Tumor cells associated with pancreatic cancer work with each other to increase tumor spread

Tumor cells associated with pancreatic cancer often behave like communities by working with each other to increase tumor spread and growth to different organs. Groups of these cancer cells are better than single cancer cells in driving tumor spread, according to new research from the Perelman School of Medicine at the University of Pennsylvania published in Cancer Discovery online in advance of the print issue.

Ben Stanger, MD, PhD, a professor in the division of Gastroenterology, and first author Ravi Maddipati , MD, an instructor in the division of Gastroenterology, say that these results may prove useful in designing better targeted therapies to stop tumor progression and provide an improved non-invasive method for detecting early disease states in this highly lethal cancer. Stanger is also a professor in the department of Cell and Developmental Biology and the Abramson Family Cancer Research Institute.

Cancer genome studies have shown that within most tumors there exists many different types of cells, which often harbor unique genetic alterations that lead to differences in their physiological properties. Previous studies using tumor cells lines suggested that these different tumor cell types may interact with each other to produce a more aggressive type of cancer. However, the mechanisms by which tumor cells interact to enhance the spread of cancer remained unclear.

From other earlier studies, the Penn team also knew that cells from a primary tumor do better replicating and surviving in a group rather than if they are grown on their own. From this, the researchers asked if the spread of cancer is primarily derived from one cell or a cell cluster derived from the interactions between different cancer cell types. Stanger and Maddipati tested the hunch that clusters of cells of different genetic makeup were better at establishing secondary tumors and found that a significant fraction of metastases involve seeding by more than one type of tumor cell during the natural course of pancreatic tumor progression.

To understand this spread, the Penn researchers developed a mouse model that uses multiple fluorescent proteins to tag and track different pancreatic cancer cells as they enter the bloodstream and spread to distant organs. In this mouse model, mutations in Kras and p53 genes resulted in the formation of individual tumor cell populations that were labeled with different colors. Similar to humans, the mice developed tumors at secondary sites including the liver, lung, peritoneum, and diaphragm. They observed that these metastases were often made of cells from at least two different colors of tumor cell populations. To understand how these multi-colored lesions originated they examined blood from these mice and found that tumor cells in circulation frequently occurred as clusters comprised of different colored cancer cells.

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What's more, they also found that once these multi-colored clusters arrived at the secondary sites, the exact characteristics of subsequent growth was heavily dependent on the organ in which they now resided. During cell expansion in the peritoneum and diaphragm the lesions remained multi-colored, whereas in the lung and liver only a single color population was able to grow out. This suggested that specific factors in each organ may also influence the evolution of metastases.

"These results provide an unprecedented window into the cellular dynamics of tumor evolution and suggest that interactions between subpopulations of tumor cell types contribute to metastatic progression from initial tumors," Stanger said. "The finding that metastases are frequently polyclonal and that subsequent cellular behavior is site-dependent also gives us insight into the origins and evolution of clonal diversity in metastatic disease."

"If cells do cooperate during metastasis, what is the molecular basis for their communication, and can we hit that?," Stanger asked. The work also reinforces the importance of finding tumor cell clusters in the blood as a mechanism of detecting cancer metastasis earlier.

http://www.news-medical.net/news/20150813/Tumor-cells-associated-with-pancreatic-cancer-work-with-each-other-to-increase-tumor-spread.aspx

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Penn Medicine

After 30 years, Tauer still ready to battle cancer

See the full article at http://www.bizjournals.com/memphis/blog/2015/08/after-30-years-tauer-still-ready-to-battle-cancer.html

Beating Pancreatic Cancer

Posted on Aug 12, 2015

Ronald Chamberlain, M.D., surgeon-in-chief and chairman of the Department of Surgery at Saint Barnabas Medical Center, doesn't sugar-coat what happened to Elizabeth Sprague of Maplewood: "She is that 'one in a million' who survives pancreatic cancer," he says.

This cancer is particularly deadly because there are no screening tests to find it early. By the time any symptoms show up, it has almost always spread to the lymph nodes and other areas of the gastrointestinal tract. The actual survival rate of patients with node-positive pancreatic cancer is about 5 percent, Dr. Chamberlain says. So while "one in a million" is a bit hyperbolic, five in 100 are still odds no one would bet on.

Yet the odds are improving, thanks to advances in surgical, chemotherapy and radiation treatments. And the future holds even more promise, with genetic testing that will be able to help oncologists target specific tumors with the treatments most likely to be successful.

Sprague, who was diagnosed in November 2007, didn't have those options yet. The retired airline employee, who will admit to being "over 39," and her husband, David, a retired engineer, have three grown children and eight grandchildren. While she was undergoing endoscopic testing for gastroesophageal reflux disease (GERD) and for noncancerous colon polyps, her physician noticed a small tumor on her pancreas. "He said, 'Do me a favor, please have another imaging test,'" Sprague says. "That one found cancer."

Her reaction, she admits, was a bit odd. "I went home and cleaned my closets," she recalls with a laugh. "That's how I dealt with it."

In truth, Sprague tackles most things with clear-headedness and humor. "I knew it was serious, but I didn't dwell on it," she says. "That wouldn't make it go away. I told my children that this was not a morbid situation; we just had to take care of it."

She was referred to Dr. Chamberlain. "I immediately felt comfortable with him," she says. "He calmly explained what he would do, and I said OK, let's go." He scheduled surgery for Jan. 3, 2008, because she wanted to wait until after the holidays.

Pancreatic cancer requires a difficult operation called the Whipple procedure. "It's very complex and involves removing parts of five different organs—the pancreas, small intestine, bile duct, gallbladder and stomach," Dr. Chamberlain says. Then the remaining pieces must be reconnected into a functioning system. "The operation used to take 20 hours, but now we can do it in about four," he says.

Dr. Chamberlain did not offer a prognosis, Sprague says. "But he did say to my husband, 'If I am out in 45 minutes, it isn't good. The longer I am in there, the better the situation," she says. "He didn't come out for quite a while, so that was promising."

