Oliver McDonald, M.D., Ph.D., Kimberly Stauffer, left, Anna Word and colleagues are studying how metastatic pancreatic cancer changes its metabolism to become more malignant. (photo by Joe Howell)

Dr. Oliver McDonald, of NMF’s Medical Board, Publishes New Study

Oliver McDonald, M.D., Ph.D., Kimberly Stauffer, left, Anna Word and colleagues are studying how metastatic pancreatic cancer changes its metabolism to become more malignant. (photo by Joe Howell)

Oliver McDonald, M.D., Ph.D., Kimberly Stauffer, left, Anna Word and colleagues are studying how metastatic pancreatic cancer changes its metabolism to become more malignant. (photo by Joe Howell)

Metastatic pancreatic cancer — cancer that has spread from the pancreas to other tissues and is responsible for most patient deaths — changes its metabolism and is “reprogrammed” for optimal malignancy, according to new findings reported Jan. 16 in Nature Genetics.

It may be possible to reverse the malignant reprogramming to treat metastatic pancreatic cancer, said Oliver McDonald, M.D., Ph.D., assistant professor of Pathology, Microbiology and Immunology at Vanderbilt, and lead author of the study.

The researchers have identified a compound that reverses the reprogramming and prevents tumor formation in model systems.

“We are not aware of other agents that selectively act on aggressive, distant metastatic disease, so this was a huge surprise to us,” McDonald said. “We’re very excited about developing more selective compounds for pre-clinical studies.”

McDonald and close collaborators from Memorial Sloan Kettering Cancer Center and Johns Hopkins University School of Medicine sought to understand how pancreatic cancer progresses from a primary tumor in the pancreas to metastatic disease in distant tissues.

The prevailing theory of cancer progression — that it’s driven by the accumulation of genetic mutations that increase tumorigenic “fitness” — holds true for the early stages of cancer progression, but metastases seem to find new ways to increase their fitness, McDonald said.

“Intensive DNA sequencing efforts to find the genetic ‘drivers’ of metastasis, which is what kills patients in up to 80 percent of cases, have thus far been disappointing, to say the least,” he said.

Instead of looking for genetic changes during cancer progression, McDonald and his colleagues examined epigenetics — modifications of chromosomal DNA and proteins that control gene function.

“Epigenetics can be thought of as the software that programs function into the DNA hardware,” McDonald said.

The researchers studied a unique set of matched primary and metastatic pancreatic cancer samples collected (by rapid autopsy) from patients who died from aggressive, widely metastatic disease.

Christine Iacobuzio-Donahue, M.D., Ph.D., now at Memorial Sloan Kettering, began collecting the patient samples and studying the primary and metastatic tumors when she was a faculty member at Johns Hopkins.

She and her colleagues sequenced genomic DNA in the tumor samples but did not find any new driver gene mutations in the metastatic samples compared to the primary tumor samples, said McDonald, who completed clinical training under Iacobuzio-Donahue at Johns Hopkins.

After moving to Vanderbilt, McDonald continued working with Iacobuzio-Donahue and Andrew Feinberg, M.D., MPH, who is also at Johns Hopkins and is a recognized pioneer in the field of cancer epigenetics.

“It was an incredibly productive collaboration that brought together Chris’s genetics expertise and amazing patient samples, Andy’s expertise and world-class sequencing facilities, and our experimental work and data analysis at Vanderbilt,” McDonald said.

The researchers were surprised to find massive epigenetic changes across the genome of distant metastases (those resulting from spread of cancer cells through the bloodstream), compared to matched primary tumor cells and peritoneal “carcinomatosis,” a localized form of intra-abdominal metastasis that is not thought to spread through the bloodstream.

The genome-wide epigenetic changes clustered in certain chromatin domains and controlled “gene expression changes that specify different malignant traits, including the ability to form tumors,” McDonald said. “Much of the epigenome gets reprogrammed right at the point of metastasis.”

To further explore the reprogramming, McDonald performed metabolic studies on the samples, with collaborators at Duke University. By painstakingly analyzing long lists of metabolites, McDonald and Vanderbilt undergraduate student Anna Word discovered that distant metastases altered their metabolism by consuming excess amounts of glucose and directing it through the pentose phosphate metabolic pathway. A particular enzyme in the pathway — phosphogluconate dehydrogenase (PGD) – turned out to be key, enabling the conversion of glucose to metabolites that “can directly fuel tumor growth,” McDonald said.

The researchers demonstrated that blocking the PGD enzyme genetically or with a pharmacologic inhibitor reversed the epigenetic reprogramming and malignant gene expression changes detected in distant metastases, and also strongly inhibited their tumor-forming capacity, with no effect on normal cells or peritoneal pancreatic cancer controls. Kimberly Stauffer, a graduate student at Vanderbilt, played an important role in uncovering the inhibitor effects.

The findings may help explain a clinical enigma — the observation that metastatic tumors often seem to progress very rapidly compared to primary tumors.

The current research suggests that pancreatic cancer cells that spread to organs that receive a blood supply rich in glucose and other nutrients, such as the liver and lungs, acquire metabolic adaptations to use these “natural resources” to increase their tumorigenic fitness.

