Drug combo supresses growth of late-stage prostate cancer turmors

By Natalie van Hoose

Low doses of metformin, a widely used diabetes medication, and a gene inhibitor known as BI2536 can successfully halt the growth of late-stage prostate cancer tumors, a Purdue University study finds.

Prostate cancer causes the second-highest number of cancer-related deaths in men in the U.S., and methods of treating advanced prostate cancer are limited.

Xiaoqi Liu (pronounced zhow-CHEE' LEE'-oo), associate professor of biochemistry and cancer research, and fellow researchers found that the drugs metformin and BI2536 can work together to suppress the spread of prostate cancer that resists all other available treatments, potentially prolonging patients' lives.

"We've found a promising way to treat late-stage prostate cancer," Liu said. "By combining low levels of two well-tolerated drugs, the progression of this disease could be significantly delayed. Completely curing the cancer at the advanced stage is pretty much impossible, but this treatment might manage it for a while - that's exciting."

A number of treatments exist for the earlier stages of prostate cancer, which grows slowly compared with many other cancers. Because prostate cancer cells need the male sex hormone androgen to develop, one way to treat the disease is to suppress androgen - a process known as castration. If the cancer continues to spread, the patient often undergoes chemotherapy. As a last resort, drugs that block the synthesis of androgen by prostate cancer cells can be used, but these medications only extend a patient's lifespan for several months.

New approaches to treating the most persistent forms of prostate cancer are "urgently needed," Liu said.

Adding to the challenge is the fact that castration treatment can inadvertently encourage the cancer to get tougher. It can heighten oxidative stress on the prostate gland, which increases the expression of Plk1, a gene that has been linked to many cancers. Over-expression of Plk1 can also trigger the synthesis of androgen.

"The goal of castration is to block androgen synthesis," Liu said. "But cancer cells eventually become 'smart' enough to make androgen anyhow, which is why the cancer continues to grow."

Additionally, castration can disrupt the body's metabolism and lead to insulin resistance, which also can stimulate the production of androgen. The cancer will spread until both of these side effects are stopped, Liu said.

Previous studies showed that metformin - an inexpensive, antidiabetic drug that has been commonly used for more than 40 years - is particularly potent to prostate cancer tumors.

Working with fellow researchers from Purdue, the University of Wisconsin-Madison and the Indiana University School of Medicine, Liu found that a combination of low levels of metformin and BI2536, a drug that stifles the activity of Plk1, could work in tandem to slow the growth of prostate tumors too advanced for current treatments by promoting the self-destruction of cancer cells and preventing androgen synthesis.

The drugs did not impact healthy prostate cells, a "key finding," Liu said. "Ideally, cancer therapy will have minimal effects on normal cells."

Because metformin helps regulate metabolism, it may reverse some of the metabolic damage caused by castration, he said.

The researchers tested the drugs in a classical cell culture assay of prostate cancer cells and in advanced prostate tumors in mice. Low concentrations of the drugs significantly slowed the development of cancer in both trials. The mice tumors were grown from the tumor cells of a late-stage prostate cancer patient, suggesting that the treatment would prove effective in humans.

"Those results were amazing," Liu said. "These are the first data we've generated from a real patient, so I was almost jumping in the air when I saw that it worked."

Liu said that the next step in the research is to test the combination of drugs in clinical trials. Further research is also needed to understand the underlying mechanism of metformin and why it is effective at suppressing prostate cancer

Source: Purdue Univesity

Reducing Myc gene activity extends healthy lifespan in mice

No bones about it Young mice have good bone density whether they have two copies (top row; +/+) or one copy (bottom row; +/-) of the Myc gene. As they age, researchers found, mice with just one copy maintain better bone density and stay healthy longer. Sedivy lab/Brown University

Mice with one rather than the normal two copies of the gene Myc (also found in humans) lived 15 percent longer and had considerably healthier lives than normal mice, according to a new Brown University-led study in Cell.

PROVIDENCE, R.I. [Brown University] — A team of scientists based at Brown University has found that reducing expression of a fundamentally important gene called Myc significantly increased the healthy lifespan of laboratory mice, the first such finding regarding this gene in a mammalian species.

Myc is found in the genomes of all animals, ranging from ancestral single-celled organisms to humans. It is a major topic of biomedical research and has been shown to be a central regulator of cell proliferation, growth, and death. It is of such widespread and fundamental importance that animals cannot live without it. But in humans and mice, too much expression of the protein that Myc encodes has been closely linked to cancer, making it a well-known but elusive target of drug developers.

In a new study in the journal Cell, the scientists report that when they bred laboratory mice to have only one copy of the gene, instead of the normal two, thus reducing the expression of the encoded protein, those mice lived 15 percent longer on average — 20 percent longer for females and 10 percent longer among males — than normal mice. Moreover, the experimental mice showed many signs of better health into old age.

The experimental — “heterozygous” — mice grew to be about 15 percent smaller than the normal mice (a probable disadvantage in the wild) but that was the only discernable downside found to date for lacking a second copy of the gene, said senior author John Sedivy, the Hermon C. Bumpus Professor of Biology and professor of medical science at Brown.

“The animals are definitely aging slower,” he said. “They are maintaining the function of their organs and tissues for longer periods of time.”

Physiological differences

That assessment is based on detailed studies of the physiology — down to the molecular level — of the heterozygous and normal mice. The researchers conducted these experiments to try to understand the longevity difference between the two groups.

John Sedivy “The animals are definitely aging slower [and[ they are maintaining the function of their organs and tissues for longer periods of time.”

Co-lead author Jeffrey Hoffman, a medical and doctoral student, led the studies of the health of the mice, including various bodily systems. In many cases they were just like their normal counterparts. They reproduced just as well, for example.

“These mice are incredibly normal, yet they are really long-lived,” Sedivy said. “The reason why we were struck by that is because in many other longevity models like caloric restriction or treatment with rapamycin, the animals live longer but they also have some health issues.”

