Molecular Sleuths...Researchers Collaborate in the Fight Against Pancreatic Cancer
Pancreatic cancer is deadly because it is so stealthy. There are no symptoms until the disease has reached an advanced stage, and in most cases there is no way to detect it any earlier. As a result, only three percent of people diagnosed with the most common form of this cancer, pancreatic adenocarcinoma, survive five years.

Yet new insights are leading to a better understanding of this disease. Although pancreatic cancer is rare, affecting about five of every 100,000 people each year, precancerous pancreatic lesions are common: They are found during one in five autopsies of people who died for other reasons. “Clearly many people are harboring the genetic changes that can lead to pancreatic cancer, yet relatively few of them actually develop it,” says Nabeel Bardeesy, PhD, who recently joined the Center for Cancer Research, the basic research program of the Massachusetts General Hospital Cancer Center. “This leads to two basic questions. Why do some people go on to develop cancer, while others do not? And is it possible to intervene in order to stop the progression?”

To answer these questions—and ultimately improve the outlook for people diagnosed with pancreatic cancer—Bardeesy is collaborating with two other researchers at Mass General—Ralph Weissleder, MD, PhD, and Sarah Thayer, MD, PhD —in a cross-disciplinary partnership aimed at better understanding the genetics and biology of pancreatic cancer.

Bardeesy is using state-of-the-art genetic engineering techniques in mice to more accurately mimic the abnormalities that lead to pancreatic cancer. Weissleder, director of the Massachusetts General Hospital Center for Molecular Imaging Research, has developed sophisticated molecular imaging agents to enable researchers to home in on particular types of cells that are being affected by specific genetic changes.

Thayer, of the hospital’s Department of Surgery, provides insights into how genetic alterations, or mutations, affect biochemical processes within cells and in surrounding tissues—processes that create the internal changes and external environment that allow pancreatic cancer to grow and spread.

This collaboration is part of a national, multi-institutional effort—which recently received funding through a major grant awarded by the National Institutes of Health (NIH)—that also involves researchers at Dana-Farber Cancer Institute, Brigham and Women’s Hospital, the Harvard Institutes of Medicine, the Massachusetts Institute of Technology, and the University of California at San Francisco.

"These collaborations within Mass General and with our colleagues at other institutions involve the type of big-picture thinking that is necessary if we are ever going to beat the most challenging types of cancer,” says Daniel A. Haber, MD, PhD, director of the Cancer Center. “By breaking down the walls that separate individual laboratories, we hope to create a synergy that will speed the development of more effective therapies.”

Pancreatic adenocarcinoma develops after a series of genetic changes induce abnormal cell growth in ducts, leading to the development of precancerous lesions known as pancreatic intraepithelial neoplasms.

Eventually some of these lesions turn malignant, resulting in pancreatic cancer. Although each biological step in the long progression to malignancy represents a potential target for therapy, the earliest targets hold the most potential for interventions that will save lives.

So far, scientists know that the earliest genetic changes in pancreatic cancer involve the type of “one-two punch” seen in other types of malignancies. First a common oncogene (a potentially cancer-inducing gene) called kRAS is activated, initiating abnormal cell growth. Then a tumor-suppressor gene, p16INK4A, is inactivated, allowing a rapid progression to malignancy. These genetic changes, as well as a number of others that occur further downstream, provide a blueprint for what goes wrong in pancreatic cancer.

But many questions remain. “The real challenge lies in determining how these genetic changes contribute to the biological abnormalities that give rise to cancer,” Bardeesy says. “We want to know what type of cell the cancer originates in, what biological changes take place as the cancer progresses, and what type of therapeutic agents might interfere with the progression.”

In the early days of genetic engineering, researchers introduced a particular genetic mutation into a fertilized egg before it underwent the multiple divisions that take place during embryonic development. One drawback of this “germline” approach was that a genetically engineered mouse was born with a mutation affecting every cell and tissue in its young body.

However, cancer affects only specific cells and tissues, and at particular times during the lifespan. In the past few years, cancer researchers have been able to refine their techniques to produce genetic changes only in particular tissues and organs, and—more recently—only in adult mice.

Bardeesy and his colleagues are currently taking genetic engineering a step further by inducing genetic changes only in particular types of cells within the adult pancreas. “We want to target the cell of origin in pancreatic cancer,” Bardeesy explains, “because genetic mutations have different consequences depending on what type of cell they affect.” Identifying the earliest biological changes that take place in pancreatic cancer would also help researchers identify the earliest possible targets for novel therapies.

Although researchers once thought that pancreatic adenocarcinoma originated in duct cells, an emerging theory is that the cancer actually starts in centroacinar cells. These cells are located at the junction between the acinar cells and the ducts, and show some features reminiscent of the stem cells that form the pancreas during embryonic development.

“We believe that these undifferentiated centroacinar cells may be particularly vulnerable to genetic changes,” Bardeesy says. “Studying genetic changes in these cells, in vivo (in a mouse model) will provide insight into how pancreatic cancer begins and, ultimately, how we might stop the process.”

The collaboration among Bardeesy, Weissleder, and Thayer—and, through the NIH grant, with colleagues at other institutions—combines genetic engineering, sophisticated imaging, and tissue analysis in a way that allows for a more dynamic and continuous view. This will improve the understanding of how pancreatic cancer begins, evolves, and responds to various treatments over time.

Weissleder, an internationally renowned leader in molecular imaging, has developed a way to “tag” cancer cells with various molecular probes, so that the malignant cells literally glow during MRI (magnetic resonance imaging)—long before they could be detected in conventional ways.

Weissleder and Bardeesy are collaborating to use these imaging approaches to determine how genetic mutations influence the development of precancerous lesions in ducts, particularly gauging how specific mutations provoke abnormal growth signals and how such changes influence cellular growth and behavior.

The advanced imaging techniques also enable Thayer, an expert in tumor biology, to better understand the biochemical changes taking place not only in the cancer cells, but also in surrounding cells and tissues—and then evaluate how new therapies might affect the process. “We can actually look at the anatomic location of cancer cells, in vivo, and investigate the biological changes accompanying the earliest stages of tumor growth,” says Thayer. “This combination of genetic engineering and imaging also allows us to identify new drug targets, and then gauge response to see if the tumors or the blood vessels supplying them with nutrients shrink in response to therapy.”
 
The ultimate goal, of course, is to move from mice to men. “If we can identify the earliest targets,” says Bardeesy, “it may be possible to develop ways to prevent pancreatic cancer from developing in the first place.”

Source: Synergy, Winter/Spring 2006