Sprague spent about two weeks in the hospital. Recovery was not bad, she says. "I have a scar that is now disappearing, but I don't wear a bikini anyway, so it doesn't matter if it completely disappears." She has fond words for the staff at the hospital. "The attitude of the people I encountered in the cancer ward was extremely nice—not morbid, very pleasant and caring," she says. "They had someone come in and play the harp, and the first time I thought, 'Oh no, that's the music they play when you go to Never-Never Land!" she says with a chuckle. "But I found it very relaxing."

Chemotherapy and radiation followed, but Sprague suffered no side effects, thanks to improvements in the therapies. And now, "I feel great," Sprague says. "I am a very lucky person." Someone in her position today is luckier still, says Dr. Chamberlain. "Medicine is in the middle of a revolution, from disease specific care to patient-specific care," he explains. Until now everyone has been treated essentially the same way. "Now they are treated differently, based on genetic aspects of their particular tumor. Today I would send a tumor like hers for bio genomic profiling," he says. "That can tell us what drugs it might respond to and what drugs it might not." For example, African- Americans tend to respond poorly to a certain drug because they typically possess an enzyme, which Caucasians don't have, that breaks the drug down. "Other genes may reveal a certain growth factor, which would make a particular drug a great choice," he says. These changes are helping to push pancreatic cancer survival rates into the 15 to 30 percent range.

"That is by no stretch a home run, but it is a substantial improvement," says the doctor. Only a reliable screening test similar to colonoscopy or mammography will bring those numbers up to the levels now seen in other cancers, but that is still year's away, he cautions.

Until then, Sprague is helping others newly diagnosed with pancreatic cancer to prepare for the daunting road ahead. "She brings a tremendous ability to look at it in a positive light and has talked to or met with 30 to 40 different patients about the Whipple surgery," Dr. Chamberlain says. "She steps in and explains that it's not the 1960s anymore. It's 2013, and medicine is advancing."

http://www.barnabashealth.org/Press-Center/Saint-Barnabas-Medical-Center-News/2015/Beating-Pancreatic-Cancer.aspx

UK Study

Birmingham Study Day by Jeni Jones.

Posted by: Information and support 12 August 2015

- See more at: http://www.pancreaticcancer.org.uk/our-blog/2015/august/birmingham-study-day-by-jeni-jones/#sthash.mmdhxbJ8.dpuf

Tuesday 7th July saw the Pancreatic Cancer UK Hepatobiliary and Pancreatic study day for Health Professionals take place at the University Hospitals of Birmingham Postgraduate Centre.

Mr.Keith Roberts explained to attendees what they could expect from the day and this was followed by an excellent presentation by his colleague, Professor Darius Mirza, who spoke about vein resection during pancreatic surgery. He emphasised the fact that studies have demonstrated a survival benefit for vein resection over palliative surgery. Keith Roberts then took to the stand for a second time on the prediction of pancreatic fistula following pancreatoduodenectomy. He commented that the rate across most HPB units was 20-25%, and that drain fluid amylase was the key to diagnosis.

We then had a very stimulating presentation by Mr Ravi Marudanayagam, Hepatobiliary and Pancreatic Surgeon at QEHB discussing the ESPAC 5 clinical trial in the surgical group of patients.  This is an excellently designed feasibility trial, with 4 arms, comparing immediate surgery (within 2 weeks of randomisation), with neoadjuvant chemo/chemo radiotherapy. Chemotherapy regimes used will be Gemcitabine/Capecitabine or Folfirinox, and in the chemorad arm, the chemotherapy is the choice of the clinician. The outcomes of this study will be very much anticipated.

Professor Sohei Satoi, from Osaka, Japan gave us two insightful presentations about his practice in Japan. The first was about surgery after down staging chemotherapy using the drug S-1. After 6 months of initial treatment with this drug, 15 out of 509 patients went on to have surgery for their previously unresectable pancreatic cancer.

His second presentation was on S-1, which is now considered as the new standard treatment for resected pancreatic cancer  patients in Japan, and it is well tolerated. It appears though, that toxicity from this drug will be greater in the Caucasian population, whereas, it is significantly less in the Japanese.

As ever, diet and the use of pancreatic enzyme replace therapy (PERT) was on our agenda. Mary Phillips gave another fantastic presentation on malnutrition in pancreatic cancer, and encouraged us to be more “aggressive” in feeding patients who are malnourished – in the inoperable setting.

Professor Harald Schrem from Hannover continued this theme presenting data from a study carried out between Hannover and Birmingham, evaluating the relationship between pancreatic enzyme replacement therapy and survival after pancreatoduodenectomy.

Our keynote lecture was from Professor Dominguez-Munoz, from Spain, who gave us a very clear and concise presentation on Pancreatic Enzyme Insufficiency (PEI). There can be no doubt after listening to him that we are not assessing these patients early enough, nor are we actually assessing all of the patients – in his opinion, all pancreatic cancer  patients will suffer from PEI and will need PERT.

Our own Anna Jewell, acting Director of Operations, gave an excellent round up of the work of Pancreatic Cancer UK, and the ongoing projects which people can get involved with.

After lunch, we had a very good presentation on enhanced recovery by Mr.Rob Sutcliffe from Queen Elizabeth Hospital, Birmingham (QEHB). Dr. Yuk Ting Ma spoke on down staging chemotherapy, and spoke about this from the point of view of the “pre Folfirinox” and “post Folfirinox” era.

Dr. Shakeeb Khan spoke on the local experience of down staging chemotherapy at QEHB, and Dr.Max Almond gave an overview of total pancreatectomy over the past 25 years.

Lewis Stephens presented on survival prediction based on lymph node ratio, showing that positive lymph node involvement has a significantly negative influence on post-op survival.