Instead the Myc heterozygous mice simply experienced fewer problems of aging. They did not develop osteoporosis, they maintained a healthier balance of immune system T cells, had less cardiac fibrosis, were more active, experienced less age-related slowing of their metabolic rate, produced less cholesterol, and exhibited better coordination.

Graduate student and co-lead author Xiaoai Zhao, meanwhile, led the molecular analysis of several pathways known to be involved in regulating longevity to find out how they might be different. Sure enough, heterozygous mice exhibited changes in IGF-1 signaling and nutrient and energy-sensing pathways, but how Myc engages those mechanisms is still not clear. Of particular interest, heterozygous mice showed less protein synthesis in several tissues. Regulation of this process is known to be under direct Myc control, and its reduction by a variety of means is known to extend lifespan in diverse species from yeast to mammals.

Genome-wide patterns of gene expression showed that Myc heterozygotes had significant differences in pathways related to metabolism and the immune system. Those patterns, however, only overlapped somewhat with patterns seen in other lifespan extending interventions.

Zhao and Hoffman’s studies also argue against a role for Myc in an oft-cited paradigm of greater longevity: upregulation of a variety of stress defense mechanisms. Their experimental mice seemed to suffer from as much stress and consequences of stress as normal mice.

The different benefits of Myc reduction compared to other laboratory longevity extenders shows that just as there are many ways the body can break down with aging, Sedivy said, there may be many ways to forestall that.

“There is more than one way to become long-lived,” Sedivy said.

Help for humans?

In the long term, Sedivy said he is optimistic that the findings about Myc could prove to matter to human health.

Finding the right target for a drug in one of Myc’s key metabolic or immune system pathways may or may not extend human lifespan, he said, but it might help people stay healthier as they age — for example, if it can reduce osteoporosis in people the way it does in mice. In particular, Sedivy said, it emphasizes the importance of the process of protein synthesis as a target of interventions that are likely to have widespread benefits on many organ systems.

And the study also offers encouragement to companies seeking to develop cancer drugs that block Myc overexpression. As important as normal Myc expression is to physiology, it appears that at least in mice there were many substantial benefits in reducing it by, say, half. Thus, Sedivy said, any drug that can target Myc directly is likely to find many applications beyond cancer.

In addition to Sedivy, Hoffman, and Zhao, the paper’s other authors are Marco De Cecco, Abigail Peterson, Luca Paglilaroli, Jayameenakshi Manivannan Bin Feng, Thomas Serre, Kevin Bath, Haiyan Xu, and Nicola Neretti of Brown; Gene Hubbard, Wenbo Qi, and Holly Van Remmen of the University of Texas; Yongqing Zhang and Rafael de Cabo of the National Institute on Aging; and Richard Miller of the University of Michigan.

The National Institutes of Health (grants R37AG016694, F30AG035592), the Ellison Medical Foundation, and the Glenn Award for Research on the Biological Mechanism of Aging supported the research. Some experiments were conducted in the Brown University molecular pathology and genomics cores.

Not just a longer life, but a healthier, stronger body “Do you think she might be a Myc hypomorph?” Drawing: Emma Sedivy

Source: Brown University

Cheap malaria drug could treat colorectal cancer effectively too, say experts

Artemisinin is isolated from the plant Artemisia annua also known as sweet wormwood. Credit: Image courtesy of University of St George's London

Medical experts say a common malaria drug could have a significant impact on colorectal cancer providing a cheap adjunct to current expensive chemotherapy.

A pilot study by researchers at St George's, University of London, has found the drug artesunate, which is a widely used anti-malaria medicine, had a promising effect on reducing the multiplication of tumour cells in colorectal cancer patients who were already going to have their cancer surgically removed.

Colorectal cancer (CRC) makes up about 10 percent of the annual 746,000 global cancer cases in men and 614,000 cases in women.

In the UK, 110 new cases are diagnosed daily, with older patients particularly at risk of death. Prognosis even with the best available treatments does not increase disease free or overall survival beyond 60 percent, five years after diagnosis.

Professor Sanjeev Krishna, an infectious disease expert at St George's who jointly-led the study, said: "There is therefore a continuing and urgent need to develop new, cheap, orally effective and safe colorectal cancer treatments.

"Our approach in this study was to take a close look at an existing drug that already had some anticancer properties in experimental settings, and to assess its safety and efficacy in patients.

"The results have been more than encouraging and can offer hopes of finding effective treatment options that are cheaper in the future."

"Larger clinical studies with artesunate that aim to provide well tolerated and convenient anticancer regimens should be implemented with urgency, and may provide an intervention where none is currently available, as well as synergistic benefits with current treatment regimens," added Professor Devinder Kumar, a leading expert in colorectal cancer at St George's and joint-lead of this study.

For most patients globally, access to advanced treatments is difficult as they are too expensive to be widely available, or associated with significant morbidity thereby further compromising their survival.

"In the St George's study, patients were examined and then were given either the anti-malaria drug artesunate or a placebo. After 42 months following surgery, there were six recurrences of cancer in the placebo group (of 12 patients) and one recurrence in an artesunate recipient (of 10 patients).The survival beyond two years in the artesunate group was estimated at 91% whilst surviving the first recurrence of cancer in the placebo group was only 57%.

This is the first randomized, double blind study to test the anti-CRC properties of oral artesunate. The anticancer properties of artemisinins have been seen in the laboratory previously but this is the first time their effect has been seen in patients in a rigorously designed study.

Source: University of St George's London

Researchers silence leading cancer-causing gene

Using bioluminescence, researchers showed that the novel molecule “KRAS silencing RNA” or "KRAS siRNA” (right) reduced the size of a tumor in mice. Researchers used a “non-KRAS silencing” molecule as the control (left) as a comparison. Credit: Image courtesy of University of North Carolina Health Care

Researchers from the UNC School of Medicine and colleagues at The University of Texas MD Anderson Cancer Center have developed a new approach to block the KRAS oncogene, one of the most frequently mutated genes in human cancer. The approach, led by Chad Pecot, MD, an assistant professor of medicine at UNC, offers another route to attack KRAS, which has proven to be an elusive and frustrating target for drug developers.

