Posts Tagged ‘cancer’

Bringing the filtering abilities of a fuel cell into the blood vessels of living organisms, a new device could cut down on toxic effects of cancer treatment.

At the heart of this approach — recently tested in pigs — is a tiny, cylindrical “sponge” created by 3-D printing. Wedged inside a vein near a tumor being treated with chemotherapy, the sponge could absorb excess drug before it spreads through the body — thus lessening chemotherapy’s harmful side effects, including vomiting, immune suppression or even heart failure.

A human study could launch “in a couple of years, if all the stars are aligned,” says Steve Hetts, a neuroradiologist at the University of California, San Francisco who came up with the drug-capture concept. He worked with engineers at UC Berkeley and elsewhere to create and test prototypes.

A test of the most recent prototype showed that the absorber captured nearly two-thirds of a common chemotherapy drug infused into a nearby vein, without triggering blood clots or other obvious problems in the pig, Hetts and his colleagues report January 9 in ACS Central Science.

The study addresses a major need, says Eleni Liapi, a radiologist at Johns Hopkins University School of Medicine not involved with the new work. Existing methods for controlling chemotherapy delivery do not fully block drug escape, she notes. “A technological advancement to reduce unwanted circulating drug is always welcome.”


This image shows a cross-sectional view of a new 3-D printed cylindrical device that could cut down on toxic side effects from cancer treatment. Resin coatings (gold) bind to a chemo drug used to treat liver cancer, experiments show.

Chemo is often delivered intravenously in the hope that some treatment reaches the cancer site. In a more localized form of chemotherapy used to treat hard-to-remove tumors, the drug travels through catheter wires snaked into arteries going straight to the tumor. Although this technique, known as transarterial chemo embolization, or TACE, is given to tens of thousands of people each year, typically some of the injected drug bypasses the tumor site and slips into general circulation where it can wreak havoc elsewhere.

Hetts uses the transarterial method to treat babies with a rare eye tumor called retinoblastoma – and it was those experiences that birthed the “sponge” idea in the first place. After the chemotherapy ran its course through transarterial catheters, the infants’ eye tumors shrank. However, several weeks later, their blood cell counts tanked, suggesting to Hetts that some of the chemo drugs were escaping the eye and affecting other cells. Those observations eight years ago led Hetts to think that “if only I had a device I could put into the vein to bind up the excess drug, then maybe these little babies wouldn’t get the side effect” of immune suppression.

Heart surgeons use a similar “filter” to remove bits of cholesterol plaque from arteries of people with atherosclerosis, a disease characterized by the clogging and hardening of arteries. Hetts envisioned a similar device for chemotherapy treatment — “but not just a dumb, inert membrane to capture debris,” he says. “I wanted a ‘smart’ membrane that chemically binds to a drug.”

Instead of trying to develop a drug-trap device for a super rare tumor — retinoblastoma has just 300 new cases per year in the United States — Hetts’ team focused on a chemo drug for liver cancer, which is estimated to strike more than 40,000 Americans this year and kill three-quarters of them.

Anand Patel, a trainee in the Hetts’ lab with a bioengineering background, tested a batch of resins and found several that could bind to this drug, known as doxorubicin. To optimize the resins and get them onto the tips of guide wires, Patel sought help with “cold call” e-mails to local professors. Nitash Balsara — a UC Berkeley chemical engineer with expertise in polymer chemistry and membranes — “was actually crazy enough to return my e-mail with interest,” says Patel, who now works as an interventional radiologist in the Los Angeles area.

Balsara’s lab develops materials to regulate ion flow in batteries and fuel cells. As it turns out, these filtration processes are “very similar to those that we needed to capture excess chemotherapy drugs from the blood,” Patel says. The team worked with Carbon, Inc., a 3-D printing company in the San Francisco Bay area, to get the drug-binding material onto a 30-millimeter-long, cylinder-shaped “sponge” about as wide as a drinking straw. Hee Jeung Oh of UC Berkeley spent more than a year working out how to attach the drug-binding material to the 3-D printed cylinder with crisscrossing struts.

In experiments, the team injected the liver cancer drug through the pigs’ leg and pelvic veins — which are similar in width to human liver veins, Hetts says. Before infusing the chemotherapy drug, the researchers inserted the 3-D printed sponge a few centimeters from the infusion site — as well as catheters above and below the sponge for collecting blood samples to measure drug absorption over time. Within a half hour, the device absorbed, on average, 64 percent of the liver cancer drug.

