Pancreatic Cancer SPORE Grant

Awarded: August, 2003
Amount: $10.7 million over five years
Principal Investigator: Gloria Petersen, Ph.D., cancer researcher, Mayo Clinic Rochester

Mayo Clinic SPORE in Pancreatic Cancer (pdf)

Mayo Clinic Cancer Center is one of three cancer centers to receive a Specialized Program of Research Excellence (SPORE) grant for pancreatic cancer. Pancreatic cancer is the fifth leading cause of cancer death in the United States. Patients with cancers of the pancreas have a particularly poor prognosis, as mortality from this type of cancer is extremely high (five-year survival rate is about 4 percent). Pancreatic cancer kills more than 32,000 people in the United States each year. Twenty percent of those who die from this disease are under age 60. Mayo Clinic’s SPORE in pancreatic cancer is designed to support and promote research focused on understanding the causes of this disease and the mechanisms and pathways by which it spreads.

This grant is supporting and promoting research in pancreatic cancer that is highly likely to benefit patients who currently have very little hope or treatment options. Mayo researchers are focused on discovery of novel mechanisms and pathways that will help understand causes and mechanisms of pancreatic cancer, which in turn will be translated into strategies for prevention, early detection, and treatment.

The four major projects funded by the SPORE include:

Project #1: Molecular epidemiology of pancreatic cancer
Studying the role of candidate carcinogen metabolism genes, smoking and diet risks of pancreatic adenocarcinoma.

Project #2: SDF-1a/CXCR4-EGFR interactions in pancreatic cancer
Determining whether the interaction between specific proteins called SDF-1a/CXCR4 and EGFR fuels the spread of pancreatic cancer.

Project #3: Mechanism of VAV1-mediated pancreatic cancer cell growth
Studying and characterizing the role that a gene called Vav1 plays in the signaling pathways that control cell growth in pancreatic cancer.

Project #4: Characterization of the role of BRCA2 in pancreatic cancer
Evaluating the role of BRCA2 in pancreatic cancer to improve our understanding of familial pancreatic cancer, the mechanisms behind pancreatic tumor development, and the most appropriate therapies for this form of familial pancreatic cancer.

In addition to these research projects, the SPORE grant provides funding for a developmental research program for pilot grants to explore innovative research ideas, and a career development program to nurture the next generation of pancreatic cancer scientists.

The SPORE grant also provides core resources for the pancreatic cancer scientists, including a tissue and patient registry, biostatistics, xenograft support, and proteomics.

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Project #1: Molecular epidemiology of pancreatic cancer
Project Leaders: Gloria Petersen, Ph.D., genetic epidemiologist and Janet Olson, Ph.D., epidemiologist, both from Mayo Clinic Rochester

Around 10 percent of pancreatic cancer patients report that they have a family member who also had the disease, which suggests that they may have a hereditary tendency. Researchers believe that most cancers are caused by interactions between genes and environmental or lifestyle factors, such as smoking. The goal of Project #1 is to identify specific genes and environmental factors that are strongly associated with pancreatic cancer.

Studying the role played by risk factors for pancreatic cancer is challenging. The late diagnosis and poor survival rate for people with this disease make it difficult to enroll large numbers of patients in clinical studies and obtain sufficient volumes of biological samples needed for research. In Project #1, Mayo Clinic researchers have overcome these research barriers by using a clinic-based study to rapidly recruit patients around the time of diagnosis.

This study includes two groups of 1,200 participants. The first group consists of people diagnosed with adenocarcinoma of the pancreas, the most common form of this cancer. The second group, which is the control group, includes unrelated Mayo patients without pancreatic cancer whose age, race, gender and region of residence match those from patients in the first group.

Participants in both groups fill out a detailed questionnaire that collects information on several suspected risk factors: smoking, use of nonsteroidal anti-inflammatory drugs (NSAIDs), consumption of dietary carcinogens in meat, and family history. Mayo researchers are also analyzing DNA from blood samples that participants provide to identify specific genes strongly associated with pancreatic cancer.

Mayo researchers hope to use Project #1 to test the hypothesis that some people have genetic variants that affect the way that they metabolize cancer-causing agents present in meat (especially grilled meat). With its large pool of participants, this study will provide important information about the validity of this and other potential risk factors.

As of March 2006, Mayo researchers were still recruiting the cases and the controls for this study. After conducting a preliminary analysis, Project #1 researchers have found that pancreatic cancer patients who smoked and nonsmokers who were exposed to secondhand smoke developed pancreatic cancer at a younger age than nonsmokers. It also appears that some genes related to DNA repair may play a role in risk of pancreatic cancer.

Collaboration
Other members of the Mayo research team include: Mariza de Andrade, Ph.D., biostatistician; William Bamlet, biostatistician; Suresh Chari, M.D., gastroenterologist; Julie Cunningham, Ph.D., molecular geneticist; and Robert McWilliams, M.D., oncologist, all from Mayo Clinic Rochester.

