Pancreatic cancer linked to developmental cell signaling pathway
Finding suggests possible treatment approach for highly lethal disease

BOSTON - September 14, 2003 - Scientists at Massachusetts General Hospital (MGH) and the University of California at San Francisco (UCSF) have found strong evidence that a cell signaling pathway active in embryonic development plays a crucial role in pancreatic cancer. The finding provides the first model of the development and growth of pancreatic cancer and suggests a clear route for treatment of this lethal malignancy. The research is being posted online today by the journal Nature, prior to publication in the print journal.

Pancreatic cancer is the fourth leading cause of cancer deaths in the U.S. Each year 30,000 cases are diagnosed, and for the majority of patients the disease is incurable.

Using human cell lines, the researchers showed that pancreatic cancer growth can be arrested by chemically blocking a signaling pathway which previously had been known to be active in human embryonic development. Known as the Hedgehog pathway, this cascade of chemical steps allows proteins to pass along a signal that ultimately leads to changes in gene activity and has already been linked to several other types of cancer. The research highlights the link between embryonic development and cancer - proteins that normally regulate rapid growth in the embryo may often be responsible for the out-of-control cell divisions in cancer, the scientists say.

"Surgery has represented the only possible cure for pancreatic cancer patients," said Sarah P. Thayer, M.D., Ph.D., of MGH, the paper's co-first and the co-senior author with Matthias Hebrok, Ph.D., of UCSF. "However, the majority of patients are diagnosed at an incurable stage of their disease. We have been stymied by our inability to diagnose patients earlier and offer effective treatments." Thayer deals principally with the surgical management of pancreatic cancer patients, and the disease is the main focus of her research.

Although much more work needs to be done before definitive conclusions can be made regarding the application of this research to clinical practice, Hebrok, assistant professor of medicine in UCSF's Diabetes Center, comments, "Identifying the role of this pathway in pancreatic cancer offers hope for developing treatments, and it also underscores how studying organ development in embryos can provide clues to cancer, diabetes and other serious diseases."

"Our funding of this research emphasizes the importance of understanding the signals and genetic networks that regulate development of the pancreatic cells," said Richard Insel, MD, vice president, Research, Juvenile Diabetes Research Foundation (JDRF) International, one of the supporters of the study. "These insights could prove relevant for activating beta cell regeneration, and for understanding how beta cell growth is disordered in pancreatic malignancies.

Normally, Hedgehog proteins influence early development by binding to another protein on the cell surface, known as the Patched receptor. This union triggers a series of chemical changes, leading to gene activity in the nucleus. Mutations in the Hedgehog pathway are known to cause several types of cancer, and this research adds pancreatic cancer to the list of serious outcomes of aberrant Hedgehog activity.

In one part of the study, the scientists compared normal adult human pancreatic tissue to specimens from patients with pancreatic cancer. No Hedgehog protein was detected in the normal tissue, but it was found in 70 percent of precancerous and cancerous specimens. Furthermore, key genes in the Hedgehog pathway were also found to be overexpressed.

"Misexpression of the Hedgehog pathway in transgenic mice resulted in the formation of abnormal pancreatic cells that resembled human precursor lesions, suggesting that this pathway may have a role in the initiation of this cancer," said Thayer, an instructor in Surgery at Harvard Medical School (HMS). "However, its true role in pancreatic cancer remains to be determined."

The researchers also examined 26 human pancreatic cancer cell lines and found Hedgehog activity in all of them. When the Hedgehog pathway was blocked experimentally, the cancer was killed half of the time. Cancer-causing mutations "downstream" from the Hedgehog pathway may cause the other half of the cancers, the researchers think. The scientists then transplanted pancreatic cancer cells into mice, creating tumors. They injected the mice with an inhibitor of the Hedgehog pathway, which resulted in a 50 to 60 percent reduction in tumor size after seven days.

The experimental results - death of tumor cells both in the Petri dish and in animals - suggest that this may one day hold promise as a treatment avenue, the researchers say. Unfortunately, the inhibitor used for these experiments is not a practical drug for clinical use, they point out. But since abnormalities in Hedgehog expression have already been linked to gliomas, basal cell carcinoma and very recently, small cell lung cancer, university and commercial labs are screening for more effective Hedgehog blockers. "If Hedgehog is involved in pancreatic cancer, these other blockers might offer a bright prospect in treating a disease that has eluded effective treatment up to now," Hebrok said.

