Researchers find potential new treatment approach for pancreatic cancer

Dec. 20, 2013 — Scientists from The University of Manchester -- part of Manchester Cancer Research Centre believe they have discovered a new way to make chemotherapy treatment more effective for pancreatic cancer patients.

Pancreatic cancer is an aggressive cancer with poor prognosis and limited treatment options and is highly resistant to chemotherapy and radiotherapy.

But researchers believe they have found an effective strategy for selectively killing pancreatic cancer while sparing healthy cells which could make treatment more effective.

Dr Jason Bruce, from the Physiological Systems and Disease Research Group, who led the research, said: "Pancreatic cancer is one of the most aggressive and deadly cancers. Most patients develop symptoms after the tumour has spread to other organs. To make things worse, pancreatic cancer is highly resistant to chemotherapy and radiotherapy. Clearly a radical new approach to treatment is urgently required. We wanted to understand how the switch in energy supply in cancer cells might help them survive."

The research, published in The Journal of Biological Chemistry this month, found pancreatic cancer cells may have their own specialised energy supply that maintains calcium levels and keeps cancer cells alive.

Maintaining a low concentration of calcium within cells is vital to their survival and this is achieved by calcium pumps on the plasma membrane.

This calcium pump, known as PMCA, is fuelled using ATP -- the key energy currency for many cellular processes.

All cells generate energy from nutrients using two major biochemical energy "factories," mitochondria and glycolysis. Mitochondria generate approximately 90% of the cells' energy in normal healthy cells. However, in pancreatic cancer cells there is a shift towards glycolysis as the major energy source. It is thought that the calcium pump may have its own supply of glycolytic ATP, and it is this fuel supply that gives cancer cells a survival advantage over normal cells.

Scientists used cells taken from human tumours and looked at the effect of blocking each of these two energy sources in turn.

Their study, funded by the Biotechnology and Biological Sciences Research Council (BBSRC), National Institute of Health Research (NIHR) Biomedical Research Centre and AstraZeneca, shows that blocking mitochondrial metabolism had no effect. However, when they blocked glycolysis, they saw a reduced supply of ATP which inhibited the calcium pump, resulting in a toxic calcium overload and ultimately cell death.

Dr Bruce added: "It looks like glycolysis is the key process in providing ATP fuel for the calcium pump in pancreatic cancer cells. Although an important strategy for cell survival, it may also be their major weakness.

"Designing drugs to cut off this supply to the calcium pumps might be an effective strategy for selectively killing cancer cells while sparing normal cells within the pancreas."

Maggie Blanks, CEO of the national charity, the Pancreatic Cancer Research Fund said: "These findings will certainly of great interest to the pancreatic cancer research community and we'd be keen to see how this approach progresses. Finding weaknesses that can be exploited in this highly aggressive cancer is paramount, so we want to congratulate the Manchester team for their discovery."

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Targeted radiation therapy safe, effective treatment for elderly with pancreatic cancer

Sep. 24, 2013 — A highly targeted cancer radiation therapy may offer a safe and effective treatment option for elderly pancreatic cancer patients unable to undergo surgery or combined chemotherapy and radiation therapy, according to researchers at Henry Ford Hospital in Detroit.

Called stereotactic body radiotherapy (SBRT), the study finds patients lived, on average, six to seven months longer following treatment with minimal side-effects even when they had other severe comorbidities such as chronic obstructive pulmonary disease (COPD), heart disease and diabetes.

Two of the patients in the study lived nearly two years.

“Elderly individuals, those ages 75 and older, account for approximately 40 percent of patients diagnosed with pancreatic cancer,” says study lead author Raphael Yechieli, M.D., with the Department of Radiation Oncology at Henry Ford Hospital.

“These patients are too ill to receive any other treatment, but with stereotactic body radiotherapy we’re able to deliver a safe and effective treatment in two weeks that can provide them with a substantial quality of life with minimal side effects.”

The study was presented at the 55nd annual American Society for Radiation Oncology (ASTRO) meeting in Atlanta.

In 2013, there will be an estimated 45,220 new cases of pancreatic cancer, and approximately 38,460 will die from the disease, according to the National Cancer Institute. Risk factors for pancreatic cancer include smoking, diabetes, obesity, family history of the disease and pancreatitis. Most people diagnosed with the disease are older than 65.