Perhaps the greatest congratulations of the day should go to Margaret Datson, who spoke about her own experience of being a pancreatic cancer patient. Margaret spoke eloquently, and replayed her journey in a measured and constructive way, from her own mother’s death from pancreatic cancer in 2000, to her diagnosis in 2006. Margaret spoke highly about the care and attention she received at QEHB. A poignant moment occurred at the end of Margaret’s talk, when she went to greet her surgeon on the front row, Professor Darius Mirza, and they exchanged a hug. This more or less epitomised the theme of the day at Birmingham, a theme of gratitude all around.

All in all, a great day was had at Birmingham, and we were delighted with the attendance. It was great to forge links with folk in QEHB, one of the largest specialist centres in the UK, and to see the day evolve after so much hard work from all involved. A massive thanks to all.

Our next study day will be in Crewe on the 19th October.

- See more at: http://www.pancreaticcancer.org.uk/our-blog/2015/august/birmingham-study-day-by-jeni-jones/#sthash.mmdhxbJ8.dpuf

For the Most Lethal Cancer: Find the Best Science

When I tell people that living with pancreatic cancer has some blessings, my statement typically is met with a curious disbelief that leaves me uncomfortable for having said it. But, the blessings are oddly true. Each day feels more alive, intense and important. I take the opportunity to tell my family and friends what they mean to me in great detail and with great regularity. It creates a life of love.

Meeting brilliant, courageous scientists and doctors (including my doctors, William Isacoff and Allyson Ocean) committed to changing the course of this disease is among these blessings as well. Knowing them helps me deal with the incomprehensible truth that there are no long-term treatments, no early detection tests and no cures for this most lethal cancer.

It may be unusual to call scientists courageous but research challenges in pancreatic cancer are immense. Pancreas tumors are complex and continually mutating. The K-RAS gene found to be mutated in the majority of pancreatic cancer patients has continued to stymie researchers' efforts to block it. The stroma, the barrier surrounding the pancreatic tumor, is a resistant shield preventing therapy from reaching the tumor effectively.

Although the past 40 years have given us very few (and no long-term) treatments for pancreatic cancer, there is now new progress from a number of exceptional scientists willing to focus on these challenges.

Getting to know some of these amazing scientists has not only enhanced my life, but it has reinforced the fact that pancreatic cancer patients and families must keep informed of the best science efforts. It is the key to extending our lives.

These organizations can provide some information. The Lustgarten Foundation is the nation's largest private funder of pancreatic cancer research; 100 percent of its funding goes to research due to the support of Cablevision. The Pancreatic Cancer Action Network is another valuable source for science and patient information.

Dr. Isacoff introduced me to Dr. David Tuveson, the director of research at The Lustgarten Foundation and director of The Lustgarten Pancreatic Cancer Research Laboratory in partnership with Cold Spring Harbor Laboratory. This is a picture of Dr. Tuveson.

When my family and I went to see the lab we were so galvanized. The scientific attack on pancreatic cancer made us feel that we were seeing history happen, giving us a fortifying glimpse into a positive future.

One of the projects of the lab is the generation of organoids, a new breakthrough investigative mechanism for pancreatic cancer. What makes organoids so exciting is that they can reproduce pancreatic tissue samples giving patients many potential benefits. This is a picture of the organoid from the lab.

Here is the paper in Cell.

First, these living tumor cells can be tested over time with a wide range of medications, enabling scientists to find biomarkers and identify new combinations of drugs to treat the disease. Simply, in the future, instead of pancreatic cancer patients being tested with new medications, organoids can endure that experience.

Second, organoids can speed up research and the search for treatment options which we urgently need. As Dr. Tuveson noted, "Patients are dying. Organoids will speed up the process for creating robust clinical trials by providing a whole new set of data based on this new access to living tumor tissue."

Third, organoids create more tissue for testing. A major research constraint has been the lack of tissue. Organoids will create a supply in pancreatic cancer tissue that will assist investigators. Indeed the lab provides an "organoid training school" so that many institutions will have access to the technology and tissue.

A young scientist, Dr. Hervé Tiriac, a postdoctoral fellow at the lab, has the responsibility to ensure that more than 40 organoids under his care are growing well and are being tested. Here is a picture of Dr. Tiriac.

Hervé's deep intelligence and passion for his work are clearly evident. He told me that he found this passion for making a difference in pancreatic cancer in a round-about way. A graduate of the University of California at Davis and San Diego, he first focused on hardcore genetics and biochemistry.

While in graduate school, he met Dannielle Engle a fellow scientist, and that changed his life. Her father had died of pancreatic cancer and her professional and personal mission is to cure the disease. Hervé and Dannie, now married, are a dynamic force for progress, working together in the lab.

I learned a lot talking to Hervé about the potential of organoids to extend life spans. Along with the organoid tumor cells, he is also growing organoids with normal cells. He said, "The hope is to weed out novel therapeutics that would be too toxic. That's why we test normal cells too."

He explained that organoids could help address the differences within pancreatic cancer by breaking tumors into subclasses that would be treated by different therapeutics. "With more tissue you have more to learn." he said. "Organoids can eventually offer models of personalized medicine for patients and become an excellent way to analyze the link between genetic mutations and treatment."

Talking to Hervé made me realize that organoid research may lead to the better design of clinical trials and faster, more effective treatment.

Staying on top of what is happening in leading scientific research is a lifeline for all pancreatic cancer patients and families. We have the most lethal cancer, and yet only 2 percent of the federal funding is directed to pancreatic cancer research!

While many extraordinary scientists are now working for cures and early detection tests, more than 40,000 people this year will die of pancreatic cancer.

We must all be familiar with the science and support these scientists. And we must advocate urgently for more private and public research funding. It will save our lives.

This blog is dedicated to Jeff Schmahl, my friend on this path, who inspired so many with his wonderful life.

Follow Anne F. Glauber on Twitter: www.twitter.com/anneglauber

MORE:

CáncerPancreatic CancerCancer AwarenessScienceCancer Research

http://www.huffingtonpost.com/anne-f-glauber/for-the-most-lethal-cance_b_7906880.html

Significant breakthrough in pancreatic cancer treatment

Dr. Sunil Hingorani, pictured with Dr. Vikas Goel, right, unraveled the secrets of how pancreatic tumors thwart chemotherapy and developed a way to penetrate those defenses. These breakthroughs are so significant, he is fast-tracking this new treatment to help patients with metastatic pancreatic cancer.

