes since about 2000, creates these tiny, cylindrical multi-walled carbon tubes for City of Hope.

City of Hope researchers, who began their quest in 2006, found good results: The nanotubes, which they used on mice, were non-toxic in brain cells, did not change cell reproduction and were capable of carrying DNA and siRNA, two types of molecules that encode genetic information.

JPL's Nano and Micro Systems Group grows the nanotubes on silicon strips a few square millimeters in area. The growth process forms them into hollow tubes as if by rolling sheets of graphite-like carbon.

Carbon nanotubes are extremely strong, flexible, heat-resistant, and have very sharp tips. Consequently, JPL uses nanotubes as field-emission cathodes -- vehicles that help produce electrons -- for various space applications such as x-ray and mass spectroscopy instruments, vacuum microelectronics and high-frequency communications.

"Nanotubes are important for miniaturizing spectroscopic instruments for space applications, developing extreme environment electronics, as well as for remote sensing," said Harish Manohara, the technical group supervisor for JPL's Nano and Micro Systems Group.

Nanotubes are a fairly new innovation, so they are not yet routinely used in current NASA missions, he added. However, they may be used in gas-analysis or mineralogical instruments for future missions to Mars, Venus and the Jupiter system.

JPL's collaboration with City of Hope began last year, after Manohara, Badie and Dr. Babak Kateb, City of Hope's former director of research and development in the brain tumor program, discussed using nanostructures to better diagnose and treat brain cancer. Badie said his team's nanomedical research continues, and the next goal will be to functionalize and attach inhibitory RNA to the nanotubes and deliver it to specific areas of the brain.

The JPL and City of Hope teams published the results of the study earlier this year in the journal NeuroImage.

Badie says that JPL's contribution to City of Hope's nanomedicine research has been invaluable.

"The fact that we can get pristine and really clean nanotubes from Manohara's department is unique," he said. "The fact that we are both collaborating for biological purposes is also really unique."

The collaboration between JPL and City of Hope is conducted under NASA's Innovative Partnership Program, designed to bring benefits of the space program to the public.

Adapted from materials provided by NASA/Jet Propulsion Laboratory.

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Turning Anthrax Toxin Into A Cancer Killer

Daily Science Journal (Jan. 5, 2008) — Most people wouldn't consider anthrax toxin to be beneficial, but this bacterial poison may someday be an effective cancer therapy. Anthrax toxin has actually been shown to be fairly selective in targeting melanoma cells, although the risk of non-cancer toxicity prevents any clinical use.

After binding to cell surface markers, the MMP-activated PA protein (PA-L1) is cleaved by surface associated MMPs, releasing the PA20 fragment. The remaining receptor-bound fragment rapidly oligomerizes to form a heptamer. Up to three molecules of anthrax lethal factor (LF) bind to the heptamer, which is then internalized. Once inside the cell, the complex encounters an acidic environment, which induces a conformational change and allows the LF to enter the cytosol. LF released into the cytosol shuts down multiple signaling pathways, leading to inhibition of tumor angiogenesis and human melanoma cell death. (Credit: Image created by Drs. Shihui Liu, Mahtab Moayeri, and Stephen H. Leppla)

To develop a better and safer treatment, Stephen Leppla and colleagues created a mutated antrax toxin that could only be turned on by matrix metalloproteinases (MMP), proteins that are overproduced only in cancer cells.

When they tested this mutated toxin in mice, the researchers observed that 100% of the animals tolerated a dose that would be lethal for the natural toxin. The MMP-toxin was also better at killing melanoma tumors than natural toxin, due to its higher specificity and longer half-life in the blood.

Even better, Leppla and colleagues saw that MMP-toxin was not limited to melanoma, and could also kill other tumors like colon and lung. This more widespread activity was due to the toxin's ability to inhibit angiogenesis, or the formation of new blood vessels.

These encouraging mouse results suggest that modified anthrax toxin could be clinically viable, and this potent killer might someday be put to good use.

Adapted from materials provided by American Society for Biochemistry and Molecular Biology, via EurekAlert!, a service of AAAS.

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Radio Waves Fire Up Nanotubes Embedded In Tumors, Destroying Liver Cancer

Daily Science Journal (Nov. 3, 2007) — Cancer cells treated with carbon nanotubes can be destroyed by non-invasive radio waves that heat up the nanotubes while sparing untreated tissue, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center and Rice University has shown in preclinical experiments.