Surgery is the only known cure for resectable pancreatic cancer, where the cancer is localized to the pancreas and hasn't spread. It is estimated that only 20 percent of pancreatic cancer patients have their tumors present with localized disease amendable to surgical removal.

A select number of those patients, however, are not candidates for surgery due to having other co-morbidities such as COPD, heart disease and diabetes. This leaves only chemotherapy and radiation, or a combination of the two, available for treatment.

But for a large portion of elderly patients with localized pancreatic cancer even chemotherapy and radiation therapy are not options.
The Henry Ford study looked to determine if SBRT – a method of giving radiation that can be highly targeted to the tumor, sparing the normal tissue around it – was a viable option for this group of patients. SBRT provides a higher dose of radiation, meaning patients have fewer treatments. In this case, treatment averaged two weeks.

The study included 20 patients with a median age of 83, all of whom were medically unable to tolerate surgery or combined chemo-radiation therapy. The majority of patients in the study (90 percent) received SBRT treatment at the time of diagnosis.

Seven patients reported side-effects from treatment: nausea, vomiting and fatigue.

Among the patients: 13 had a recurrence of cancer; nine had cancer spread from the original tumor to distant organs or distant lymph nodes.

Median overall survival was 6.7 months, and median recurrence-free survival was 8.1 months. At six months post-treatment, 61 percent of patients were alive; two patients in the study survived nearly two years.

“National trends tell us that very few patients over the age of 75 are getting any treatment at all for pancreatic cancer due to comorbidity risks,” notes Dr. Yechieli. “So we want to push the envelope to give them a treatment option that, while not a cure, is short, effective and safe, and has the potential to give them a good quality of life.”

The next step in this research, Dr. Yechieli says, is to closely follow patients after SBRT and get their direct feedback to measure post-treatment quality of life.

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Pancreatic stem cells isolated from mice

Sep. 17, 2013 — Scientists have succeeded in growing stem cells that have the ability to develop into two different types of cells that make up a healthy pancreas. The research team led by Dr. Hans Clevers of the Hubrecht Institute, The Netherlands, have isolated and grown stem cells from the pancreases of mice using a 3-D culture system previously developed by the scientists. The results, which are reported in The EMBO Journal, could eventually lead to ways to repair damaged insulin-producing beta cells or pancreatic duct cells.

Cell signalling molecules known as Wnts and a protein called Lgr5 are essential to produce adult stem cells that can be coaxed to grow and divide rapidly. However, these signaling pathways and molecules are inactive in the adult pancreas. "We have found a way to activate the Wnt pathway to produce an unlimited expansion of pancreatic stem cells isolated from mice," Clevers said. "By changing the growth conditions we can select two different fates for the stem cells and generate large numbers of either hormone-producing beta cells or pancreatic duct cells." He added: "This work is still at a very early stage and further experiments are needed before we can use such an approach for the culture of human cells but the results are a promising proof-of-concept."

In the study, the pancreases of mice were altered in a way that makes duct cells proliferate and differentiate. Some cells in this new population were stem cells that were capable of self-renewal. The scientists were able to culture these cells to give rise to large numbers of pancreatic cells or tiny clumps of tissue referred to as organoids.

Therapeutic strategies for pancreatic disease have been hampered by a lack of cell culture systems that allow scientists to grow replacement tissue in a test tube or on a dish. Alternative approaches such as tissue transplantation are limited by the scarcity of donors and the possibility of tissue rejection. The new work offers access to an unlimited supply of pancreatic stem cells that would be beneficial for the development of new therapeutic interventions for pancreatic diseases like diabetes.

The next steps for the scientists will include further refinement of the cell culture methods developed in this study and investigation of ways to extend the approach to human pancreatic cells.

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Story Source:

The above story is based on materials provided by EMBO - excellence in life sciences.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Meritxell Huch, Paola Bonfanti, Sylvia F Boj, Toshiro Sato, Cindy J M Loomans, Marc van de Wetering, Mozhdeh Sojoodi, Vivian S W Li, Jurian Schuijers, Ana Gracanin, Femke Ringnalda, Harry Begthel, Karien Hamer, Joyce Mulder, Johan H van Es, Eelco de Koning, Robert G J Vries, Harry Heimberg, Hans Clevers. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. The EMBO Journal, 2013; DOI: 10.1038/emboj.2013.204

Note: If no author is given, the source is cited instead.

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