Figuring out why drugs don’t work on pancreatic cancer | Ars Technica

A mix of cancerous and normal cells alters interactions with the immune system.

by Mohit Kumar Jolly June 24 2014, 3:01pm CDT

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Pancreatic cancer is one of the most lethal cancers, with the survival period after diagnosis being only four to six months. The main reason for the poor prognosis is that chemotherapy, which has had some success in extending lives for patients with other cancers, doesn’t seem to slow down pancreatic cancer.

People had thought that this failure was caused by the tissue that surrounds the tumor, called the stroma, blocking the delivery of chemotherapy drugs to the tumor. A new study, published in Cancer Cell, raises questions about this idea. It shows that rather than supporting tumor progression, the stroma inhibits the progression by recruiting the body’s immune system to attack the tumor.

Tumorous tale

All tumors are composed of a mix of cancerous and normal cells. But pancreatic cancer is unusual in that only around 10 percent of the cells in the tumor are cancerous, the lowest proportion in any cancer. The remaining 90 percent is stroma that consists of cells known as myofibroblasts.

In keeping with this distinctive property of pancreatic cancer, a previous study had indicated that the stroma can act as a physical barrier to keep chemotherapy drugs away from the tumor. This finding triggered a slew of clinical trials that combined chemotherapy with “stromal depletion therapy”—that is, removing the stroma from the tumor. However, these trials had to be stopped abruptly when patients receiving this combination therapy were found to have an accelerated tumor progression when compared to patients who only received chemotherapy.

In a new study, Raghu Kalluri and his colleagues at MD Anderson Cancer Center may have found an explanation for these disappointing results.

Using mice, Kalluri and colleagues showed that the depletion of myofibroblasts—the major component of stroma—at any stage of pancreatic cancer does not improve the efficiency of chemotherapy. Instead, tumors grow more aggressively. This indicated to Kalluri that the stroma could inhibit the tumor rather than promote its growth.

“We did these experiments thinking that we would show the importance of myofibroblasts and fibrosis in pancreas cancer progression, but the results went completely against that hypothesis,” Kalluri said in a statement. “This supportive tissue that is abundant in pancreatic cancer tumors is not a traitor as we thought, but rather an ally that is fighting to the end. It’s a losing battle with cancer cells, but progression is much faster without their constant resistance. It is like having a car with weak yet functioning brakes vs having one with no brakes."

Dump me not just yet

It is not all bad news for this cancer therapy, however. Kalluri found that tumors with less stroma had higher levels of CTLA-4, a protein that is responsible for slowing down the immune system response. When these tumors were treated with ipilumimab, a drug that blocks CTLA-4, survival time of the mice increased by 60 percent compared to the untreated control mice.

This is a shot in the arm for cancer immunotherapy—therapies that enable the body’s immune system to fight cancer directly—which was named the Breakthrough of the Year in 2013 by the journal Science. This sort of therapy might be more effective in pancreatic cancer patients where CTLA-4 is blocked. It’s also possible that a combination of immunotherapy and stromal depletion therapy might be more effective for pancreatic cancer patients with dense stroma.

The development offers hope for patients with a disease in which only seven out of 100 patients survive for five years after being diagnosed.

Cancer Cell, 2014. DOI: 10.1016/j.ccr.2014.04.005 (About DOIs).

Mohit Kumar Jolly is a graduate student in cancer systems biology at Rice University. This article was first published on The Conversation.