Pancreatic cancer is a formidable foe. It grows fast and spreads quickly, often before any symptoms appear. And because of its notorious resistance to treatment, 97 percent of patients aren't alive five years after diagnosis.

Dr. Sunil Hingorani understands all too well the pain inflicted by a pancreatic cancer diagnosis. He lost his father to the disease, leading him on a personal and professional mission to find ways to beat it. His dedication is paying off with some of the most significant contributions in the fight against pancreatic cancer—including a breakthrough discovery that could change the way it is treated.

A few years ago, Hingorani developed the first mouse model that faithfully mimics human pancreatic cancer, from its precancerous inception to its advanced stages. This powerful tool has enabled researchers to get closer to understanding pancreatic cancer’s defenses better than ever before, opening the door to more effective ways to detect and treat the disease.

Using this model, Hingorani recently made two potentially momentous discoveries. He unraveled the secrets of how pancreatic tumors thwart therapies and then developed a way to penetrate those defenses. Most cancerous tumors grow blood vessels to deliver nutrients and oxygen to them, providing an entrance for chemotherapy drugs to gain access to the tumor.

In pancreatic cancer, however, Hingorani discovered that pancreatic tumors build a tough, protective shell—similar to scar tissue—that physically keeps chemotherapy from entering the tumor. This revelation explains why treatments that eliminate other cancers are ineffective here; the cancer drugs never reach the pancreatic cancer cells.

With this knowledge, Hingorani and colleagues found a way around the protective shell: Using their mouse model, the team employed an enzyme that digests and removes the scar-like tissue around the tumor. With the tumor defenses breached, the chemotherapy can enter and attack the cancerous tissue.

The results were so successful, Hingorani worked to get clinical trials fast-tracked. Hingorani, with his unwavering dedication to patients, is now leading an international trial for patients with metastatic pancreatic cancer, using a combination of the enzyme and chemotherapy.

Already, his work is bringing new hope to patients at Seattle Cancer Care Alliance, the treatment arm of the Hutchinson Center. “We’re not just treating a disease,” he said. “We are treating a person. Patients are not statistics. We think about this disease day and night.”

The Giles W. and Elise G. Mead Foundation is a longtime supporter of Dr. Sunil Hingorani’s pancreatic cancer research. In addition, a generous donation from Maryanne Tagney-Jones and David Jones challenged a community of supporters, and collectively their gifts helped make possible his potential breakthrough in treatment.

New treatment option for pancreatic cancer shows early promise

ANN ARBOR, MI - When someone is diagnosed with pancreatic cancer, surgery to remove the tumor offers the greatest potential for survival. But in the vast majority of cases, surgery is not an option, forcing patients and their doctors to look to other, less-effective treatments - often involving radiation together with chemotherapy, or chemotherapy alone. .

Even with these therapies, nearly all pancreatic cancer patients show evidence that the cancer has spread throughout the body within months of diagnosis, making it one of the most deadly and difficult cancers to treat. In 1996, the Food and Drug Administration approved a more effective chemotherapy drug called gemcitabine for use, and several leading medical centers have investigated techniques to combine this drug with radiation. But many of these studies have found the combination causes unacceptable side effects.

Now, a new University of Michigan study has now shown that the drug can be delivered safely in combination with accurately targeted radiation. In fact, the combination could actually be more beneficial than currently available therapy, without an increased risk of severe side effects.

In a paper published today in the Journal of Clinical Oncology, a team of pancreatic cancer specialists at the U-M Comprehensive Cancer Center reports that gemcitabine can be delivered at the recommended standard dose together with carefully aimed radiation without substantial side effects. This clinical study results from years of laboratory research at the U-M to understand the mechanism of interaction between gemcitabine and radiation, and technical advances in the delivery of radiation.

Previous research on this combination has focused on broadly targeted radiation therapy techniques with the addition of relatively low doses of gemcitabine. Although promising, the combination proved to result in unacceptable nausea, vomiting, and excessive weight loss.

The study reported today shows that the U-M technique, co-developed by Cornelius McGinn, M.D., assistant professor of radiation oncology and Mark Zalupski, M.D., clinical associate professor in medical oncology at the U-M Health System, produced relatively modest side effects and allowed the chemotherapy to be kept at a standard dose, rather than a reduced dose.

"Since pancreatic cancer spreads very easily, it is important to attack it throughout the body with effective chemotherapy. But treatment must also target the tumor in the pancreas itself, and that's where focused radiation comes in," McGinn says. "By investigating the appropriate radiation dose using a conformal radiation technique that spares non-cancerous tissue, we have effectively targeted the primary cancer while still delivering systemic therapy for potential spread, something no other study has attempted."

Encouraged by the initial results, the team of researchers will embark on a new trial later this year, testing the approach at the U-M and other medical centers throughout the country. The development of a specific clinic for patients with pancreatic cancer within the U-M Comprehensive Cancer Center is being considered as well, as a means to provide coordinated multidisciplinary care for this special patient population and develop further research efforts.

Pancreatic cancer is the fourth leading cancer killer, claiming almost 30,000 lives every year in the United States. Even more alarming is the fact that by the time pancreatic cancer is diagnosed, it is usually too late for surgical removal, with the average life expectancy being only six to nine months.

But the findings of the study conducted at the U-M Health System offer a glimmer of hope that survival time could be extended while patients enjoy a better quality of life.

The study looked at 37 patients with locally advanced pancreatic cancer, including many with evidence that the cancer had already spread. Over the course of three weeks, gemcitabine was given once a week during a course of radiation therapy delivered every weekday. The radiation was administered by conformal therapy directed at the primary tumor, without targeting any other areas at risk. After a week break, a second three week course of gemcitabine alone was given. Additional chemotherapy was then given to many patients, but not as part of the trial.