The new method relies upon a specifically sequenced type of small interfering RNA -- or siRNA. The findings, published in the journal Molecular Cancer Therapeutics, show that using a form of siRNA to halt KRAS not only dramatically stunted the growth of lung and colon cancers in cultured cells and mice but also stopped metastasis -- the main cause of cancer deaths.

"KRAS has been widely regarded as an undruggable protein, but we show that that's simply not the case," said Pecot, the study lead author and member of the UNC Lineberger Comprehensive Cancer Center.

KRAS is a signaling molecule -- a protein switch that triggers a cascade of molecular events that tell cells to grow and survive. Mutations in the KRAS gene create a switch that is perpetually "on," causing cells to divide uncontrollably. KRAS mutations are present in roughly 30 percent of human cancers, particularly lung, colon, pancreatic, and thyroid.

"It is the elephant in the room," Pecot said. "KRAS was one of the first cancer-causing genes ever discovered, and it was the obvious target to go after. People have been trying for decades to hit it, but they haven't had much luck."

Inhibiting KRAS signaling has been tricky because it lacks good pockets or crevices for small molecules and drugs to bind to. Some researchers have tried instead to target the proteins downstream in the KRAS signaling cascade, but those attempts have also had limited success.

Rather than try another conventional approach, Pecot decided to use a new genetic tool known as RNA interference -- or RNAi -- to destroy the KRAS protein before it fully forms. RNAi uses bits of synthetically engineered RNA -- the single-stranded molecule transcribed from DNA -- to silence specific genes. These bits of RNA bind to specific genetic messages called mRNA in the cell and direct enzymes to recognize the messages as enemies. In this context, the enzymes destroyed the genetic messages of KRAS mRNA so that KRAS can't be made. As a result, the cells don't grow, replicate, or move nearly as well.

RNAi has shown great promise in the treatment of liver diseases, viral infections, and cancers. To see if this approach could thwart the KRAS oncogene, Pecot and his colleagues first had to test different sequences of RNA to determine which one most effectively tagged KRAS for destruction. Of five RNA sequences, the researchers identified two candidates worthy to take into cancer models.

When they delivered these sequences into tissue culture cells, they found that the siRNAs destroyed more than 90 percent of the KRAS gene messages, significantly impairing the growth of cancer cell lines. The technique also led to marked reduction of two signaling molecules called pERK and pMEK, which lie downstream of KRAS and have been implicated in cancer cell proliferation and tumor growth.

Next, Pecot and his colleagues tested the siRNAs in mouse models of lung and colon cancer. They wrapped the sequences in protective lipid nanoparticles and delivered the siRNA solution into the mice. The researchers found that this treatment significantly slowed the growth of primary tumors. For example, tumors from colon cancer models that had been treated with the KRAS siRNAs were 69 percent smaller than tumors treated with control RNA sequences.

In addition, the researchers discovered that silencing KRAS stemmed the spread of cancer cells to other organs. The siRNA treatment reduced the number of these secondary malignant growths by about 80 percent in mice with lung cancer and to a similar degree in colon cancer models.

Pecot's findings come on the heels of two other papers using siRNAs to target KRAS, one from Frank McCormick's laboratory at the University of California at San Francisco and the other from Tyler Jacks' laboratory at the Massachusetts Institute of Technology. What sets the UNC study apart is that it demonstrates that this approach can be used to control the development of metastatic disease.

"Having all three papers come out at about the same time is encouraging because it means that KRAS is druggable if you use outside-the-box methods," Pecot said. "Now, we essentially have three platforms for targeting KRAS with siRNAs that may get to the clinic."

Pecot said the results, while promising, are just a first step in combating this cancer-causing gene. Ultimately, the siRNA sequences will have to be designed to specifically target the mutant form of KRAS without disrupting the normal form of the gene, which is necessary for maintaining normal growth in healthy cells.

Source: University of North Carolina Health Care

Rewiring metabolism slows colorectal cancer growth

Many cancers have less MPC in them than normal adult tissues. Re-introducing MPC into cancer cells slows growth of tumors following injection into mice as compared to unmanipulated cells. Credit: Ralph DeBerardinis

Cancer is an unwanted experiment in progress. As the disease advances, tumor cells accumulate mutations, eventually arriving at ones that give them the insidious power to grow uncontrollably and spread. Distinguishing drivers of cancer from benign mutations open opportunities for developing targeted cancer therapies.

A University of Utah-led study reports that cancers select against a protein complex called the mitochondrial pyruvate carrier (MPC), and re-introduction of MPC in colon cancer cells impairs several properties of cancer, including growth. The research, which appears online on Oct. 30 in Molecular Cell, implicates changes in a key step in metabolism -- the way cellular fuel is utilized -- as an important driver of colon cancer that is also likely to be important in many other cancer settings.

Cancers appear to do whatever they can to get rid of MPC, a protein involved in carbohydrate metabolism, shows the study led by Jared Rutter, Ph.D., professor of biochemistry and Dee Glen and Ida W. Smith Endowed Chair for Cancer Research at the University of Utah. At least 18 types of cancers -- colon, brain, breast, and liver among them -- have significantly less MPC than normal adult cells. Some cancers simply delete a region of the genome that contains one of the MPC genes, others find different ways to dampen MPC expression. In fact, a survey of patient biopsies shows that the less MPC there is, the more aggressive the cancer becomes.

"Loss of MPC seems to be a biomarker for cancer aggressiveness and patient survival," said Rutter, also co-director of the Diabetes and Metabolism Center at the University of Utah, and co-leader of the Nuclear Control of Cell Growth and Differentiation Program at the Huntsman Cancer Institute. "That was our first clue that MPC might be important."

Even more striking, when Rutter's group reintroduced MPC into colon cancer cell lines, properties that define them as cancerous, reverted. The cells divide less frequently under certain conditions and decrease expression of stem cell markers, an early step frequently defining the potential to form tumors and spread. Further, the engineered cells are dramatically impaired in their ability to form tumors after injection into mice. Tumors containing cells with MPC were as small as one-fourth the size of tumors made from cells without the protein complex.