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Nanomedical Devices

By Frank Boehmhttps://www.linkedin.com/pub/frank-boehm/34/b40/7ab

NANOmagazine_Issue28-1_pdf__page_1_of_40_

Exploring the Possibilities of Nanomedical Devices
http://www.futuremedicineonline.com/detail_news.php?id=138

 

Conceptual Nanomedical Lipofuscin Removal Strategy
http://www.nanobotmodels.com/node/73

Nano-medical Robotics: Non-Invasive Surgery and Cell Repair
http://www.roboticsbusinessreview.com/article/nano_medical_robotics_non_invasive_surgery_and_cell_repair

Upcoming Book Explores Nanomedical Device and Systems Design
http://www.foresight.org/nanodot/?p=5898

 

How Medical Nanotech Will Change Humanity Forever

http://io9.com/how-medical-nanotech-will-change-humanity-forever-1476398307

 

CBC Interview with Cathy Alex

http://www.cbc.ca/voyagenorth/2014/01/13/the-future-is-small/


Nanomedicine – past, present and future: an interview with Frank Boehm, CEO NanoApps Medical Inc.

http://www.news-medical.net/news/20140304/Nanomedicine-e28093-past-present-and-future-an-interview-with-Frank-Boehm-CEO-NanoApps-Medical-Inc.aspx

 

Please also find attached an article that I co-authored with artist and scientist, Dr. Angelika Domschke, for NANOmagazine, UK. “Advanced Nanomedical Diagnostics: New and Future Paradigms for the Enhanced Measurement of Health.”

 

Also a Google Hangout called Nanomedicine Weekly that I recently did with Angelika. http://internetmedicine.com/nanomedicine-weekly/

 

Related/Additional Reading

Nanomedical Device and Systems Design: Challenges, Possibilities, Visions – http://www.amazon.com/Nanomedical-Device-Systems-Design-Possibilities/dp/0849374987

Nano Magazine – NANOmagazine Issue28

Stash of stem cells found in a human parasite

A composite image of a scanning electron micrograph of a pair of male and female Schistosoma mansoni with the outer tegument (skin) of the male worm “peeled back” (digitally) to reveal the stem cells (orange) underneath. (Credit: Jim Collins, Ana Vieira and Phillip Newmark, Howard Hughes Medical Institute and University of Illinois at Urbana-Champaign)

Feb. 22, 2013 — The parasites that cause schistosomiasis, one of the most common parasitic infections in the world, are notoriously long-lived. Researchers have now found stem cells inside the parasite that can regenerate worn-down organs, which may help explain how they can live for years or even decades inside their host.

Schistosomiasis is acquired when people come into contact with water infested with the larval form of the parasitic worm Schistosoma, known as schistosomes. Schistosomes mature in the body and lay eggs that cause inflammation and chronic illness. Schistosomes typically live for five to six years, but there have been reports of patients who still harbor parasites decades after infection.

According to new research from Howard Hughes Medical Institute (HHMI) investigator Phillip Newmark, collections of stem cells that can help repair the worms’ bodies as they age could explain how the worms survive for so many years. The new findings were published online on February 20, 2013, in the journal Nature.

The stem cells that Newmark’s team found closely resemble stem cells in planaria, free-living relatives of the parasitic worms. Planaria rely on these cells, called neoblasts, to regenerate lost body parts. Whereas most adult stem cells in mammals have a limited set of possible fates—blood stem cells can give rise only to various types of blood cells, for example —planarian neoblasts can turn into any cell in the worm’s body under the right circumstances.

Newmark’s lab at the University of Illinois at Urbana-Champaign has spent years focused on planaria, so they knew many details about planarian neoblasts —what they look like, what genes they express, and how they proliferate. They also knew that in uninjured planarians, neoblasts maintain tissues that undergo normal wear and tear over the worm’s lifetime.

“We began to wonder whether schistosomes have equivalent cells and whether such cells could be partially responsible for their longevity,” says Newmark.

Following this hunch, and using what they knew about planarian neoblasts, post-doctoral fellow Jim Collins, Newmark, and their colleagues hunted for similar cells in Schistosoma mansoni, the most widespread species of human-infecting schistosomes.

Their first step was to look for actively dividing cells in the parasites. To do this, they grew worms in culture and added tags that would label newly replicated DNA as cells prepare to divide; this label could later be visualized by fluorescence. Following this fluorescent tag, they saw a collection of proliferating cells inside the worm’s body, separate from any organs.