During the trial, seven different radiation dose levels were investigated in as many groups of patients. Some patients who received the highest doses of radiation did experience toxic side effects. As a result, the next trial will use a slightly lower radiation dose that was well tolerated.

McGinn says the overall results were promising. On average, patients lost less than 1 percent of their pretreatment body weight. In fact, more than 40 percent of patients were actually able to gain weight during the course of therapy. This is significant achievement when compared to results of previous studies of gemcitabine and radiation, in which patients often experienced substantial nausea, vomiting and weight loss occasionally resulting in hospitalization. The time required for daily radiation (three weeks) was appealing as well, when compared with more conventional course of radiation which requires five to six weeks.

Survival time for patients ranged from five months to longer than two years. Median survival was just over 11 months. Compared to the expected survival time for this group of patients, this result is encouraging. However, McGinn cautions that this doesn't represent a cure and noted that the trial was not designed to investigate outcome as a primary endpoint. It is possible, he says, that this approach represents new strategy which could be built upon for additional gains.

"Pancreatic cancer is a terribly tragic disease. We believe we have made a small step towards giving patients a chance at a longer and better life," he says. "The reality is we're still trying to learn more about pancreatic cancer and ways to treat it, without jeopardizing quality of life."

For more information on cancer care at the U-M contact the UMHS Cancer AnswerLine™ at 1-800-865-1125.

Research Advances in Pancreas Cancer

From John Hopkins ...

At the Kimmel Cancer Center, state-of-the-art is just the starting point of what we provide patients with pancreas cancer.

Researcher Anirban Maitra created a
system that makes cancer therapies easier
to give to patients.

About 80 percent of patients diagnosed with pancreas cancer will need novel therapies. The goal of the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care is to pursue clinical innovation and develop new treatments based on our laboratory discoveries. The transfer of research findings to clinical research has resulted in the development of a pancreas cancer vaccineand other promising therapies.

• Pancreas Cancer Vaccine
• Metabolic Pathways for Pancreas Cancer
  Johns Hopkins investigators test and develop drugs that target faulty enzymes that process glutamine, glucose and fatty acids in some pancreatic cancers. Researchers scan patients' DNA for genes that could benefit from glutamine- and glucose-blocking drugs.

This research was made possible by a $3.75 million grant and clinical trial funding fromStand Up to Cancer, established by the Entertainment Industry Foundation. Funds were raised during a simultaneous, primetime television broadcast on the ABC, CBS and NBC television networks in September 2008.

Team members on this project include Chi Dang, M.D., Ph.D., vice dean for research at the Johns Hopkins University School of Medicine, Manuel Hidalgo, M.D., Ph.D., director of the Centro Integral Oncológico Clara Campal (CIOCC) in Madrid, Spain, Ralph Hruban, M.D.,Kenneth Kinzler, Ph.D., Daniel Laheru, M.D., Anirban Maitra, M.D., Martin Pomper, M.D., Ph.D., Victor Velculescu, M.D., Ph.D., from the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins, and David L. Vander Jagt, Ph.D. of the University of New Mexico.

• The National Familial Pancreas Tumor Registry
   
• Rapid Autopsy Program
  
  A selfless act by terminal cancer patients is helping Christine Iacobuzio-Donahue, M.D., Ph.D., and Daniel Laheru, M.D. decipher how pancreas cancer originates and spreads as well as identify potential new ways to treat the disease.
• Iacobuzio-Donahue directs the Johns Hopkins Gastrointestinal Cancer Rapid Medical Donation Program, a unique program in which patients who lose their battle with cancer volunteer to have a rapid autopsy so that investigators can study their tumors, cells, and genes to find answers that may save the lives of future patients. She has performed more than 150 autopsies to identify the genetic differences in pancreas cancer that underlie its progression and spread to other organs.
  This research, funded by the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care, allowed Iacobuzio-Donahue, Laheru, and colleagues to link a gene discovered by another Johns Hopkins investigator to pancreas cancer metastasis.
  "This work was considered way 'outside of the box' thinking, and no one would fund it," says Laheru. "We were the only cancer center in the country doing this kind of research."
  Their findings have been key to research projects aimed at identifying new drugs to specifically target late-stage cancers.

Identifying a window for cancer prevention

• More recently, Iacobuzio-Donahue developed a mathematical model that allows clinicians, for the first time, to quantify the development of pancreas cancer and how best to treat it. Their work was transformative, disproving common scientific thought that this type of cancer progresses to a deadly stage very early in its development. To the contrary, she calculated that it takes an average of 11 years before a cancer cell arises from a precancerous pancreas lesion. Still another seven years may pass as that cancer grows to form a tumor, giving at least one cell the potential to break away and spread the cancer outside of the pancreas in a process known as metastasis.
  "This spread represents a lethal turning point in the progression of the cancer. Once it occurs, these patients die, on average, two and half years later," says Laheru. "This was a revolutionary idea that a disease this clinically aggressive could be have such potential opportunity for intervention early on while it is still curable. It moves us closer to the ultimate prize-prevention."
  To make the calculations, Iacobuzio-Donahue and team studied tissue collected at autopsy from seven patients who died of metastatic pancreas cancer. The research team identified and classified the genetic alterations in each patient's pancreas tumor and the sites to which it spread.
  In all of the patients, the investigators found similar mutations in both the originating tumor and the body sites where it spread, genetically linking the metastatic lesions to the original pancreas tumor from which it arose. They classified mutations that occurred prior to metastasis and those that happened after the cancer began to spread. Then, they applied their findings to mathematical models and created a timeline of progression from precancerous lesion to deadly, metastatic disease.
  In search of a screening tool
  Although the research reveals a large window of time before a pancreas cancer turns deadly, currently, "pretty much everybody is diagnosed after that window has closed," says Iacobuzio-Donahue. "New, early diagnostic tests to detect these cancers during this 11- to 18-year window, would provide an opportunity to intervene, and potentially cure these cancers, with surgery."
  The discovery has led to the development of technology that rapidly picks out proteins and other biomarkers that help predict and diagnose pancreas cancer.
  Iacobuzio-Donahue's goal is to create a screening method, similar to those used to screen for breast and colon cancers, to detect very early pancreas cancers, long before they cause symptoms. She suggests that just as colonoscopies are used to look inside the colon for precancerous lesions called polyps, physicians could use a similar technique called endoscopy, which uses an endoscope inserted through the mouth, to examine the pancreas for precancerous lesions.