"We think these results show that elimination of MPC is an early and important step in development of cancer," said John Schell, who is co-first author with Kristofor Olson, both M.D.-Ph.D. students at the University of Utah. "Finding the stem cell connection was probably the most exciting part for us, and is something we'll pursue further to understand how loss of MPC changes cell behavior."

The role of MPC in the normal cell, and what loss of MPC does to a cancer cell, addresses an observation first made nearly one century ago. Nobel Prize-wining biochemist Otto Warburg noted that cancer cells change their metabolism to support uncontrolled growth and proliferation. Scientists later found the way in which the metabolite pyruvate is processed is key to these metabolic changes. In normal adult cells, pyruvate enters the mitochondria, the cell's powerhouse, and fuels energy production. In cancer, pyruvate is diverted from the mitochondria to an alternative metabolic pathway that makes cell-building material.

Scientists had long suspected the so-called Warburg effect seen in cancer was contingent upon controlling entry of pyruvate into the mitochondria. But there was no way to directly test the idea until two years ago, when Rutter's group and others identified MPC as pyruvate's doorway to the mitochondria. The current report in Molecular Cell shows that cancer cells shut that door by repressing MPC, and that experimentally re-opening the door by re-introducing MPC not only inhibits cancer growth, but also redirects pyruvate to the metabolic pathway used in normal cells. In other words, MPC counteracts the Warburg effect.

"This makes sense because MPC is a pinch point in metabolism," said Rutter. "Our work, taken together with that from many other laboratories, shows that most cancer cells are completely reliant on this unusual metabolism known as the Warburg effect."

Understanding the Warburg effect has been an area of intense interest in recent years because of the potential to translate those discoveries into new cancer therapeutics. "We think this information can be used to design therapies that are specifically toxic to cancer cells," said Rutter.

Source: University of Utah Health Sciences

Transplant drug could boost power of brain tumor treatments, study finds

Drs. Maria Castro and Pedro Lowenstein, both of the U-M Department of Neurosurgery, co-led the research. Credit: Image courtesy of University of Michigan Health System

Every day, organ transplant patients around the world take a drug called rapamycin to keep their immune systems from rejecting their new kidneys and hearts. New research suggests that the same drug could help brain tumor patients by boosting the effect of new immune-based therapies.

In experiments in animals, researchers from the University of Michigan Medical School showed that adding rapamycin to an immunotherapy approach strengthened the immune response against brain tumor cells.

What's more, the drug also increased the immune system's "memory" cells so that they could attack the tumor if it ever reared its head again. The mice and rats in the study that received rapamycin lived longer than those that didn't.

Now, the U-M team plans to add rapamycin to clinical gene therapy and immunotherapy trials to improve the treatment of brain tumors. They currently have a trial under way at the U-M Health System which tests a two-part gene therapy approach in patients with brain tumors called gliomas in an effort to get the immune system to attack the tumor. In future clinical trials, adding rapamycin could increase the therapeutic response.

The new findings, published online in the journal Molecular Cancer Therapeutics, show that combining rapamycin with a gene therapy approach enhanced the animals' ability to summon immune cells called CD8+ T cells to kill tumor cells directly. Due to this cytotoxic effect, the tumors shrank and the animals lived longer.

But the addition of rapamycin to immunotherapy even for a short while also allowed the rodents to develop tumor-specific memory CD8+ T cells that remember the specific "signature" of the glioma tumor cells and attacked them swiftly when a tumor was introduced into the brain again.

"We had some indication that rapamycin would enhance the cytotoxic T cell effect, from previous experiments in both animals and humans showing that the drug produced modest effects by itself," says Maria Castro, Ph.D., senior author of the new paper. Past clinical trials of rapamycin in brain tumors have failed.

"But in combination with immunotherapy, it became a dramatic effect, and enhanced the efficacy of memory T cells too. This highlights the versatility of the immunotherapy approach to glioma." Castro is the R.C. Schneider Collegiate Professor of neurosurgery and a professor of cell and developmental biology at U-M.

Rapamycin is an FDA-approved drug that produces few side effects in transplant patients and others who take it to modify their immune response. So in the future, Castro and her colleagues plan to propose new clinical trials that will add rapamycin to immune gene therapy trials like those already ongoing at UMHS.

She notes that other researchers currently studying immunotherapies for glioma and other brain tumors should also consider doing the same. "This could be a universal mechanism for enhancing efficacy of immunotherapies in glioma," she says.

Rapamycin inhibits a specific molecule in cells, called mTOR. As part of the research, Castro and her colleagues determined that brain tumor cells use the mTOR pathway to hamper the immune response of patients.

This allows the tumor to trick the immune system, so it can continue growing without alerting the body's T cells that a foreign entity is present. Inhibiting mTOR with rapamycin, then, uncloaks the cells and makes them vulnerable to attack.

Castro notes that if the drug proves useful in human patients, it could also be used for long-term prevention of recurrence in patients who have had the bulk of their tumor removed. "This tumor always comes back," she says.

Source: University of Michigan Health System

Handheld scanner could make brain tumor removal more complete, reducing recurrence

A handheld device that resembles a laser pointer could someday help surgeons remove all of the cells in a brain tumor. Credit: Moritz Kircher

Cancerous brain tumors are notorious for growing back despite surgical attempts to remove them -- and for leading to a dire prognosis for patients. But scientists are developing a new way to try to root out malignant cells during surgery so fewer or none get left behind to form new tumors. The method, reported in the journal ACS Nano, could someday vastly improve the outlook for patients.

Moritz F. Kircher and colleagues at Memorial Sloan Kettering Cancer Center point out that malignant brain tumors, particularly the kind known as glioblastoma multiforme (GBM), are among the toughest to beat. Although relatively rare, GBM is highly aggressive, and its cells multiply rapidly. Surgical removal is one of the main weapons doctors have to treat brain tumors. The problem is that currently, there's no way to know if they have taken out all of the cancerous cells. And removing extra material "just in case" isn't a good option in the brain, which controls so many critical processes. The techniques surgeons have at their disposal today are not accurate enough to identify all the cells that need to be excised. So Kircher's team decided to develop a new method to fill that gap.