The researchers isolated those cells from the schistosomes and studied them individually. They looked like typical stem cells, filled with a large nucleus and a small amount of cytoplasm that left little room for any cell-type-specific functionality. Newmark’s lab observed the cells and found that they often divided to give rise to two different cells: one cell that continued dividing, and another cell that did not.

“One feature of stem cells,” says Newmark, “is that they make more stem cells; furthermore, many stem cells undergo asymmetric division.” The schistosomes cells were behaving like stem cells in these respects. The other characteristic of stem cells is that they can differentiate into other cell types.

To find out whether the schistosome cells could give rise to multiple types of cells, Newmark’s team added the label for dividing cells to mice infected with schistosomes, waited a week, and then harvested the parasites to see where the tag ended up. They could detect labeled cells in the intestines and muscles of the schistosomes, suggesting that stem cells incorporating the labels had developed into both intestinal and muscle cells.

Years of previous study on planarians by many groups paved the way for this type of work on schistosomes, Newmark says.

“The cells we found in the schistosome look remarkably like planarian neoblasts. They aren’t associated with any one organ, but can give rise to multiple cell types. People often wonder why we study the ‘lowly’ planarian, but this work provides an example of how basic biology can lead you, in unanticipated and exciting ways, to findings that are directly relevant to important public health problems.”

Newmark says the stem cells aren’t necessarily the sole reason schistosome parasites survive for so many years, but their ability to replenish multiple cell types likely plays a role. More research is needed to find out how the cells truly affect lifespan, as well as what factors in the mouse or human host spur the parasite’s stem cells to divide, and whether the parasites maintain similar stem cells during other stages of their life cycle.

The researchers hope that with more work, scientists will be able to pinpoint a way to kill off the schistosome stem cells, potentially shortening the worm’s lifespan and treating schistosome infections in people.

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‘Quadruple helix’ DNA discovered in human cells

Researchers have shown that four-stranded ‘quadruple helix’ DNA structures — known as G-quadruplexes — exist within the human genome. (Credit: Jean-Paul Rodriguez and Giulia Biffi)

Jan. 20, 2013 — In 1953, Cambridge researchers Watson and Crick published a paper describing the interweaving ‘double helix’ DNA structure — the chemical code for all life.

Now, in the year of that scientific landmark’s 60th Anniversary, Cambridge researchers have published a paper proving that four-stranded ‘quadruple helix’ DNA structures — known as G-quadruplexes — also exist within the human genome. They form in regions of DNA that are rich in the building block guanine, usually abbreviated to ‘G’.

The findings mark the culmination of over 10 years investigation by scientists to show these complex structures in vivo — in living human cells — working from the hypothetical, through computational modelling to synthetic lab experiments and finally the identification in human cancer cells using fluorescent biomarkers.

The research, published January 20 in Nature Chemistry and funded by Cancer Research UK, goes on to show clear links between concentrations of four-stranded quadruplexes and the process of DNA replication, which is pivotal to cell division and production.

By targeting quadruplexes with synthetic molecules that trap and contain these DNA structures — preventing cells from replicating their DNA and consequently blocking cell division — scientists believe it may be possible to halt the runaway cell proliferation at the root of cancer.

“We are seeing links between trapping the quadruplexes with molecules and the ability to stop cells dividing, which is hugely exciting,” said Professor Shankar Balasubramanian from the University of Cambridge’s Department of Chemistry and Cambridge Research Institute, whose group produced the research.

“The research indicates that quadruplexes are more likely to occur in genes of cells that are rapidly dividing, such as cancer cells. For us, it strongly supports a new paradigm to be investigated — using these four-stranded structures as targets for personalised treatments in the future.”

Physical studies over the last couple of decades had shown that quadruplex DNA can form in vitro — in the ‘test tube’, but the structure was considered to be a curiosity rather than a feature found in nature. The researchers now know for the first time that they actually form in the DNA of human cells.