• Mouse Models
  
  Investigator James Eshleman, M.D., Ph.D., has developed a mouse that grows pancreas cancer cells providing some of the groundwork for a massive exploration of the pancreas cancer genome. Ralph Hruban, M.D., and Eshleman are working with Bert Vogelstein, M.D., in the sequencing of 24,000 known genes and then validating them in some 96,000 pancreas cancers.

• Preventing Pancreas Cancer

Endoscopy

Our endoscopy specialists help people with a family history of pancreas cancer learn if they have precancerous lesions that could develop into cancer. Early precancerous lesions can be surgically removed and the pancreas saved. Some patients may choose prophylactic removal of the pancreas to stave off cancer.

Nanopill

Johns Hopkins scientists combined nanoscience with the Indian spice curcumin to develop a novel pancreas cancer prevention strategy. Curcumin has the ability to activate cancer detoxifying enzymes, but is not absorbed well by cells when eaten. To overcome the absorption problem, the investigators created a nanoparticle carrier for the curcumin. The engineered nanocurcumin can be given intravenously or orally.

Recruiting Genes to Kill Cancer

The Johns Hopkins Kimmel Cancer Center team who discovered the pivotal genes abundant in pancreas cancer patients also is investigating the potential for gene therapy. Studies suggest that a tumor suppressor gene, DCP4, is either missing or inactivated in more than half of all patients with pancreas cancer. Losing the function of both copies of this gene is like losing the brakes on a car. When left unchecked, these cells begin to multiply. Studies are under way to see whether bystander genes can be activated to replace the lost tumor suppressor function and put the brakes on cancer cells.

• Pancreas Cancer Stem Cells
  
  Cancer stem cells are small in number, almost undetectable, but they can be the fuel that promotes certain cancers to grow and spread. Recent research has brought these cells into focus. Johns Hopkins scientists have developed a method to identify cells marked with the proteins CD44 and CD24 and those with high levels of the enzyme aldehyde dehydrogenase, believed to be characteristics of pancreas cancer stem cells.
  
  The investigators found that pancreas cancer stem cells marked with aldehyde dehydrogenase indicated decreased survival. Researchers are working to further define pancreas cancer stem cell populations and decipher the processes that control them. Using drugs to target cancer stem cells has provided new therapeutic strategies for other cancers, and these advances could be applied to pancreatic cancer.
• 
  
• The Pancreatic Cancer Action Network and the American Association for Cancer Research have awarded Zeshaan A. Rasheed, M.D., Ph.D., of the Johns Hopkins Kimmel Cancer Center, the 2010 Pancreatic Cancer Action Network-AACR Pathway to Leadership Grant. This grant, totaling $600,000 over five years, will support Rasheed's efforts to examine the relevance of cancer stem cells in pancreatic adenocarcinoma.
  
  Cancer stem cells are a subset of cells hypothesized to mediate the growth and spread of cancer. Rasheed earned his medical degree and doctorate in cellular and molecular pharmacology from the University of Medicine and Dentistry of New Jersey - Robert Wood Johnson Medical School and Graduate School of Biomedical Sciences. Currently, he is a medical oncology fellow at The Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins. . His research focuses on how different populations of pancreatic cancer stem cells are related to one another and which factors regulate cancer stem cell growth and spread throughout the body. By making these determinations, Rasheed will then investigate how cancer stem cell inhibition is possible, which may lead to the development of novel cancer stem cell-targeting therapies. The grant will be formally awarded at the AACR Annual Meeting on April 20, 2010. The term for the grant begins on July 1, 2010.

• Targeting Genes That Make Therapies Work Better
  
  Three genes, BRCA2, FANCC, and FANCG, have long been linked to a rare, inherited disease known as Fanconi's Anemia (FA) and appear to play a role in 10 percent or more of pancreas cancers. People affected are born with only a single, normal copy of one or more of the genes. Though they do not develop FA, these people often develop pancreas cancer, usually in their 40s and 50s, about a decade earlier than the average person who develops the disease.
  
  Investigators believe these gene mutations may be the tumor's Achilles' heel of the tumor and make these particular cancers more responsive to treatment. The presence of these three genes appear to make pancreas cancer cells highly susceptible to treatment with two FDA-approved cancer drugs, mitomycin C and cisplatin.

• Calculating Cancer Risk
  
  A novel computer software tool, called PancPRO, helps identify people at risk of developing pancreas cancer because they have inherited gene alterations linked to the cancer. The program's calculator computes the likelihood that a person carries a pancreas cancer-related gene and the person's lifetime risk of developing this disease. Physicians and genetic counselors use the tool to identify people who may benefit from pancreas cancer screening.
• Misdirected Cell Pathway
  
  Johns Hopkins researchers have uncovered a genetic defect that may be triggering the development of pancreas cancer. A growth signal that should be turned off in adult tissues is mistakenly turned back on. The growth signal appears to be activated in response to injury to, or inflammation of the pancreas. Investigators suspect that reactivation could be a first step in the initiation of pancreas cancer, occurring even before gene alterations.
• Cells at the Root of Pancreatic Cancer

In the laboratory at Johns Hopkins Kimmel Cancer Center in Baltimore, Hopkins researchers are working diligently to figure out how to interfere with pancreas cancer-initiating cells.

A select group of researchers have shown that pancreas cancer, like many types of cancer, contains colonies of cancer-promoting cells. These cells, while small in number, appear to be a major force in cell growth by evading anticancer drugs and perpetually giving rise to the larger number of cancer cells that make up the bulk of tumors. Maitra is working with Viragh Scholars Ana De Jesus-Acosta, M.D., and Zeshaan Rasheed, M.D., Ph.D., to determine if targeting these cells with new therapies could help combat pancreas cancer.

