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.
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• 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.