“Our laboratory findings on Chris’s autopsy patient samples suggest that metastatic cells in these patients evolved an incredibly aggressive combination of metabolic, epigenetic and gene expression changes that allowed them to form numerous tumors in a short amount of time,” McDonald said. “However, if you hit the PGD enzyme, at least in the experimental setting, then you block their ability to do that.”

McDonald is working with medicinal chemists at Vanderbilt to develop more selective and potent PGD inhibitors for testing in animal models, with the ultimate goal of moving these inhibitors into clinical trials for pancreatic cancer patients.

This research was supported by grants from the National Institutes of Health (CA038548, CA140599, CA179991, CA180682), and by the AACR Pancreatic Cancer Action Network, Vanderbilt GI SPORE and Vanderbilt-Ingram Cancer Center.

by Leigh MacMillan for Vanderbilt University Research News | Jan. 19, 2017

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Nutrition’s Role In Managing Pancreatic Cancer Symptoms

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Nutrition, though often overlooked, plays a key role in mitigating the symptom burden of patients with pancreatic cancer. 

When diagnosed with pancreatic cancer, one of the last things on a patient’s mind may be diet and nutrition, yet these are two key components that medical experts say can affect the outcome of treatment.

Patients with pancreatic cancer often experience weight loss, loss of appetite, fatigue, nausea, as well as back and belly pain. The cancer itself plays a large role in preventing patients from having a normal diet and nutrition.

During a live broadcast of CURE Connections, held during the Seventh Annual Ruesch Center Symposium: Fighting a Smarter War on Cancer on Dec. 3 in Washington, D.C., a panel that included an oncologist, a nurse, an oncology dietitian and a patient advocate discussed the importance of nutrition when trying to manage a long list of symptoms.

“These cancers are well-known to release hormones that we don’t fully understand that rob a patient of their appetite,” said Michael Pishvaian, M.D., director, Phase 1 Clinical Trials Program, Division of Hematology/Oncology, Georgetown Lombardi Comprehensive Cancer Center. “It makes them feel like they don’t want to eat or drink anything. It robs them of their calories even if they are very conscientious about getting enough nutrition in. It can even cause changes to taste, so a patient with pancreatic cancer will often complain about an abnormal taste sensation long before they even start chemotherapy.”

Pishvaian explained that the pancreas creates digestive enzymes that help digest food properly. When the cancer invades the pancreas, this disrupts proper digestion. The lack of digestion also leads to bacterial overgrowth lower down into the gastrointestinal (GI) tract and can cause a lot of discomfort, gassiness, bloating and diarrhea, he added.

There are ways to try to manage these symptoms before, during and after the cancer journey. The panel recommended patients make it a priority to meet with a dietician one-on-one. Some cancer centers already have a dietician in place.

“Often pancreatic cancer patients will undergo a surgery called a Whipple Procedure (pancreaticoduodenectomy), which can impair a patient’s ability to digest certain foods like fats, carbohydrates and proteins – particularly in fats,” said Rachel Wong, R.D., oncology dietician, Georgetown Lombardi Comprehensive Cancer Center.

She added, that this is where digestive enzymes, which help break down fats, proteins and carbohydrates, should be consumed with meals and snacks.

Patients should consume energy-dense nutritious foods such as quinoa, oatmeal and avocado, which all have healthy fats. As far as sugars go, they should continue to eat fruits, but stay away from simple sugars like candy bars.

It is also recommended that patients with pancreatic cancer eat small, frequent meals, eat slowly and also keep a diary of everything they are eating and drinking each day.

Patricia Reilly, a holistic health counselor, nutrition expert and patient advocate, says the best way a caregiver can be there for a loved one with pancreatic cancer is to help with nutrition. She became that person for her husband, who had pancreatic cancer.

“We recognized that he wanted to feel good every day. As a caregiver, I looked at the foods,” Reilly said. “I want my doctor to know about those clinical trials. I want him to be on top of that and let me create a team to support my husband in terms of what he’s eating for breakfast, lunch and dinner, again looking for nutrient-dense foods that will support him to be stronger so he will get to that clinical trial.”

The panel also opened up the discussion on marijuana and if there is a benefit there for patients with pancreatic cancer, which they agreed there is.

“We are seeing that their appetite goes up, their sense of well-being is greater and their pain levels are reduced,” said Pishvaian. “It is not a treatment for their cancer, but universally makes them feel better. Try things, see what works and stick with it.”

By Katie Kosko for Curetoday.com

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Coping with Cancer During the Holidays

1419370395896Holidays are traditionally viewed as a time to celebrate. Many people enjoy reuniting with family and friends, giving and receiving gifts, and celebrating religious traditions during this time. However, sometimes people with cancer and their loved ones feel “out of step” from the rest of the world during the holidays. In fact, the holiday season can prompt new questions, such as: How do I take care of the holiday rush and myself at the same time? How can I celebrate when I have so many other things on my mind? What will my life be like next year? Sharing these concerns with the people you love and who love you can help you feel more connected.