Maitra has shown that a chemical pathway called Hedgehog is more active in pancreas cancer- initiating cells and tested agents that inhibit it. In animal models, he found that blocking Hedgehog activity increased survival. De Jesus-Acosta and Daniel Laheru, M.D., co-director of the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care, are now translating this laboratory research into a clinical trial for patients with advanced pancreas cancer to determine whether giving patients a Hedgehog inhibitor in combination with standard drug therapy extends survival.

De Jesus-Acosta has started another clinical study for earlier stage pancreas cancer, focusing on patients whose tumors could not be treated with surgery but have not yet spread outside the pancreas. Her goal is to achieve enough regression of the tumor with the Hedgehog inhibitor/chemotherapy combination to get patients to surgery.

In the laboratory, Rasheed is using biopsy and blood samples from patients to develop technologies to isolate pancreas cancer-initiating cells and measure the effect of the inhibitor on these cells. Because biopsy is an invasive procedure that requires local anesthesia, he is working to develop a first-of-its-kind method to collect the elusive cells from circulating blood.

While researchers at other institutions are studying Hedgehog inhibitors in pancreas cancer, the Kimmel Cancer Center team was the only group who collected biopsy and blood samples. As a result, our research continues as investigators conduct one-of-a-kind studies of Hedgehog pathway regulation in cancer-initiating cells. In the first trial, the inhibitor did not thwart pancreas cancer cell growth as it did in animal models, but the blood and biopsy samples are allowing Maitra and Rasheed to go back into the laboratory, figure out why, and make necessary adjustments.

By comparing the molecular composition of tumors from patients whose cancers did not respond to treatment with those that did, our scientists may be able to create a profile of specific characteristics, such as a defined level of Hedgehog activity, to help identify those patients whose cancers are most likely to benefit. This work is part of expanded efforts at the Skip Viragh Center to sequence the genome of each patient's tumor cells and improve treatment outcomes through personalized treatment approaches tailored to the unique molecular fingerprint of an individual's tumor.

Former President Jimmy Carter Has Advanced Cancer

 AUG 14 2015, 11:18 AM ET

Watch the video at: http://www.nbcnews.com/health/health-news/former-u-s-president-jimmy-carter-has-advanced-cancer-n408751

Former President Jimmy Carter says he has cancer that has spread, although it's not yet clear what kind of cancer he has.

Carter, 90, had a mass removed from his liver on Aug. 3.

"Recent liver surgery revealed that I have cancer that now is in other parts of my body. I will be rearranging my schedule as necessary so I can undergo treatment by physicians at Emory Healthcare. A more complete public statement will be made when facts are known, possibly next week," Carter said in a statement.

James Earl Carter Jr. was 39th president of the United States, from 1977 to 1981. He's kept active despite his age, working with groups such as Habitat for Humanity, winning the Nobel Peace Prize in 2002 and founding the nonprofit Carter Center in his home state of Georgia.

"RECENT LIVER SURGERY REVEALED THAT I HAVE CANCER THAT NOW IS IN OTHER PARTS OF MY BODY."

Carter's family has a history of pancreatic cancer. His father, both his sisters and his brother died of pancreatic cancer, and his mother had pancreatic cancer as well.

In 2007, Carter told The New York Times that he had CT scans twice a year and later MRI (magnetic resonance imaging) to look for tumors in his pancreas.

In May, Carter left Guyana early from a stint monitoring elections there, saying he was feeling unwell.

Pancreatic cancer can spread to other organs, including the liver, and cancer can also originate in the liver and spread elsewhere. Carter did not give details of what type of cancer he has or how far it has spread.

However, when cancer spreads from one organ to elsewhere in the body, it is considered Stage IV cancer -- the most advanced stage. Stage IV cancer is generally incurable, although it can be treated, depending on the type.

Dr. Robert Mayer, a gastrointestinal cancer specialist at the Dana Farber Cancer Institute, says that at age 90, Jimmy Carter is unlikely to tolerate much treatment.

There are many different possible cancers that Carter could have, Mayer said.

"THIS IS A 90 YEAR OLD GENTLEMEN WITH APPARENT WIDESPREAD DISEASE. THE GOALS OF TREATMENT WOULD BE HIS COMFORT."

"I really don't know from paucity of information which of these would be the situation for President Carter. I don't know what his symptoms were. I don't know what led to surgery on his liver," Mayer told NBC News.

"This is a 90-year-old gentleman with apparent widespread disease. The goals of treatment would be his comfort. If chemo is considered it would need to take into account his age."

Mayer says a 90-year-old patient cannot tolerate the same treatment that could buy years of life for cancer patients in their 60s or 70s.

Statements of support poured in, including from President Barack Obama.

"Our thoughts and prayers are with Rosalynn and the entire Carter family as they face this challenge with the same grace and determination that they have shown so many times before," Obama's statement read.

"Jimmy, you're as resilient as they come, and along with the rest of America, we are rooting for you."

What’s new in pancreatic cancer research and treatment?

Research into the causes, diagnosis, and treatment of pancreatic cancer is under way in many medical centers throughout the world.

Genetics and early detection

Scientists are learning more about some of the changes in DNA that cause cells in the pancreas to become cancerous. Inherited changes in genes such as BRCA2, p16, and the genes responsible for hereditary non-polyposis colorectal cancer (HNPCC) can increase a person’s risk of developing pancreatic cancer.

Researchers are now looking at how these and other genes may be altered in pancreatic cancers that do not seem to be inherited. They have discovered that pancreatic cancer does not form suddenly. It develops over many years in a series of steps known as pancreatic intraepithelial neoplasia or PanIN. In the early steps, such as PanIN 1, there are changes in a small number of genes, and the duct cells of the pancreas do not look very abnormal. In later steps such as PanIN 2 and PanIN 3, there are abnormalities in several genes and the duct cells look more abnormal.