The researchers used a handheld device resembling a laser pointer that can detect "Raman nanoprobes" with very high accuracy. These nanoprobes are injected the day prior to the operation and go specifically to tumor cells, and not to normal brain cells. Using a handheld Raman scanner in a mouse model that mimics human GBM, the researchers successfully identified and removed all malignant cells in the rodents' brains. Also, because the technique involves steps that have already made it to human testing for other purposes, the researchers conclude that it has the potential to move readily into clinical trials. Surgeons might be able to use the device in the future to treat other types of brain cancer, they say.

The authors acknowledge funding from the National Institutes of Health.

Source: American Chemical Society

What makes pancreatic cancer so aggressive? New study sheds light

“We know that patients with the earliest stage of pancreatic cancer have a survival rate of only 30 percent. This suggests that even in that very early stage of invasive cancer there are already cells that have spread to distant parts of the body,” says study author Diane M. Simeone, M.D. Credit: Image courtesy of University of Michigan Health System

New research from the University of Michigan Comprehensive Cancer Center helps explain why pancreatic cancer is so lethal, with fewer than a third of patients surviving even early stage disease.

The researchers found a gene known to be involved in nearly 90 percent of pancreatic cancers promotes cancer growth and spread. The gene, ATDC, plays a key role in how a tumor progresses from a preinvasive state to an invasive cancer to metastatic cancer.

"We know that patients with the earliest stage of pancreatic cancer have a survival rate of only 30 percent. This suggests that even in that very early stage of invasive cancer there are already cells that have spread to distant parts of the body," says study author Diane M. Simeone, M.D., director of the Pancreatic Cancer Center at the University of Michigan Comprehensive Cancer Center.

"This study sheds important light on what it is about pancreatic cancer that makes it so aggressive early in the game," she adds. The study appears Jan. 15 in Genes and Development.

Researchers used a mouse model to replicate pancreatic cancer as it appears in humans. They also studied pancreatic cancer tissue samples and samples of pre-invasive pancreatic lesions. They found ATDC was expressed in a subset of the pre-invasive cells and played a role in the development of pancreatic cancer stem cells, the small number of cells in a tumor that fuel its growth and spread. This suggests that ATDC promotes a tumor's invasiveness and spread early in the course of disease.

The researchers suspect that ATDC may be a potent drug target. No drugs currently exist to target this pathway in part because researchers do not understand the crystal structure of the protein. Simeone's team, working with the University of Michigan Center for Structural Biology has made crystals of the protein and begun to create a three-dimensional structure that they can use as a model for drug development.

Preliminary data suggests that ATDC may also play a role in other cancer types, including bladder, ovarian, colorectal and lung cancers and multiple myeloma. But, Simeone notes, it's particularly critical to find new treatment options for pancreatic cancer. About 46,400 Americans will be diagnosed with pancreatic cancer this year, and more than 39,000 will die of the disease. Pancreatic cancer is expected to become the second-leading cause of cancer death in the United States by 2030.

Source: University of Michigan Health System

3-D culture system for pancreatic cancer has potential to change therapeutic approaches

A team of researchers has developed a method to grow pancreatic tissue in a three-dimensional culture system, called organoids. The scientists are able to use tissue not only from laboratory mouse models, but also from human patients. The technology promises to change the way pancreatic cancer research is done, offering a path to personalized treatment approaches in the future. Credit: D. Tuveson/ Cold Spring Harbor Laboratory

Cold Spring Harbor and Bethpage, N.Y. -- Pancreatic cancer is one of the most deadly forms of cancer, with only 6 percent of patients surviving five years after diagnosis. Today, Cold Spring Harbor Laboratory (CSHL) and The Lustgarten Foundation jointly announce the development of a new model system to grow both normal and cancerous pancreatic cells in the laboratory. Their work offers the potential to change the way pancreatic cancer research is done, allowing scientists to interrogate the pathways driving this devastating disease while searching for new drug targets.

In work published in Cell, the research team describes a three-dimensional "organoid" culture system for pancreatic cancer. Co-led by David Tuveson, CSHL Professor and Director of Research for The Lustgarten Foundation, and Hans Clevers, Professor and Director of the Hubrecht Institute and President of the Royal Netherlands Academy of Arts and Sciences, the team developed a method to grow pancreatic tissue not only from laboratory mouse models, but also from human patient tissue, offering a path to personalized treatment approaches in the future.

All cancer research relies on a steady supply of cells -- both normal and cancerous -- that can be grown in the laboratory. By comparing normal cells to cancer cells, scientists can then identify the changes that lead to disease. However, both types of pancreatic cells have been extremely difficult to culture in the laboratory.

Furthermore, the normal ductal cells that are able to develop into pancreatic cancer represent about 10 percent of the cells in the pancreas, complicating efforts to pinpoint the changes that occur as the tumor develops. Until now, scientists have been entirely unable to culture human normal ductal pancreatic cells under standard laboratory conditions. 

Because of these limitations, most pancreatic cancer research relies on genetically engineered mouse models of the disease, which can take up to one year to generate. "With this development, we are now able to culture both mouse and human organoids, providing a very powerful tool in our fight against pancreatic cancer," explains Tuveson.

The organoids are entirely made up of ductal cells, eliminating the surrounding cell types that often contaminate samples from the pancreas. They grow as hollow spheres within a complex gel-like substance filled with growth-inducing factors and connecting fibers. Once they have grown to a sufficient size, the organoids can be transplanted back into mice, where they fully recapitulate pancreatic cancer. "We now have a model for each stage in the progression of the disease," says Chang-Il Hwang, Ph.D., one of the lead authors working in The Lustgarten Foundation's Pancreatic Cancer Research Lab at CSHL directed by Dr. Tuveson.