“This research further highlights the potential for exploiting these unusual DNA structures to beat cancer — the next part of this pipeline is to figure out how to target them in tumour cells,” said Dr Julie Sharp, senior science information manager at Cancer Research UK.

“It’s been sixty years since its structure was solved but work like this shows us that the story of DNA continues to twist and turn.”

The study published January 20 was led by Giulia Biffi, a researcher in Balasubramaninan’s lab at the Cambridge Research Institute.

By building on previous research, Biffi was able to generate antibody proteins that detect and bind to areas in a human genome rich in quadruplex-structured DNA, proving their existence in living human cells.

Using fluorescence to mark the antibodies, the researchers could then identify ‘hot spots’ for the occurrence of four-stranded DNA — both where in the genome and, critically, at what stage of cell division.

While quadruplex DNA is found fairly consistently throughout the genome of human cells and their division cycles, a marked increase was shown when the fluorescent staining grew more intense during the ‘s-phase’ — the point in a cell cycle where DNA replicates before the cell divides.

Cancers are usually driven by genes called oncogenes that have mutated to increase DNA replication — causing cell proliferation to spiral out of control, and leading to tumour growth.

The increased DNA replication rate in oncogenes leads to an intensity in the quadruplex structures. This means that potentially damaging cellular activity can be targeted with synthetic molecules or other forms of treatments.

“We have found that by trapping the quadruplex DNA with synthetic molecules we can sequester and stabilise them, providing important insights into how we might grind cell division to a halt,” said Balasubramanian.

“There is a lot we don’t know yet. One thought is that these quadruplex structures might be a bit of a nuisance during DNA replication — like knots or tangles that form.

“Did they evolve for a function? It’s a philosophical question as to whether they are there by design or not — but they exist and nature has to deal with them. Maybe by targeting them we are contributing to the disruption they cause.”

The study showed that if an inhibitor is used to block DNA replication, quadruplex levels go down — proving the idea that DNA is dynamic, with structures constantly being formed and unformed.

The researchers also previously found that an overactive gene with higher levels of Quadruplex DNA is more vulnerable to external interference.

“The data supports the idea that certain cancer genes can be usefully interfered with by small molecules designed to bind specific DNA sequences,” said Balasubramanian.

“Many current cancer treatments attack DNA, but it’s not clear what the rules are. We don’t even know where in the genome some of them react — it can be a scattergun approach.

“The possibility that particular cancer cells harbouring genes with these motifs can now be targeted, and appear to be more vulnerable to interference than normal cells, is a thrilling prospect.

“The ‘quadruple helix’ DNA structure may well be the key to new ways of selectively inhibiting the proliferation of cancer cells. The confirmation of its existence in human cells is a real landmark.”

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Specific Antibodies Halt Alzheimer’s Disease in Mice

Amyloid beta (cyan blue) binds to nerve cells of the hippocampus (red) and attacks synapses resulting in the loss of memories in Alzheimer’s disease. New research has led to important insights into the mechanisms that induce synapse loss. The discovery brings hope for the development of new therapies that protect synapses and therefore prevent memory loss in Alzheimer’s disease. (Credit: Silvia Purro/Patricia Salinas/UCL)

Antibodies that block the process of synapse disintegration in Alzheimer’s disease have been identified, raising hopes for a treatment to combat early cognitive decline in the disease.

Alzheimer’s disease is characterized by abnormal deposits in the brain of the protein Amyloid-ß, which induces the loss of connections between neurons, called synapses.

Now, scientists at UCL have discovered that specific antibodies that block the function of a related protein, called Dkk1, are able to completely suppress the toxic effect of Amyloid-ß on synapses. The findings are published March 6 in the Journal of Neuroscience.

Professor Patricia Salinas (UCL Department of Cell & Developmental Biology) who led the study, said: “These novel findings raise the possibility that targeting this secreted Dkk1 protein could offer an effective treatment to protect synapses against the toxic effect of Amyloid-ß.