Researchers are using this information to develop tests for detecting acquired (not inherited) gene changes in pancreatic cancer pre-cancerous conditions. One of the most common DNA changes in these conditions affects theKRAS oncogene, which affects regulation of cell growth. New diagnostic tests are often able to recognize this change in samples of pancreatic juice collected during an ERCP (endoscopic retrograde cholangiopancreatography).

For now, imaging tests like endoscopic ultrasound (EUS), ERCP, and genetic tests for changes in certain genes (such as KRAS) are options for people with a strong family history of pancreatic cancer. But these tests are not recommended for widespread testing of people at average risk who do not have any symptoms.

Treatment

The major focus of much research is on finding better treatments for pancreatic cancer. Improving surgery and radiation therapy are major goals, as is determining the best combination of treatments for people with certain stages of cancer.

Surgery

Surgery to remove pancreatic cancer (most often a Whipple procedure) is a long and complex operation that can be hard both for the surgeon and the patient. It often requires a hospital stay of a week or more, at least in part because of the long incision made in the belly.

A newer approach now used at some major medical centers is to do the operation laparoscopically. For this approach, the surgeon makes several small incisions in the belly instead of one large one. Long, thin surgical instruments and a tiny video camera are then inserted through these cuts to do the operation. One advantage of this surgery is that people often recover from it more quickly. But this is still a difficult operation. Surgeons are looking to see how it compares to the standard operation and which patients might be helped the most by it.

Radiation therapy

Some current studies are looking at different ways to give radiation to treat exocrine pancreas cancer. These include intraoperative radiation therapy (in which a single large dose of radiation is given to the pancreas in the operating room at the time of surgery) and proton beam radiation (which uses a special type of radiation that might do less damage to nearby normal cells).

Chemotherapy

Many clinical trials are testing new combinations of chemotherapy drugs for pancreatic cancer. Studies have looked to see if combining gemcitabine with other drugs would help patients live longer. For example, adding capecitabine (Xeloda) to gemcitabine seems to help some patients. The combination of gemcitabine, irinotecan, and celecoxib (an arthritis drug) also shows promise.

Other studies are testing the best ways to combine chemotherapy with radiation therapy or newer targeted therapies.

Targeted therapies

As researchers have learned more about what makes pancreatic cancer cells different from normal cells, they have developed newer drugs that should be able exploit these differences by attacking only specific targets. These targeted therapies may provide another option for treating pancreatic cancer. They may prove to be useful along with, or instead of, current treatments. In general, they seem to have fewer side effects than traditional chemo drugs. Looking for new targets to attack on cancers is an active area of research.

Growth factor inhibitors: Many types of cancer cells, including pancreatic cancer cells, have certain molecules on their surface that help them grow. These molecules are called growth factor receptors. One example is epidermal growth factor receptor (EGFR). Several drugs that target EGFR are now being studied. One, known as erlotinib (Tarceva), is already approved for use along with gemcitabine.

Anti-angiogenesis factors: All cancers depend on new blood vessels to nourish their growth. To block the growth of these vessels and thereby starve the tumor, scientists have developed anti-angiogenesis drugs. These are being studied in clinical trials for patients with pancreatic cancer.

Drugs that target the tumor stroma (supporting tissue): Pancreatic cancer does not always respond well to chemotherapy. This is partly because of the cancer cells themselves, but another reason might be the dense surrounding supportive tissue (stroma) in the tumor. The stroma seems to form a barrier that helps protect the cancer cells from the effects of chemo drugs. Researchers are now looking at drugs that attack the stroma directly to help break it down. This might allow chemo or other drugs to be more effective. Some of these types of drugs are now inclinical trials.

Other targeted therapies: Many drugs targeting other aspects of cancer cells are now being studied for use in pancreatic cancer. Some of these drugs, such as sunitinib (Sutent), have several different targets.

Immune therapy

Immune therapies attempt to boost a person’s immune system or give them ready-made components of an immune system to attack cancer cells. Some studies of these treatments have shown promising results.

Monoclonal antibodies: One form of immune therapy uses injections of man-made monoclonal antibodies. These immune system proteins are made to home in on a specific molecule, such as carcinoembryonic antigen (CEA), which is sometimes found on the surface of pancreatic cancer cells. Toxins or radioactive atoms can be attached to these antibodies, which bring them directly to the tumor cells. The hope is that they will affect cancer cells while leaving normal cells alone. For use in pancreatic cancer, these types of treatments are available only in clinical trials at this time.

Cancer vaccines: Several types of vaccines for boosting the body’s immune response to pancreatic cancer cells are being tested in clinical trials. Unlike vaccines against infections like measles or mumps, these vaccines are designed to help treat, not prevent, pancreatic cancer. One possible advantage of these types of treatments is that they seem to have very limited side effects. At this time, vaccines are available only in clinical trials.

Drugs that target immune system checkpoints: The immune system normally keeps itself from attacking other normal cells in the body by using “checkpoints” – molecules on immune cells that need to be activated (or inactivated) to start an immune response. Cancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system. Newer drugs that target these checkpoints have shown a lot of promise in treating some types of cancer, and are now being studied for use in pancreatic cancer.

Individualization of therapy

Some drugs seem to work better if certain types of mutations can be found in the patient’s tumor. For example, erlotinib may work better in patients whose tumors have a particular change in the EGFR gene. This concept is an area of intense study. There might also be some gene alterations that affect how well gemcitabine will work in a particular patient. Identifying markers that may predict how well a drug will work before it is given is an important area of research in many types of cancer.

New treatments for pancreatic neuroendocrine tumors (NETs)

Many pancreatic NETs have receptors for somatostatin on their cells. These tumors can be treated with octreotide and other drugs like it. Newer drugs that use a radioactive form of octreotide have been shown to shrink some tumors and keep others from growing in early studies.

Last Medical Review: 06/11/2014
Last Revised: 01/09/2015