The next round of studies will monitor the capture of doxorubicin by drug sponges inserted directly into the pigs’ liver veins.

https://www.sciencenews.org/article/new-3d-printed-sponge-sops-excess-chemo-cancer-drugs

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by Laura Elizabeth Mason

Elephants have developed a way to resist cancer, by resurrecting a ‘zombie’ gene known as leukemia inhibitory factor 6 (LIF6). Activated LIF6 responds to damaged DNA and efficiently kills cells that are destined to become cancer cells.

Cancer is a complex genetic disease that is caused by specific changes to the genes in one cell or group of cells. These genetic alterations cause the cell to divide uncontrollably. If all mammalian cells were equally susceptible to the genetic mutations that cause cancer, then theoretically the risk of developing cancer should be greater in larger animals – due to them having more cells and a longer life-span. However, previous studies have demonstrated that elephants have a lower-than-expected rate of cancer, compared to other mammals.

“Elephants get cancer far less than we’d expect based on their size, so we want to understand the genetic basis for this cancer resistance,” said senior author Vincent Lynch from the University of Chicago, in a recent press release.

“We found that elephants and their relatives have many non-functioning copies of the LIF gene, but that elephants themselves evolved a way to turn one of these copies, LIF6, back on.”

p53 wakes up LIF6

The TP53 gene is found in all animals, it codes for the protein p53, a tumor suppressor, that stops cells with damaged DNA from dividing. Unlike humans, who only have one copy of TP53, elephants have 20. An increased number of TP53 genes enhances the DNA-damage response, providing elephants with a distinct advantage – they are able to either repair the damaged cells or ‘kill off’ irreparable cells more efficiently.

In their latest study the researchers found that in response to DNA damage, LIF6 is transcriptionally upregulated by p53. LIF6 codes for a protein that rapidly translocates to the cell’s mitochondria. Once it reaches the mitochondrion it causes the outer mitochondrial membrane pore to open – leading to mitochondrial dysfunction, causing the cell to die.

The researchers plan to conduct additional studies to further define the molecular mechanisms by which LIF6 induces cell death.

The team hope their findings will aid efforts to therapeutically target cancer. “Maybe we can find ways of developing drugs that mimic the behaviors of the elephant’s LIF6 or of getting cancerous cells to turn on their existing zombie copies of the LIF gene,” concluded Lynch.

Reference
Vazquez et al. A zombie LIF gene in elephants is up-regulated by TP53 to induce apoptosis in response to DNA damage. Cell Reports. 2018. http://dx.doi.org/10.1016/j.celrep.2018.07.042

Elephants’ secret to their low rates of cancer might be explained in part by a so-called zombie gene—one that was revived during evolution from a defunct duplicate of another gene. In the face of DNA damage, elephant cells fire up the activity of the zombie gene LIF6 to kill cells, thereby destroying any cancer-causing genetic defects, researchers reported in Cell Reports.

“From an evolutionary biology perspective, it’s completely fascinating,” Joshua Schiffman, a pediatric oncologist at the University of Utah who was not involved in the work, tells National Geographic.

The better-known LIF gene has a number of functions in mammals, including as an extracellular cytokine. In elephants, LIF is duplicated numerous times as pseudogenes, which don’t have the proper sequence to produce functioning transcripts. For the latest study, the researchers wanted to see whether the duplications might have anything to do with elephant cells’ unusual response to DNA damage: indiscriminant destruction.

The team found that one of the pseudogenes, LIF6, evolved after LIF was duplicated in a way that produces a transcript, and that the gene product is controlled by TP53, a tumor suppressor. When the researchers overexpressed LIF6 in elephant cells, the cells underwent apoptosis. The same thing happened with they introduced the gene to Chinese hamster ovary cells, indicating that LIF6 has a role in elephants’ defense against DNA damage.

More work needs to be done to determine whether the LIF6 revival is responsible for elephants’ low cancer rates. There are likely to be other contributors, says coauthor Vincent Lynch, an evolutionary biologist at the University of Chicago, in an interview with The New York Times. “There are lots of stories like LIF6 in the elephant genome, and I want to know them all.”

https://www.the-scientist.com/news-opinion/elephants-revived-a-zombie-gene-that-perhaps-fends-off-cancer-64643


Lung cancer seen on chest X ray.

Researchers have identified a gene that when inhibited or reduced, in turn, reduced or prevented human non-small cell lung cancer tumors from growing.

When mice were injected with non-small cell lung cancer cells that contained the gene NOVA1, three of four mice formed tumors. When the mice were injected with cancer cells without NOVA1, three of four mice remained tumor-free.