Here are some additional tips for coping with cancer during the holidays:

Make plans to get together with friends, family or co-workers over the holidays. Trying to celebrate alone can be very difficult, so accept some invitations from others, or join an organized group activity through your local YMCA, YWCA, church or synagogue. Find the right balance between celebrating with family and friends and spending the time you may need on your own. Give yourself permission to pace your activities and to decline an invitation or two so that you have the energy to enjoy the gatherings that are most important to you.

Create a new holiday season tradition that makes the most of your energy.Change your usual holiday activities so you relieve yourself of some of the pressures of entertaining. Have a “pot luck,” with family members each bringing a dish for the meal, have someone else host the meal, or suggest eating out at a favorite restaurant.

Enjoy special moments. Try to focus on new traditions that have been established, rather than dwelling on how cancer has changed a holiday or special occasion.

Talk to your health care team about upcoming special events. They may be flexible about appointments in order to accommodate travel or other needs.

Be an innovative shopper or gift giver. Use mail order catalogues, shop over the telephone, or try online shopping this year. You can also make a gift of sharing your thoughts and feelings. Write a short note or make a phone call to let others know that you are thinking about them.

Express your feelings in ways that help you receive the support of the important people in your life. Tears can bring a sense of relief. Laughter can be relaxing. Sharing can be comforting. It is common to experience a mixture of anticipation, excitement and apprehension about the future. Let your feelings breathe, and talk them over with a loved one, friend or professional counselor.

Celebrate strengths you and your loved ones have developed. Many families who face the day-to-day challenges of cancer discover strengths and courage they didn’t know they had. Reflect on the strengths you have developed, and build on them during the holidays.

Article reposted from cancercare.org

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Thanksgiving Meals for patients and their families

l-ncjbmzrwlnsfcfjz-copyBeing from Texas, Nikki chose to go home for Christmas and stay in Nashville for Thanksgiving. She started a tradition for her friends with a home cooked meal for “Friendsgiving”. It was one of her favorite things to do and her friends who had family out of town had a warm, inviting place to go. Having pancreatic cancer, going to treatments and feeling sick didn’t stop her from this tradition. She made sure there was a Friendsgiving meal for everyone.

This year we are doing the same thing for cancer patients –  Nikki’s foundation is providing a “Friendsgiving Meal” for PC patients and those living with them. NMF is asking you to donate to the Bridge of Wings program. In addition to helping cancer patients with their daily living expenses, we’re providing holiday meals for them and their families.

MATCHING DONATIONS – A loyal supporter of NMF who has been impacted by pancreatic cancer has pledged to match donations up to $2500! 

To donate to our Bridge of Wings program for Thanksgiving meals, click here and to learn more about BOW, check it out here.

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PC Symptoms and Jamie’s Story

image2Symptoms of pancreatic cancer can be weight loss, abdominal or back pain, diabetes, or jaundice. Physical symptoms are not very specific to the disease and are often mistaken for something else. Patients can even be asymptomatic. The bottom line is pancreatic cancer is hard to diagnose and even harder to treat. Nikki Mitchell Foundation is working hard to prevent, detect and cure pancreatic cancer.

Jamie Thornton, a friend of NMF, shares the story of her father’s journey:
My father, James Drury, was a Vietnam veteran (a captain and platoon leader), a general manager, and a great leader and father. He loved life, outdoors, people and food. He was a heavy-set guy and we were excited at first when he started to lose weight, but when he started having severe pain in his stomach, he finally went to the doctor. The doctor was positive about his weight loss and encouraged him to keep cutting back on food.

Around November, a few months after the initial pain and losing 50 pounds, he started hurting a little more when he ate and I talked him into going back to the doctor twice. By the end of the week we had a diagnoses of a tumor in his pancreas. After a slew of hospital visits and tests, we found out he had two pancreatic tumors, with one on a lymph node, liver tumors, and spots in his lungs. The oncologist recommended he start chemotherapy and also participate in an additional clinical trial that might decrease the spread of the tumors from the lymph node.

Throughout all of this, Dad was very positive and strong in his faith and believed that with any outcome he was a winner because he either got to stay with us on earth or go to heaven.

We scheduled the chemo and he made it through only two treatments. After the second round was over, Dad could barely stand up. He had an adverse reaction to the drugs, wound up in the hospital twice, and then we were told he only had a few weeks to two months to live. We were sent home with hospice care.

We were blessed that Daddy came out of hospital feeling better this time and over the next month, as the chemo left his body, he was able to return to some fun activities that he enjoyed like fishing, shooting and visiting with friends he hadn’t seen in years. He actually had a full pain-free week once and felt like maybe he was cured. Then, at the end of May, and after watching my daughter graduate from middle school, he started declining rapidly. A week and half later he was gone. I believe he is a winner in that he is in heaven and he has left a wonderful legacy to his kids, grandkids, friends and family. He maintained a wonderful outlook throughout the whole experience.

We experienced some difficulties, like doctors not being clear about survival rates and honestly explaining to us what to expect. I also wish we had known earlier that weight loss is a major indication that something is wrong and that maybe he could have had a chance of beating the disease.