“Importantly, these results raise the hope for a treatment and perhaps the prevention of cognitive decline early in Alzheimer’s disease.”

Story Continues -> http://www.sciencedaily.com/releases/2012/03/120306181155.htm

New Bandage Spurs, Guides Blood Vessel Growth

After the stamp is removed its pattern is revealed in the pattern of blood vessels below. (Credit: Photo courtesy Micro and Nanotechnology Lab)

Researchers have developed a bandage that stimulates and directs blood vessel growth on the surface of a wound. The bandage, called a “microvascular stamp,” contains living cells that deliver growth factors to damaged tissues in a defined pattern. After a week, the pattern of the stamp “is written in blood vessels,” the researchers report.

A paper describing the new approach will appear as the January 2012 cover article of the journal Advanced Materials.

“Any kind of tissue you want to rebuild, including bone, muscle or skin, is highly vascularized,” said University of Illinois chemical and biomolecular engineering professor Hyunjoon Kong, a co-principal investigator on the study with electrical and computer engineering professor Rashid Bashir. “But one of the big challenges in recreating vascular networks is how we can control the growth and spacing of new blood vessels.”

“The ability to pattern functional blood vessels at this scale in living tissue has not been demonstrated before,” Bashir said. “We can now write features in blood vessels.”

Other laboratories have embedded growth factors in materials applied to wounds in an effort to direct blood vessel growth. The new approach is the first to incorporate live cells in a stamp. These cells release growth factors in a more sustained, targeted manner than other methods, Kong said.

The stamp is nearly 1 centimeter across and is built of layers of a hydrogel made of polyethylene glycol (an FDA-approved polymer used in laxatives and pharmaceuticals) and methacrylic alginate (an edible, Jell-O-like material).

The stamp is porous, allowing small molecules to leak through, and contains channels of various sizes to direct the flow of larger molecules, such as growth factors.

Story Continues -> New Bandage Spurs, Guides Blood Vessel Growth

Particle Trap Paves Way for Personalized Medicine

Scientists were able to trap a single particle between four microelectrodes, paving the way for a faster and cheaper way to sequence DNA. (Credit: Weihua Guan and Mark Reed/Yale University)

Sequencing DNA base pairs — the individual molecules that make up DNA — is key for medical researchers working toward personalized medicine. Being able to isolate, study and sequence these DNA molecules would allow scientists to tailor diagnostic testing, therapies and treatments based on each patient’s individual genetic makeup.

But being able to isolate individual molecules like DNA base pairs, which are just two nanometers across — or about 1/50,000th the diameter of a human hair — is incredibly expensive and difficult to control. In addition, devising a way to trap DNA molecules in their natural aqueous environment further complicates things. Scientists have spent the past decade struggling to isolate and trap individual DNA molecules in an aqueous solution by trying to thread it through a tiny hole the size of DNA, called a “nanopore,” which is exceedingly difficult to make and control.

Now a team led by Yale University researchers has proven that isolating individual charged particles, like DNA molecules, is indeed possible using a method called “Paul trapping,” which uses oscillating electric fields to confine the particles to a space only nanometers in size. (The technique is named for Wolfgang Paul, who won the Nobel Prize for the discovery.) Until now, scientists have only been able to use Paul traps for particles in a vacuum, but the Yale team was able to confine a charged test particle — in this case, a polystyrene bead — to an accuracy of just 10 nanometers in aqueous solutions between quadruple microelectrodes that supplied the electric field.

Their device can be contained on a single chip and is simple and inexpensive to manufacture. “The idea would be that doctors could take a tiny drop of blood from patients and be able to run diagnostic tests on it right there in their office, instead of sending it away to a lab where testing can take days and is expensive,” said Weihua Guan, a Yale engineering graduate student who led the project.

Story Continues -> Particle Trap Paves Way for Personalized Medicine