Researchers show that the technique completely destroyed liver cancer tumors in rabbits. There were no side effects noted. However, some healthy liver tissue within 2-5 millimeters of the tumors sustained heat damage due to nanotube leakage from the tumor.

"These are promising, even exciting, preclinical results in this liver cancer model," says senior author Steven Curley, M.D., professor in M. D. Anderson's Department of Surgical Oncology. "Our next step is to look at ways to more precisely target the nanotubes so they attach to, and are taken up by, cancer cells while avoiding normal tissue."

Targeting the nanotubes solely to cancer cells is the major challenge in advancing the therapy, Curley says. Research is under way to bind the nanotubes to antibodies, peptides or other agents that in turn target molecules expressed on cancer cells. To complicate matters, most such molecules also are expressed in normal tissue.

Curley estimates that a clinical trial is at least three to four years away.

Curley conducted the research at M. D. Anderson in collaboration with nanotechnology experts at Rice University and with Erie, Pennsylvania, entrepreneur John Kanzius of ThermMed LLC, who invented the experimental radiofrequency generator used in the experiments. Kanzius is a cancer survivor and former radio station owner whose insights into the potential of targeted radio waves inspired this line of research.

At Rice, the work was begun by Nobel laureate Richard Smalley, several months before his untimely death from cancer in October 2005. Smalley was the founder of Rice's Carbon Nanotechnology Laboratory and one of the world's foremost experts on carbon nanotubes. He shared the Nobel Prize for the 1985 discovery of fullerenes, the family of carbon molecules that includes nanotubes. His research in 2005 was concentrated largely on the radiofrequency cancer research project.

Rice materials scientist professor Boris Yakobson, Ph.D., a co-author on the paper, recalled meeting with Smalley in his hospital room at M. D. Anderson five days before his death.

"He looked very ill, breathing heavily through the oxygen mask, but all he wanted to do was talk about the physics of this very phenomenon," Yakobson said. "Oblivious of his ebbing health, Rick was focused in the future. He had told Congress in 1999 that nanotechnology would help revolutionize cancer treatment, and he was a scientist wanting to know whether this technology might be one of the things that would make that possible."

In the liver cancer experiment, a solution of single-walled carbon nanotubes was injected directly into the tumors. Four treated rabbits were then exposed to two minutes of radiofrequency treatment, resulting in thermal destruction of their tumors.

Carbon nanotubes are hollow cylinders of pure carbon that measure about a billionth of a meter, or one nanometer, across.

Control group tumors that were treated only by radiofrequency exposure or only by nanotubes were undamaged.

In lab experiments, two lines of liver cancer cells and one pancreatic cancer cell line were destroyed after being incubated with nanotubes and exposed to the radiofrequency field.

"I'm humbled by the results of this research," says Kanzius. "I realize it's early in the race, but Dr. Curley and his team have moved on this carefully with utmost speed. I look forward to continuing to work with them and hopefully to watching the first person be treated with this procedure. The race isn't over but it needs to be taken to the finish line."

Radiofrequency energy fields penetrate deeply into tissue, so it would be possible to deliver heat anywhere in the body if targeted nanotubes or other nanoparticles can be delivered to cancerous cells, Curley says. Without such a target, radio waves will pass harmlessly through the body.

An invasive technique known as radio frequency ablation is used to treat some malignant tumors, the authors note. It requires insertion of needle electrodes directly into the tumors. ncomplete tumor destruction occurs in 5 to 40 percent of cases, normal tissue is damaged and complications arise in 10 percent of patients who suffer such damage. Radiofrequency ablation is limited to liver, kidney, breast, lung and bone cancers.

This research appeared online ahead of December publication in the journal Cancer.

The research was supported by an American Association of Cancer Research Littlefield Grant, NASA and the Houston-based Alliance for NanoHealth, the National Science Foundation, the Center for Biological and Environmental Nanotechnology and the Fulbright Foundation.

Co-authors with Curley, Smalley, Kanzius and Yakobson are first authors Christopher J. Gannon, M.D., also of M. D. Anderson's Department of Surgical Oncology, and Paul Cherukuri, Ph.D. of Rice's Carbon Nanotechnology Laboratory and Department of Chemistry; Carter Kittrell, Ph.D., R. Bruce Weisman, Ph.D., Matteo Pasquali, Ph.D., and Howard K. Schmidt, Ph.D., all of Rice; and Laurent Cognet, Ph.D., of Rice and the Centre de Physique Moléculaire Optique et Hertzienne, Université Bordeaux, France.

Adapted from materials provided by University of Texas M. D. Anderson Cancer Center.

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