Traditionally, cancer cells are isolated during surgery or autopsies. Unfortunately, approximately 85 percent of cancer patients are ineligible for surgery at the time of diagnosis, either because the tumor is entwined in critical vasculature or the disease has progressed too far. Researchers therefore have had limited access to patient samples. The new research provides a way for scientists to grow organoids from biopsy material, which is comparatively easy to obtain. "Biopsies are the standard for diagnosis," says Dannielle Engle, Ph.D., also a lead author on the paper. "We can now rapidly generate organoids from any patient, which offers us the potential to study the disease in a much wider population."

The team is now working to create a repository of pancreatic tumor samples, coordinating with the National Cancer Institute. "We hope to make this available to the entire pancreatic cancer research community," says Tuveson. Additionally, Lindsey Baker, Ph.D., another lead author of the paper, has started holding an "organoid school" for other researchers, and has already taught six laboratories from around the world this technique.

Source: Cold Spring Harbor Laboratory

'Sugar-coated' microcapsule eliminates toxic punch of experimental anti-cancer drug

3BrPA (red) is illustrated encased in a sugar-based microshell. Credit: Jean-Francois Geschwind, Johns Hopkins

Johns Hopkins researchers have developed a sugar-based molecular microcapsule that eliminates the toxicity of an anticancer agent developed a decade ago at Johns Hopkins, called 3-bromopyruvate, or 3BrPA, in studies of mice with implants of human pancreatic cancer tissue. The encapsulated drug packed a potent anticancer punch, stopping the progression of tumors in the mice, but without the usual toxic effects.

"We developed 3BrPA to target a hallmark of cancer cells, namely their increased dependency on glucose compared with normal cells. But the nonencapsulated drug is toxic to healthy tissues and inactivated as it navigates through the blood, so finding a way to encapsulate the drug and protect normal tissues extends its promise in many cancers as it homes in on tumor cells," says Jean-Francois Geschwind, M.D., chief of the Division of Interventional Radiology at Johns Hopkins Medicine.

The Johns Hopkins team used a microshell made of a sugar-based polymer called cyclodextrin to protect the 3BrPA drug molecules from disintegrating early and to guard healthy tissue from the drug's toxic effects, such as weight loss, hypothermia and lethal hypoglycemic shock.

Geschwind, a professor in the Russell H. Morgan Department of Radiology and Radiological Science at the Johns Hopkins University School of Medicine and its Kimmel Cancer Center, and others at Johns Hopkins have been studying the experimental drug as a cancer treatment for over a decade because of its ability to block a key metabolic pathway of cancer cells.

Most cancer cells, he explains, rely on the use of glucose to thrive, a process known as the Warburg effect, for Otto Heinrich Warburg, who was awarded the Nobel Prize in Physiology for the discovery in 1931. By using the same cellular channels that funnel glucose into a cancer cell, 3BrPA can travel inside the cancer cell and block its glucose metabolic pathway, Geschwind says.

However, animal studies have shown that in its free, nonencapsulated state, the drug is very toxic, says Geschwind.

The toxicity associated with the free-form version of the drug, he says, has prevented physicians from using the drug as a systemic treatment in people, one that can travel throughout the whole body.

In a report about their study published online Oct. 17 in Clinical Cancer Research, the researchers described minimal or zero tumor progression in mice treated with the microencapsulated 3BrPA. By contrast, a signal of tumor activity increased sixty-fold in mice treated with the widely used chemotherapy drug gemcitabine. Activity increased 140-fold in mice who received the drug without encapsulation.

Specifically, daily injections of nonencapsulated 3BrPA were highly toxic to the animals, as only 28 percent of the animals survived the 28-day treatment. All of the mice who received the encapsulated drug survived to the end of the study.

Geschwind says the "extremely promising results" of the study make the encapsulated drug a good candidate for clinical trials, particularly for patients with pancreatic ductal adenocarcinoma. These cancers rank as the fourth most common cause of cancer-related deaths in the world, with a five-year survival rate of less than 5 percent. In the mouse studies, the encapsulated medication also reduced the metastatic spread of pancreatic cancer cells.

Source: Johns Hopkins Medicine

First steps in formation of pancreatic cancer identified

Shown is a region of a pancreas with preneoplastic lesions. Red labeling indicates macrophages, green labeling indicates pancreatic acinar cells that dedifferentiate, and grey labeling indicates further progressed pancreatic lesions. Credit: Image courtesy of Mayo Clinic

Researchers at Mayo Clinic's campus in Jacksonville say they have identified first steps in the origin of pancreatic cancer and that their findings suggest preventive strategies to explore.

In an online issue of Cancer Discovery, the scientists described the molecular steps necessary for acinar cells in the pancreas -- the cells that release digestive enzymes -- to become precancerous lesions. Some of these lesions can then morph into cancer.

"Pancreatic cancer develops from these lesions, so if we understand how these lesions come about, we may be able to stop the cancer train altogether," says the study's lead investigator, Peter Storz, Ph.D., a cancer biologist.

The need for new treatment and prevention strategies is pressing, Dr. Storz says. Pancreatic cancer is one of the most aggressive human cancers -- symptoms do not occur until the cancer is well advanced. One-year survival after diagnosis is only 20 percent. It is the fourth leading cause of cancer death in this country.

The scientists studied pancreatic cells with Kras genetic mutations. Kras produces a protein 

that regulates cell division, and the gene is often mutated in many cancers. More than 95 percent of pancreatic cancer cases have a Kras mutation.

The researchers detailed the steps that led acinar cells with Kras mutations to transform into duct-like cells with stem cell-like properties. Stem cells, which can divide at will, are also often implicated in cancer.

They found that Kras proteins in the acinar cells induce the expression of a molecule, ICAM-1, which attracts macrophages, a specific kind of immune cells. These inflammatory macrophages release a variety of proteins, including some that loosen the structure of the cells, allowing acinar cells to morph into different types of cells. These steps produced the precancerous pancreatic lesions.

"We show a direct link between Kras mutations and the inflammatory environment that drive the initiation of pancreatic cancer," Dr. Storz says.