The fourth developed a tumor, but it was very small compared to the mice with the NOVA1 tumor cells, said Andrew Ludlow, first author on the study and assistant professor at the University of Michigan School of Kinesiology.

The research appears online today in Nature Communications. Ludlow did the work while a postdoctoral fellow at the University of Texas Southwestern Medical Center, in the shared lab of Woodring Wright, professor of cell biology and internal medicine, and Jerry Shay, professor of cell biology.

The study found that in cancer cells, the NOVA1 gene is thought to activate telomerase, the enzyme that maintains telomeres—the protective caps on the ends of chromosomes that preserve genetic information during cell division (think of the plastic aglets that prevent shoelace ends from fraying).

Telomerase isn’t active in healthy adult tissues, so telomeres degrade and shorten as we age. When they get too short, the body knows to remove those damaged or dead cells.

In most cancers, telomerase is reactivated and telomeres are maintained, thus preserving the genetic material, and these are the cells that mutate and become immortal.

Telomerase is present in most cancer types, and it’s an attractive therapeutic target for cancer. However, scientists haven’t had much luck inhibiting telomerase activity in cancer, Ludlow said.

Ludlow’s group wanted to try a new approach, so they screened lung cancer cell lines for splicing genes (genes that modify RNA) that might regulate telomerase in cancer, and identified NOVA1.

They found that reducing the NOVA1 gene reduced telomerase activity, which led to shorter telomeres, and cancer cells couldn’t survive and divide.

Researchers only looked at non-small cell lung cancers, and NOVA1 was present in about 70 percent of them.

“Non-small cell lung cancer is the most prevalent form of age-related cancer, and 80 to 85 percent of all lung cancers are non-small cell,” Ludlow said. “But there really aren’t that many treatments for it.”

According to the American Cancer Society, lung cancer causes the most cancer deaths among men and women, and is the second most common cancer, aside from skin cancer.

Before researchers can target NOVA1 or telomerase splicing as a serious potential therapy for non-small cell lung cancer, they must gain a much better understanding of how telomerase is regulated. This research is a step in that direction.

Ludlow’s group is also looking at ways to directly impact telomerase splicing, in addition to reducing NOVA1.

Explore further: Blocking two enzymes could make cancer cells mortal

More information: Andrew T. Ludlow et al, NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer, Nature Communications (2018). DOI: 10.1038/s41467-018-05582-x

https://medicalxpress.com/news/2018-08-nova1-gene-tumor-growth-common.html

As the result of a six-year long research process, Fredrick R. Schumacher, a cancer epidemiology researcher at Case Western Reserve University School of Medicine, and an international team of more than 100 colleagues have identified 63 new genetic variations that could indicate higher risk of prostate cancer in men of European descent. The findings, published in a research letter in Nature Genetics, contain significant implications for which men may need to be regularly screened because of higher genetic risk of prostate cancer. The new findings also represent the largest increase in genetic markers for prostate cancer since they were first identified in 2006.

The changes, known as genetic markers or SNPs (“snips”), occur when a single base in the DNA differs from the usual base at that position. There are four types of bases: adenine (A), thymine (T), guanine (G) and cytosine (C). The order of these bases determines DNA’s instructions, or genetic code. They can serve as a flag to physicians that a person may be at higher risk for a certain disease. Previously, about 100 SNPs were associated with increased risk of prostate cancer. There are 3 billion base pairs in the human genome; of these, 163 have now been associated with prostate cancer.

One in seven men will be diagnosed with prostate cancer during their lifetimes.

“Our findings will allow us to identify which men should have early and regular PSA screenings and these findings may eventually inform treatment decisions,” said Schumacher. Prostate-specific antigen (PSA) screenings measure how much PSA, a protein produced by both cancerous and noncancerous tissue in the prostate, is in the blood.

Adding the 63 new SNPs to the 100 that are already known allows for the creation of a genetic risk score for prostate cancer. In the new study, the researchers found that men in the top one percent of the genetic risk score had a six-fold risk-increase of prostate cancer compared to men with an average genetic risk score. Those who had the fewest number of these SNPs, or a low genetic risk score, had the lowest likelihood of having prostate cancer.

In a meta-analysis that combined both previous and new research data, Schumacher, with colleagues from Europe and Australia, examined DNA sequences of about 80,000 men with prostate cancer and about 60,000 men who didn’t have the disease. They found that men with cancer had a higher frequency of 63 different SNPs (also known as single nucleotide polymorphisms) that men without the disease did not have. Additionally, the more of these SNPs that a man has, the more likely he is to develop prostate cancer.