A second paper in the same issue of Nature reports that Hedgehog signaling is active in pancreatic and other cancers along the gastrointestinal tract. These results provide further evidence that deregulation of this pathway is a more general phenomenon than previously anticipated.

Marina Pasca di Magliano, Ph.D., of the UCSF Diabetes Center, is co-first author on the paper. Other UCSF co-authors are Patrick W. Heiser, Yan Ping Qi, Stephan Grysin, Ph.D., and Martin McMahon, Ph.D. Co-authors at MGH and HMS are Drucilla Roberts M.D., Gregory Lauwers, M.D., Corinne Nielsen, M.S., Carlos Fernández-del Castillo, M.D., Bozena Antoniu, M.S., Vijay Yajnik, M.D., Ph.D, and Andrew Warshaw, M.D. In addition to the JDRF funding, the research was supported by grants from the Lustgarten Foundation for Pancreatic Cancer Research and the National Institutes of Health.


Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $350 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physic

http://www.massgeneral.org/news/releases/091403hedgehog.htm

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More info in the science section http://www.pathway2curis.com/pancreatic-cancer-hedgehog-antagonist-vt37.html

The data are being presented by a Genentech, Inc. researcher as part of the "New Horizons in the Development of Targeted Therapies for the Treatment of Cancer" Symposium. These data were generated as part of Curis' ongoing collaboration with Genentech to develop systemically administered Hedgehog small molecule antagonists for the potential treatment of solid tumors.

For these studies, researchers used a primary tumor xenograft model, whereby a human tumor is grown and expanded directly in recipient mice. Treatment with a small molecule Hedgehog antagonist inhibited the rate of tumor growth in mouse xenograft models initiated from both a human small cell lung cancer and a human pancreatic cancer.

The American Cancer Society predicts that, in 2006, about 33,730 people in the United States will be found to have pancreatic cancer and about 32,300 will die of the disease. This kind of cancer is the fourth leading cause of cancer death. About 1 out of 4 patients with cancer of the exocrine pancreas will live at least 1 year after the cancer is found. Only about 1 in 25 will survive for 5 years or more.

Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers.

Cancer Res. 2007 Mar 1;67(5):2187-96

Authors: Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio-Donahue C, Jimeno A, Gabrielson KL, Matsui W, Maitra A

In the context of pancreatic cancer, metastasis remains the most critical determinant of resectability, and hence survival. The objective of this study was to determine whether Hedgehog (Hh) signaling plays a role in pancreatic cancer invasion and metastasis because this is likely to have profound clinical implications. In pancreatic cancer cell lines, Hh inhibition with cyclopamine resulted in down-regulation of snail and up-regulation of E-cadherin, consistent with inhibition of epithelial-to-mesenchymal transition, and was mirrored by a striking reduction of in vitro invasive capacity (P < 0.0001). Conversely, Gli1 overexpression in immortalized human pancreatic ductal epithelial cells led to a markedly invasive phenotype (P < 0.0001) and near total down-regulation of E-cadherin. In an orthotopic xenograft model, cyclopamine profoundly inhibited metastatic spread; only one of seven cyclopamine-treated mice developed pulmonary micrometastases versus seven of seven mice with multiple macrometastases in control animals. Combination of gemcitabine and cyclopamine completely abrogated metastases while also significantly reducing the size of "primary" tumors. Gli1 levels were up-regulated in tissue samples of metastatic human pancreatic cancer samples compared with matched primary tumors. Aldehyde dehydrogenase (ALDH) overexpression is characteristic for both hematopoietic progenitors and leukemic stem cells; cyclopamine preferentially reduced "ALDH-high" cells by approximately 3-fold (P = 0.048). We confirm pharmacologic Hh pathway inhibition as a valid therapeutic strategy for pancreatic cancer and show for the first time its particular efficacy against metastatic spread. By targeting specific cellular subpopulations likely involved in tumor initiation at metastatic sites, Hh inhibitors may provide a new paradigm for therapy of disseminated malignancies, particularly when used in combination with conventional antimetabolites that reduce "bulk" tumor size. [Cancer Res 2007;67(5):2187-96].