Popular Diabetes Drug Might Cut Pancreatic Cancer Risk: Study

TUESDAY, Jan. 31 (HealthDay News) -- A new Swiss-American study indicates that long-term use of the popular diabetes medication metformin may lower the risk of developing pancreatic cancer, at least among women.

The researchers also found that the long-term use of another class of diabetes medications known as sulfonylureas was associated with a "substantial" bump in pancreatic risk and long-term insulin use was linked to a bump in pancreatic cancer risk in men.

"This result is somewhat unexpected," the team wrote in its paper, which is published in the Jan. 31 online issue of The American Journal of Gastroenterology.

Pancreatic cancer is the fourth most deadly cancer in the United States, with an overall survival rate of less than 5 percent, even though it is fairly rare, according to the U.S. National Institutes of Health.

The researchers noted that previous research has suggested that metformin may lower the risk for other cancers, breast and ovarian cancer in particular.

To explore metformin's protective potential against pancreatic cancer, the team sifted through drug prescription, diagnostic, hospitalization and fatality information that had been collected by the British "General Practice Research Database." The data also included significant demographic information, such as smoking, alcohol use and body mass index.

The team honed in on statistics regarding nearly 2,800 patients (all under the age of 90) who had been diagnosed with pancreatic cancer for the first time between 1995 and 2009. Data concerning almost 16,600 patients who did not have pancreatic cancer was used as a comparison.

The result: Short-term use of metformin or sulfonylureas and/or insulin had no appreciable impact on pancreatic cancer risk.

However, long-term use of each of these medications did appear to have a sizeable impact on pancreatic cancer risk among diabetics. While female patients saw their risk go down with metformin treatment and up with sulfonylureas, male patients saw their risk go up with insulin.

Dr. Michael Choti, a professor of surgery and oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, stressed the "importance of trying to identify causes for a devastating disease that is often diagnosed late."

"Over the years, many groups have tried to look at a variety of risk factors, dietary and other things, and there have been some reports over the years," he noted. "But nothing has really panned out well. So this is indeed an interesting study."

"But it's also important to say," Choti added, "that while these could be associations, we cannot really say that what we have here is a cause-and-effect. Pancreatic cancer is a multi-factorial disease. So, while it makes sense conceptually that these drugs could have an impact on the pancreas, which is a metabolic organ, it's still too early to be sure what's happening. And it's too early to recommend metformin as a preventive therapy for pancreatic cancer."

"So this is interesting and important," he said. "But it's not definitive."

More information

For more on pancreatic cancer, visit the U.S. National Library of Medicine.

SOURCES: Michael Choti, M.D., professor, surgery and oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore; Jan. 31, 2012, The American Journal of Gastroenterology, online

Copyright © 2012 HealthDay. All rights reserved.

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Study Identifies Components Responsible For Therapy-Blocking Solid Stress, Suggests Therapeutic Cancer Strategies

Main Category: Pancreatic Cancer
Also Included In: Lung Cancer;  Breast Cancer
Article Date: 24 Sep 2012 - 1:00 PDT Current ratings for:
Study Identifies Components Responsible For Therapy-Blocking Solid Stress, Suggests Therapeutic Cancer Strategies

It's a high-pressure environment within solid tumors. Abnormal blood and lymphatic vessels cause fluids to accumulate, and the uncontrolled proliferation of cancer cells within limited space leads to the buildup of what is called solid stress. Both types of pressure can interfere with the effectiveness of anticancer treatments, but while strategies have been developed that reduce fluid pressures, little has been known about the impact of solid stress or potential ways to alleviate it. Now a Massachusetts General Hospital (MGH) research team has identified factors that contribute to solid stress within tumors, suggesting possible ways to alleviate it, and has developed a simple way to measure such pressures.

"Traditionally cancer research has focused on cancer cells and, more recently, on the biochemical microenvironment of tumors," says Rakesh Jain, PhD, director of the Steele Laboratory for Tumor Biology at MGH and senior author of the study in the Proceedings of the National Academy of Sciences. "Our work shows that the physical or mechanical microenvironment plays an equally important role in tumor progression and treatment resistance."

Jain and his colleagues have been leaders in understanding the impact of elevated fluid pressures that make it difficult for drugs to enter and permeate tumors. Their work showed that fluid pressures are relieved when antiangiogenesis drugs normalize the abnormal blood vessels characteristically found within solid tumors, improving the effectiveness of other anticancer therapies. But that approach can only work if vessels have not been squeezed shut by solid stress in surrounding tissues. In recent studies Jain's team showed that solid stress also increases the invasiveness of cancer cells.

The current study was designed to develop techniques that measure solid stress in tumors, to identify factors that contribute to the generation of this solid stress and to determine whether previously compressed blood vessels would open when stress-inducing components were depleted. Based on predictions from mathematical models, the MGH-based team developed a remarkably simple way to measure solid stress within tumor tissues.

In experiments using both tumors experimentally grown in mice and tumors removed from human patients, the researchers found that, when a solid tumor is cut in two, each segment begins to swell along the sliced surface, releasing stored solid stress. In contrast, when a sample of normal tissue is cut in two, the separated halves of tissue retain their size and shape (links to video files below). Measuring the extent of shape relaxation along with other mechanical properties of tumor tissue enabled calculation of the amount of solid stress within a tumor sample.