The researchers estimate that there are about 500-1,000 genetic variants possibly linked to prostate cancer, not all of which have yet been identified. “We probably only need to know 10 percent to 20 percent of these to provide relevant screening guidelines,” continued Schumacher, who is an associate professor in the Department of Population and Quantitative Health Sciences at Case Western Reserve School of Medicine.

Currently, researchers don’t know which of the SNPs are the most predictive of increased prostate cancer risk. Schumacher and a number of colleagues are working to rank those most likely to be linked with prostate cancer, especially with aggressive forms of the disease that require surgery, as opposed to slowly developing versions that call for “watchful waiting” and monitoring.

The research lays a foundation for determining who and how often men should undergo PSA tests. “In the future, your genetic risk score may be highly indicative of your prostate cancer risk, which will determine the intensity of PSA screening,” said Schumacher. “We will be working to determine that precise genetic risk score range that would trigger testing. Additionally, if you have a low score, you may need screening less frequently such as every two to five years.” A further implication of the findings of the new study is the possibility of precise treatments that do not involve surgery. “Someday it may be feasible to target treatments based on a patient’s prostate cancer genetic risk score,” said Schumacher.

In addition to the work in the new study, which targets men of European background, there are parallel efforts underway looking at genetic signals of prostate cancer in men of African-American and Asian descent.

http://thedaily.case.edu/researchers-identify-dozens-new-gene-changes-point-elevated-risk-prostate-cancer-men-european-descent/


Researching tuberous sclerosis from the left are Adelaide Hebert, M.D.; John Slopis, M.D.; Mary Kay Koenig, M.D.; Joshua Samuels, M.D., M.P.H.; and Hope Northrup, M.D. PHOTO CREDIT Maricruz Kwon, UTHealth

Addressing a critical issue for people with a genetic disorder called tuberous sclerosis complex (TSC), doctors at The University of Texas Health Science Center at Houston (UTHealth) reported that a skin cream containing rapamycin significantly reduced the disfiguring facial tumors affecting more than 90 percent of people with the condition.

Findings of the multicenter, international study involving 179 people with tuberous sclerosis complex appear in the journal JAMA Dermatology.

“People with tuberous sclerosis complex want to look like everyone else,” said Mary Kay Koenig, M.D., the study’s lead author, co-director of the Tuberous Sclerosis Center of Excellence and holder of the Endowed Chair of Mitochondrial Medicine at McGovern Medical School at UTHealth. “And, they can with this treatment.”

Tuberous sclerosis complex affects about 50,000 people in the United States and is characterized by the uncontrolled growth of non-cancerous tumors throughout the body.

While benign tumors in the kidney, brain and other organs pose the greater health risk, the tumors on the face produce a greater impact on a patient’s daily life by making them look different from everyone else, Koenig said.

Koenig’s team tested two compositions of facial cream containing rapamycin and a third with no rapamycin. Patients applied the cream at bedtime for six months.

“Eighty percent of patients getting the study drug experienced a significant improvement compared to 25 percent of those getting the mixture with no rapamycin,” she said.

“Angiofibromas on the face can be disfiguring, they can bleed and they can negatively impact quality of life for individuals with TSC,” said Kari Luther Rosbeck, president and CEO of the Tuberous Sclerosis Alliance.

“Previous treatments, including laser surgery, have painful after effects. This pivotal study and publication are a huge step toward understanding the effectiveness of topical rapamycin as a treatment option. Further, it is funded by the TSC Research Program at the Department of Defense. We are so proud of this research,” Rosbeck said.

Rapamycin is typically given to patients undergoing an organ transplant. When administered by mouth, rapamycin suppresses the immune system to make sure the organ is not rejected.

Rapamycin and tuberous sclerosis complex are linked by a protein called mTOR. When it malfunctions, tuberous sclerosis complex occurs. Rapamycin corrects this malfunction.

Rapamycin was initially used successfully to treat brain tumors caused by tuberous sclerosis complex, so researchers decided to try it on TSC-related facial tumors. Building on a 2010 pilot study on the use of rapamycin to treat TSC-related facial tumors, this study confirmed that a cream containing rapamycin shrinks these tumors.

As the drug’s toxicity is a concern when taken by mouth, researchers were careful to check for problems tied to its use on the skin. “It looks like the medication stays on the surface of the skin. We didn’t see any appreciable levels in the bloodstreams of those participating in the study,” Koenig said.