Also collaborating are: Kristin Anderson, Ph.D., epidemiologist, University of Minnesota; Rashmi Sinha, Ph.D., nutritional epidemiologist, National Cancer Institute; and Rachael Stolzenberg-Solomon, Ph.D., nutritional epidemiologist, National Cancer Institute.

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Project #2: SDF-1a/CXCR4-EGFR interactions in pancreatic cancer
Project Leader: Raul Urrutia, M.D., gastroenterologist and Charles Erlichman, M.D., oncologist, both from Mayo Clinic Rochester

Although pancreatic cancer accounts for just 2 percent of new cancer cases in the United States, it’s the fourth leading cause of all cancer deaths. That’s because pancreatic cancer spreads rapidly and is seldom detected in its early stages. Lack of knowledge about the basic molecular mechanisms that are responsible for how pancreatic cancer spreads and progresses significantly impairs the development of more effective treatments for this painful and often fatal disease.

Chemokines are a group of proteins released by the cells of the immune system to help mobilize the body’s immune response. SDF-1alpha and its receptor, CXCR, are chemokines that normally function to promote cell movement. Another protein, epidermal growth factor receptor (EFGR), has been shown to drive tumor growth and aggressiveness in several forms of cancer. Both ingredients – cell movement and growth – allow cancers to spread.

In Project #2, Mayo researchers are attempting to determine whether the interaction between SDF-1a/CXCR4 and EGFR fuels the spread of pancreatic cancer. They are examining this molecular chain of events in pancreatic cancer cell samples and animal models, with the hope of identifying new treatments that inhibit this process.

Preliminary studies indicate that neutralizing the activity of this receptor (CXCR) impairs tumor cell growth in animal models. Mayo researchers are also extending studies in order to design a therapy that includes targeting this receptor in combination with other factors that inhibit the formation of blood vessels.

Future studies using molecular biophysics techniques will focus on the rational design of additional small molecule drugs to target this receptor.

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Project #3: Mechanism of VAV1-mediated pancreatic cancer cell growth
Project Leaders: Daniel Billadeau, Ph.D., cancer researcher and Charles Erlichman, M.D., oncologist, both from Mayo Clinic Rochester

Most of the pancreas is composed of cells (called exocrine cells) that produce digestive enzymes and juices. These cells are arranged in clusters and connected to a series of small ducts. Most pancreatic tumors originate in the epithelial cells of the ducts or in the cells that produce digestive enzymes (acinar cells). Called adenocarcinomas, these tumors account for nearly 95 percent of pancreatic cancers.

Pancreatic ductular adenocarcinoma accounts for more than 90 percent of all pancreatic cancers and ranks fifth as a cause of death by cancer in the United States. Although researchers still don’t know what causes this lethal cancer, efforts to understand the molecular mechanisms underlying the development of pancreatic cancer and how it spreads may lead to preventive and treatment strategies to improve the outcome of the disease.

Vav1 is a proto-oncogene, a gene with the potential to cause the transformation of normal cells into cancerous tumor cells. Mayo researchers have identified the expression of Vav1 in more than 50 percent of primary pancreatic ductular adenocarcinomas. In Project #3, Mayo researchers will test the central hypothesis that Vav1 expression in certain pancreatic cancers controls tumor cell growth.

To test this hypothesis, Mayo researchers will:

1. Determine the role of Vav1 in pancreatic tumor growth. Specifically, they will study the effect of expression of Vav1 on tumor cell proliferation and survival using pancreatic tumor cell lines that express and do not express Vav1.
2. Study and characterize the role that Vav1 plays in the signaling pathways that control cell growth in pancreatic cancer. Signaling pathways are a molecular chain of events that control the life cycle of cells and determine how they multiply and differentiate.
3. Implement Vav1-based translational efforts for pancreatic cancer. Based on the observation made in aims 1 and 2, Mayo researchers will attempt to identify Vav1-regulated pathways in pancreatic cancer cells that can be targeted pharmacologically to affect tumor cell proliferation and survival.

The enzymatic activity of Vav1 requires chemical changes caused by receptor and nonreceptor tyrosine kinases, enzymes that activate signaling pathways leading to cellular activation. In cancer cells, many tyrosine kinases are dysregulated and promote cancer cell proliferation, survival and metastasis. Mayo researchers have begun to investigate the utility of tyrosine kinase inhibitors as a means to inhibit Vav1 function. Additionally, one pathway that is regulated by Vav1 in pancreatic cancer cells is the NFκB. This pathway is a transcription factor that regulates genes involved in cell survival, proliferation and angiogenesis (the formation of blood vessels). Thus, affecting the activity of this transcription factor could potentially affect tumor cell growth and survival. Mayo researchers have recently found that inhibitors of GSK-3β, a kinase involved in the regulation of NFκB, affects the proliferation and survival of pancreatic tumor cells (Vav1+ and Vav1-). This work has resulted in a phase II clinical trial in pancreatic cancer that Mayo researchers hope to begin during the latter half of 2006.