But the process can be halted in laboratory mice, he adds. "We could do this two ways -- by depleting the macrophages or by treating the transformed cells with a blocking antibody that shuts down ICAM-1," says Dr. Storz. "Doing either one reduced the number of precancerous lesions."

Dr. Storz noted that a neutralizing antibody that blocks ICAM-1has already been developed. It is being tested for a wide variety of disorders, including stroke and rheumatoid arthritis.

"Understanding the crosstalk between acinar cells with Kras mutations and the microenvironment of those cells is key to developing targeted strategies to prevent and treat this cancer," he says.

Source: Mayo Clinic

New combination therapy developed for multiple myeloma

This is Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Cancer Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center. Credit: VCU Massey Cancer Center

Each year, more than 25,000 Americans are diagnosed with multiple myeloma, a form of blood cancer that often develops resistance to therapies. However, researchers at Virginia Commonwealth University Massey Cancer Center are reporting promising results from laboratory experiments testing a new combination therapy that could potentially overcome the resistance hurdle.

While several drugs are effective against multiple myeloma, including the proteasome inhibitor bortezomib, multiple myeloma cells are often able to survive by increasing the production of a protein known as Mcl-1. Mcl-1 regulates a number of processes that promote cell survival and has been implicated in resistance to anti-myeloma drugs that were initially effective. However, a team of researchers led by Xin-Yan Pei, M.D., Ph.D., and Steven Grant, M.D., recently published the findings of a study in the journal PLoS ONE demonstrating that a novel drug combination both reduces Mcl-1 expression and disrupts its interactions with other proteins to effectively kill multiple myeloma cells. The therapy combines a type of drug known as a Chk1 inhibitor with another called a MEK inhibitor. Chk1 inhibitors prevent cells from arresting in stages of the cell cycle that facilitate the repair of DNA damage, while MEK inhibitors prevent cells from activating a variety of proteins that regulate DNA repair processes while promoting the accumulation of pro-death proteins.

"This research builds on our previous studies that showed exposing multiple myeloma and leukemia cells to Chk1 inhibitors activated a protective response through the Ras/MEK/ERK signaling pathway," says Pei, instructor in the Department of Internal Medicine at the VCU School of Medicine. "By combining a Chk1 inhibitor with a MEK inhibitor, we have developed one of only a limited number of strategies shown to circumvent therapeutic resistance caused by high expressions of Mcl-1."

In laboratory experiments, the scientists enforced overexpression of Mcl-1 in human multiple myeloma cells. They found that this caused the cells to become highly resistant to bortezomib, but it failed to protect them from the Chk1/MEK inhibitor regimen. 

Additionally, the combination therapy was able to completely overcome resistance due to microenvironmental factors associated with increased expression of Mcl-1. A cell's microenvironment consists of surrounding cells and the fluids in which they reside, and the communication between cancer cells and their surrounding cells can significantly impact resistance. Mcl-1 plays a key role in this communication by facilitating events that promote cancer cell survival.

"Not only was the combination therapy effective against multiple myeloma cells, it notably did not harm normal bone marrow cells, raising the possibility of therapeutic selectivity," says Grant, the study's lead investigator and Shirley Carter Olsson and Sture Gordon Olsson Chair in Cancer Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center. "We are hopeful that this research will lead to better therapies for multiple myeloma, and help make current therapies more effective by overcoming resistance caused by Mcl-1."

The researchers have started initial discussions with clinical investigators and drug manufacturers with hopes of developing a clinical trial testing a combination of Chk1 and MEK inhibitors in patients with refractory multiple myeloma. It is too early to estimate when the trial will open.

Source: Virginia Commonwealth University

Scientists discover new way protein degradation is regulated

Chamber of doom. Rockefeller scientists have identified a new way that proteins are degraded in the proteasome (green). They found that the enzyme tankyrase regulates proteasome activity by promoting the assembly of proteasome subunits into the active complex called 26S. Credit: Image by Sigi Benjamin-Hong, Strang Laboratory of Apoptosis and Cancer Biology

Proteins, unlike diamonds, aren't forever. And when they wear out, they need to be degraded in the cell back into amino acids, where they will be recycled into new proteins. Researchers at Rockefeller University and the Howard Hughes Medical Institute have identified a new way that the cell's protein recycler, the proteasome, takes care of unwanted and potentially toxic proteins, a finding that has implications for treating muscle wasting, neurodegeneration and cancer.

The consensus among scientists has been that the proteasome is constantly active, chewing up proteins that have exceeded their shelf life. A mounting body of evidence now suggests that the proteasome is dynamically regulated, ramping up its activity when the cell is challenged with especially heavy protein turnover. The researchers, postdoctoral associate Park F. Cho-Park and Hermann Steller, head of the Strang Laboratory of Apoptosis and Cancer Biology at Rockefeller, have shown that an enzyme called tankyrase regulates the proteasome's activity. In addition, Cho-Park and Steller demonstrate that a small molecule called XAV939, originally identified by scientists at Novartis who developed it as therapeutic for colon cancer, inhibits tankyrase and blocks the proteasome's activity. The research is reported in today's issue of the journal Cell.

"Our findings have tremendous implications for the clinic since it gives a new meaning to an existing class of small-molecule compound," says Steller, Strang Professor at Rockefeller and an investigator at HHMI. "In particular, our work suggests that tankyrase inhibitors may be clinically useful for treating multiple myeloma."

Tankyrase was originally identified in the late 1990s by Rockefeller's Titia de Lange and her colleagues in the Laboratory for Cell Biology and Genetics, who showed that it plays a role in elongating telomeres, structures that cap and protect the ends of chromosomes. In a series of experiments in fly and human cells, Cho-Park and Steller discovered that tankyrase uses a process called ADP-ribosylation to modify PI31, a key factor that regulates the activity and assembly of proteasome subunits into the active complex called 26S. By promoting the assembly of more 26S particles, cells under stress can boost their ability to break down and dispose of unwanted proteins.