Sample of breast tumor grown in mouse expands after cutting, releasing solid stress *

Sample of normal mouse kidney tissue, showing no change in shape after cutting **

Additional experiments utilizing the newly developed technique identified several components that contribute to increased solid stress within tumors, including the proliferation not only of cancer cells but also of fibroblasts and other components of the tumor's extracellular matrix. In pancreatic tumors implanted into mice, the researchers showed that inhibition of a pathway leading to the growth of fibroblasts reduced solid stress associated with tumor growth and opened up compressed blood and lymphatic vessels, which could both relieve fluid pressure and improve the delivery of chemotherapy drugs.

The authors note that their results may explain why the use of antiangiogenesis drugs has not improved treatment of highly fibrotic tumors - including dangerous pancreatic, lung and breast cancers - and suggest that a strategy targeting both aspects of intratumor pressure should be explored. "Now that we have seen how tumors exploit physical forces to facilitate progression and treatment resistance, we need to learn how to tame these fluid and solid forces to improve treatment outcomes," says Jain, the Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School. "We urgently need to identify safe pharmaceutical agents that reduce solid stress and then add them judiciously to current treatments."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our pancreatic cancer section for the latest news on this subject. * http://www.pnas.org/content/suppl/2012/08/29/1213353109.DCSupplemental/sm01.mov
** http://www.pnas.org/content/suppl/2012/08/29/1213353109.DCSupplemental/sm02.mov
Co-lead authors of the PNAS paper are Triantafyllos Stylianopoulos, PhD, and John D. Martin of the Steele Laboratory. Additional co-authors are Vikash Chauhan, Saloni Jain, Benjamin Diop-Frimpong, Yves Boucher, PhD, and Lance Munn, PhD, Steele Lab; Nabeel Bardeesy, PhD, MGH Center for Cancer Research; Barbara Smith, MD, MD, and Cristina Ferrone, MD, MGH Department of Surgery; and Francis J. Horniceki, MD, PhD, MGH Orthopaedic Oncology. The study was supported by grants from the National Institutes of Health and the Department of Defense.
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Cancer-Causing Gene Alone Doesn't Trigger Pancreatic Cancer, Mayo-Led Study Finds

Main Category: Pancreatic Cancer
Also Included In: Cancer / Oncology;  Genetics
Article Date: 12 Sep 2012 - 1:00 PDT Current ratings for:
Cancer-Causing Gene Alone Doesn't Trigger Pancreatic Cancer, Mayo-Led Study Finds

More than a cancer-causing gene is needed to trigger pancreatic cancer, a study led by Mayo Clinic has found. A second factor creates a "perfect storm" that allows tumors to form, the researchers say. The study, published in the Sept. 10 issue of Cancer Cell, overturns the current belief that a mutation in the KRAS oncogene is enough to initiate pancreatic cancer and unrestrained cell growth.

The findings uncover critical clues on how pancreatic cancer develops and why few patients benefit from current therapies. The findings also provide ideas about how to improve treatment and prevention of pancreatic cancer.

The research team, led by Howard C. Crawford, Ph.D., a cancer biologist at Mayo Clinic's campus in Florida, and Jens Siveke, M.D., at Technical University in Munich, Germany, found that for pancreatic cancer to form, mutated KRAS must recruit a second player: the epidermal growth factor receptor, or EGFR.A third genetic participant known as Trp53 makes pancreatic tumors very difficult to treat, the study showed.

The scientists also found that EGFR was required in pancreatic cancer initiated by pancreatic inflammation known as pancreatitis.

"We believe the perfect storm needed to trigger pancreatic cancer include KRAS mutations and inflammation in the organ, which then work synergistically to turn on EGFR," says Dr. Crawford.

"The bottom line is, without EGFR, tumors don't form - and that was never known before this study," he says. "We also think that inflammation in the pancreas has a big impact on turning on EGFR."

The researchers discovered that when they blocked EGFR activity, the mice studied were protected against developing chronic pancreatitis and pancreatic cancer.

They further found that in mice that had lost expression of the TP53 tumor suppressor - a situation that mirrors up to 60 percent of human pancreatic cancer cases - tumors escape the dependency on EGFR for initiation and continued growth of pancreatic cancer, Dr. Crawford says.

Pancreatic cancer is a highly lethal disease; no drug has been able to target the mutant KRAS protein. The study suggests some patients, such as those with chronic pancreatitis, may be good candidates for treatment with EGFR inhibitors to fight or prevent pancreatic cancer, Dr. Crawford says.

"The clinical implications of this study are exciting. It suggests that pancreatic cancer patients with normal p53 activity, as well as patients with chronic pancreatitis, may be good candidates for treatment with EGFR inhibitors," Dr. Crawford says.

The EGFR inhibitor erlotinib is part of the standard therapy for pancreatic cancer patients, but has minimal effects in the patient population as a whole, he adds. "But that may be because many of the patients likely had a mutation in the TRP53 tumor suppressor, so erlotinib would not help them, since EGFR was no longer necessary for tumor growth.

"Perhaps erlotinib or other EGFR inhibitors would work much better in patients who do not have a TRP53 mutation," he says. "We also believe this kind of drug could prevent pancreatic cancer formation in patients with chronic pancreatitis, which is a significant risk factor for development of pancreatic tumors."

"These findings give us some greatly needed clues about how pancreatic cancer develops and progresses," Dr. Crawford says. "The more we understand about these early tumors, the more we will be able to work on diagnosis and therapy."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our pancreatic cancer section for the latest news on this subject. The study was funded by the National Cancer Institute.

Mayo Clinic

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'Cancer-Causing Gene Alone Doesn't Trigger Pancreatic Cancer, Mayo-Led Study Finds'

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