The Topical Rapamycin to Erase Angiofibromas in TSC – Multicenter Evaluation of Novel Therapy or TREATMENT trial involved 10 test sites including one in Australia.

Koenig said additional studies are needed to gauge the long-term impact of the drug, the optimal dosage and whether the facial cream should be a combined with an oral treatment.

Koenig’s coauthors include Adelaide Hebert, M.D.; Joshua Samuels, M.D., M.P.H.; John Slopis, M.D.; Cynthia S. Bell; Joan Roberson, R.N.; Patti Tate; and Hope Northrup, M.D. All are from McGovern Medical School at UTHealth with the exception of Slopis, who is with The University of Texas MD Anderson Cancer Center. Hebert is also on the faculty of the MD Anderson Cancer Center and Northrup on the faculty of The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences.

The study was supported in part by the United States Department of Defense grant DOD TSCRP CDMRP W81XWH-11-1-0240 and by the Tuberous Sclerosis Alliance of Australia.

“The face is our window to the world and when you look different from everyone else, it impacts your confidence and your ability to interact with others. This treatment will help those with TSC become more like everyone else,” Koenig said.

https://www.uth.edu/media/story.htm?id=37af25df-14a2-4c5e-b1ee-ac9585946aa0

As many as one in three women treated for breast cancer undergo unnecessary procedures, but a new method for diagnosing it could do a better job distinguishing between benign and aggressive tumors.

Researchers at the University of Michigan are developing a pill that makes tumors light up when exposed to infrared light, and they have demonstrated that the concept works in mice.

Mammography is an imprecise tool. About a third of breast cancer patients treated with surgery or chemotherapy have tumors that are benign or so slow-growing that they would never have become life-threatening, according to a study out of Denmark last year. In other women, dense breast tissue hides the presence of lumps and results in deaths from treatable cancers. All that, and mammograms are notoriously uncomfortable.

“We overspend $4 billion per year on the diagnosis and treatment of cancers that women would never die from,” said Greg Thurber, U-M assistant professor of chemical engineering and biomedical engineering, who led the team. “If we go to molecular imaging, we can see which tumors need to be treated.”

The move could also catch cancers that would have gone undetected. Thurber’s team uses a dye that responds to infrared light to tag a molecule commonly found on tumor cells, in the blood vessels that feed tumors and in inflamed tissue. By providing specific information on the types of molecules on the surface of the tumor cells, physicians can better distinguish a malignant cancer from a benign tumor.

Compared to visible light, infrared light penetrates the body easily—it can get to all depths of the breast without an X-ray’s tiny risk of disrupting DNA and seeding a new tumor. Using a dye delivered orally rather than directly into a vein also improves the safety of screening, as a few patients in 10,000 can have severe reactions to intravenous dyes. These small risks turn out to be significant when tens of millions of women are screened every year in the U.S. alone.

But it’s not easy to design a pill that can carry the dye to the tumor.

“To get a molecule absorbed into the bloodstream, it needs to be small and greasy. But an imaging agent needs to be larger and water-soluble. So you need exact opposite properties,” Thurber said.

Fortunately, they weren’t the only people looking for a molecule that could get from the digestive system to a tumor. The pharmaceutical company Merck was working on a new treatment for cancer and related diseases. They got as far as phase II clinical trials demonstrating its safety, but unfortunately, it wasn’t effective.

“It’s actually based on a failed drug,” Thurber said. “It binds to the target, but it doesn’t do anything, which makes it perfect for imaging.”

The targeting molecule has already been shown to make it through the stomach unscathed, and the liver also gives it a pass, so it can travel through the bloodstream. The team attached a molecule that fluoresces when it is struck with infrared light to this drug. Then, they gave the drug to mice that had breast cancer, and they saw the tumors light up.

The research is described in a study in the journal Molecular Pharmaceutics, titled, “Oral administration and detection of a near-infrared molecular imaging agent in an orthotopic mouse model for breast cancer screening.”

This work was done in collaboration with David Smith, the John G. Wagner Collegiate Professor of Pharmaceutical Sciences at the U-M College of Pharmacy. It was supported by the Foundation for Studying and Combating Cancer and the National Institutes of Health.
Bhatnagar, S., Verma, K. D., Hu, Y., Khera, E., Priluck, A., Smith, D., & Thurber, G. M. (2018). Oral Administration and Detection of a Near-Infrared Molecular Imaging Agent in an Orthotopic Mouse Model for Breast Cancer Screening. Molecular Pharmaceutics. doi:10.1021/acs.molpharmaceut.7b00994