The proteasome is currently a target for developing cancer therapeutics. The FDA has approved Velcade, a proteasome inhibitor, for the treatment of multiple myeloma and mantle cell lymphoma. However, patients on Velcade can experience peripheral neuropathy or become resistant to the drug.

Multiple myeloma cells need increased proteasome activity to survive. Preliminary data from Cho-Park and Steller show that XAV939 can block the growth of multiple myeloma cells by inhibiting the assembly of additional proteasomes without affecting the basal level of proteasomes in the cell. This selective targeting may mean fewer side effects for patients. 

"Drugs, such as XAV939, that inhibit the proteasome through other mechanisms than Velcade may have significant clinical value," says Steller.

The findings by Cho-Park and Steller also link, for the first time, metabolism and regulation of the proteasome. Sometimes the proteasome digests too much protein, which can lead to loss of muscle, says Steller.

"This discovery reveals fundamental insights into protein degradation, a process important for normal cell biology, and a key factor in disorders such as muscle wasting and neurodegeneration," said Stefan Maas of the National Institutes of Health's National Institute of General Medical Sciences, which partly supported the study. "Intriguingly, the findings also enlighten ongoing research on cancer therapies, exemplifying the impact of basic research on drug development."

Source: Rockefeller University

Powerful new system for classifying tumors revealed

This diagram illustrates how tumors with different tissues of origin were reclassified on the basis of molecular analyses. Credit: Zhong Chen, NIH/NIDCD

Cancers are classified primarily on the basis of where in the body the disease originates, as in lung cancer or breast cancer. According to a new study, however, one in ten cancer patients would be classified differently using a new classification system based on molecular subtypes instead of the current tissue-of-origin system. This reclassification could lead to different therapeutic options for those patients, scientists reported in a paper published August 7 in Cell.

"It's only ten percent that were classified differently, but it matters a lot if you're one of those patients," said senior author Josh Stuart, a professor of biomolecular engineering at UC Santa Cruz.

Stuart helped organize the study as part of the Pan-Cancer Initiative of the Cancer Genome Atlas (TCGA) project. A large team of researchers from multiple institutions performed a comprehensive analysis of molecular data from thousands of patients representing 12 different types of cancer. This was the most comprehensive and diverse collection of tumors ever analyzed by systematic genomic methods. Each tumor type was characterized using six different "platforms" or methods of molecular analysis--mostly genomic platforms such as DNA and RNA sequencing, plus a protein expression analysis.

The research team used statistical analyses of the molecular data to divide the tumors into groups or "clusters," first analyzing the data from each platform separately and then combining them in an integrated cross-platform analysis developed by co-first author Katherine Hoadley of the University of North Carolina. All six platforms as well as the integrated analysis converged on the same divisions of the cancers into 11 major subtypes. 

Five of those subtypes were nearly identical to their tissue-of-origin counterparts. But some tissue-of-origin categories split into several different molecular subtypes, and some subtypes encompass tumors with several different tissues of origin.

Bladder cancer was a particularly interesting group, because it split into seven different clusters, with most samples falling into one of three subtypes. One subtype was bladder cancer only, but some bladder cancers clustered with lung adenocarcinomas, and others with a subtype called 'squamous-like' that includes some lung cancers, some head-and-neck cancers, and some bladder cancers.

"If you look at survival rates, the bladder cancers that clustered with other tumor types had a worse prognosis. So this is not just an academic exercise," Stuart said.

Other findings from the study reconfirmed cancer subtypes that were already recognized, such as the different subtypes of breast cancer based on well-characterized biomarkers. The findings provide a more refined, quantitative picture of the differences between breast cancer subtypes, Stuart said. For example, the results reinforce the idea that 'basal-like' breast cancers are a unique tumor type. "Basal-like breast cancers are as different from luminal breast cancers as they are from lung cancers," he said.

The fact that all six platforms for molecular analysis identified the same set of subtypes, both individually and in multi-platform analyses, is an important result, Stuart noted. Not only does it give the researchers confidence in the subtypes they identified, it also means that different kinds of data can be used to classify a tumor.

"We can now say what the telltale signatures of the subtypes are, so you can classify a patient's tumor just based on the gene expression data, or just based on mutation data, if that's what you have," Stuart said. "Having a molecular map like this could help get a patient into the right clinical trial."

Although follow-up studies are needed to validate the findings, this new analysis lays the groundwork for classifying tumors into molecularly defined subtypes. The new classification scheme could be used to enroll patients in clinical trials and could lead to different treatment options based on molecular subtypes.

According to Stuart, the percentage of tumors that are reclassified based on molecular signatures is likely to grow as more samples and tumor types are included in the analysis (the next major Pan-Cancer analysis will include 21 tumor types). Coauthor Christopher Benz, an oncologist at the Buck Institute for Research on Aging and UC San Francisco, noted that the 10 percent reclassification rate in the current study is likely an underestimate due to the unequal representation of different tumors. "If our study had included as many bladder cancers as breast cancers, for example, we would have reclassified 30 percent," Benz said.

The researchers reported that each molecular subtype may reflect tumors arising from distinct cell types. For example, the data showed a marked difference between cancers of epithelial and non-epithelial origins. "We think the subtypes reflect primarily the cell of origin. Another factor is the nature of the genomic lesion, and third is the microenvironment of the cell and how surrounding cells influence it," Stuart said. "We are disentangling the signals from these different factors so we can gauge each one for its prognostic power."

The study involved an enormous amount of molecular and clinical data, which was managed by data coordinator Kyle Ellrott, a software developer in Stuart's lab at UC Santa Cruz. The data sets and results have been made available to other researchers through the Synapse web site (http://www.synapse.org). Stuart worked with the bioinformatics company Sage Bionetworks to create Synapse as a data repository for the Pan-Cancer Initiative.

"It's a huge amount of information, and all the data is available as programmable data sets that other researchers can use to do further analysis," Stuart said. "The scale of this project is hard to imagine. All of the data that the TCGA project has been churning out got funneled into this paper, and it's giving us an unbiased look at what the data have to tell us about cancer."

Source: University of California - Santa Cruz