Together these studies will provide an experimental basis for understanding the molecular events that are involved in the regulation of pancreatic tumor cell growth by Vav1, and will, in a broader context, advance our understanding of fundamental processes involved in the molecular chain of events controlling cell growth in epithelial tumors. In addition, Mayo researchers hope that this work will lay the groundwork for developing diagnostic and therapeutic options for treating this deadly disease.

Collaboration
In addition to Drs. Billadeau and Erlichman, the Project #3 research team includes: Suresh T. Chari, M.D., Mayo Clinic Rochester; Martin Fernandez-Zapico, M.D., Mayo Clinic Rochester; George Kim, M.D., Mayo Clinic Jacksonville; Andrei Ougolkov, M.D., Ph.D., Mayo Clinic Rochester; Thomas C. Smyrk, M.D., Mayo Clinic Rochester; and Raul Urrutia, M.D., Mayo Clinic Rochester.

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Project #4: Characterization of the role of BRCA2 in pancreatic cancer
Project leaders: Fergus Couch, Ph.D., cancer researcher and Steven Alberts, M.D., oncologist, both from Mayo Clinic Rochester

Mutations in the BRCA2 gene account for up to 10 percent of familial pancreatic cancer families and play a role in as many as 10 percent of pancreatic ductal adenocarcinomas in the Ashkenazi Jewish population. Usually this gene helps prevent cancer by making proteins that slow or stop cell division. The gene also allows the cell to check for any damage in its DNA and make repairs before dividing again. Mutations in this gene allow genetic changes to accumulate in cells. The cells may then continue dividing and pass damage to future generations of new cells, which increases the likelihood that the cells will become cancerous.

While BRCA2 appears to have a significant role in the development of pancreatic cancer, researchers are still exploring the following questions:

1. What are the specific functions of the BRCA2 protein that must be deactivated in order for pancreatic tumor formation to occur?
2. Is there significant interaction between BRCA2 and the molecular pathways that are regulated by other pancreatic tumor suppressors and oncogenes?
3. Given that BRCA2 mutant pancreatic tumors appear to be significantly different from sporadic tumors (nonfamilial cancer) at the genetic and molecular level, can we identify therapies that target the familial form of pancreatic cancer?

To address these questions, Mayo researchers have undertaken the following studies:

1. To determine the effect of disrupting specific links in the chain of amino acids that forms BRCA2 in pancreatic cells in an effort to identify those portions of BRCA2 that are responsible for normal function of BRCA2. The investigators have shown that BRCA2 has a previously undefined role in regulating the process of cell division through its ability to regulate the number and function of structures called centrosomes. Centrosomes are small bodies within cells that work to separate DNA and chromosomes into daughter cells during cell division. The investigators have also identified regions of BRCA2 that interact with other DNA repair proteins and regulate the ability of BRCA2 to repair DNA damage. These novel findings are being pursued further.
2. To evaluate whether disruption of other signaling pathways (those involving the ras and p53 genes that have a central role in pancreatic cancer development) cooperate with BRCA2 inactivation to promote pancreatic tumor formation. Mayo researchers have generated a “knockout model” in mice that involves removing the BRCA2 genes from the cells of the pancreas in these animals. This model has unexpectedly shown that BRCA2 has a critical role in the development of the pancreas and in the formation of premalignant lesions in the pancreas. Detailed characterization of these effects in this mouse model is ongoing.
3. To evaluate the efficacy of mitomycin C and cisplatin as treatments for BRCA2 mutant pancreatic tumors. Mayo researchers hypothesize that agents such as mitomycin C and cisplatin, which induce high levels of the type of DNA damage normally repaired by BRCA2, will cause accelerated cell death of BRCA2 mutant tumors. To test this hypothesis, Mayo researchers will use the BRCA2 “knockout” mouse model following the development of pancreatic tumors.

Mayo researchers hope that this comprehensive evaluation of the role of BRCA2 in pancreatic cancer will improve our understanding of familial pancreatic cancer, the mechanisms behind pancreatic tumor development, and the most appropriate therapies for this form of familial pancreatic cancer.

Mayo Clinic Cancer Center is a National Cancer Institute (NCI) -designated Comprehensive Cancer Center, a national recognition of excellence in education, research and treatment of cancer. The Pancreatic Cancer SPORE continues a tradition of cutting-edge research across Mayo’s three locations in Arizona, Florida and Minnesota. Mayo Clinic has also been awarded SPOREs in brain, breast and prostate cancer, and shares SPOREs for lymphoma and myeloma with other institutions.

The NCI established the SPORE program in 1992 to promote interdisciplinary research and speed the transition of basic research findings from the laboratory to applied settings involving patients and populations. The program’s goal is to bring into clinical care novel ideas that have the potential to reduce cancer incidence and mortality, improve survival and enhance patients’ quality of life. Laboratory and clinical scientists work collaboratively to plan, design and implement research programs focused on cancer prevention and control, early detection, diagnosis, treatment and survival.

For more information on SPORE grants, visit the National Cancer Institute at www.nci.nih.gov. To find out more about Mayo Clinic research, visit www.mayo.edu. For more information about pancreatic cancer treatment at Mayo Clinic, visit www.mayoclinic.org/pancreatic-cancer/index.html.