- Mouad Edderkaoui, PhD
- Srinivas Gaddam, MD
- Laith Jamil, MD
- Quin Liu, MD
- Simon Lo, MD
- Aurelia Lugea, PhD
- Stephen Pandol, MD
- Kenneth Park, MD
- Qiang Wang, PhD
- Jingzhen Yuan, PhD
Cedars-Sinai is dedicated to being the international leader in pancreatic research through its advances in prevention, early diagnosis and treatment of pancreatic cancer, pancreatitis and diabetes.
Each year 250,000 patients worldwide (including more than 40,000 in the United States) are diagnosed with pancreatic cancer. Because only a limited number are diagnosed early enough for successful surgical intervention, 225,000 die. In an effort to improve pancreatic cancer patients' survival rate, research is focused on finding ways to enable early diagnosis, develop novel treatments for the cancer, and prevent the initial occurrence and recurrence after treatment.
Pancreatitis is life threatening in its acute stage and causes immense and painful suffering in its chronic stages. In the United States, the number of hospital admissions for pancreatitis is greater than for any other gastrointestinal disease. Pancreatitis is also a risk factor for pancreatic cancer. Thus, focusing on pancreatitis treatment and prevention will have an impact on pancreatic cancer rates.
Diabetes is a key risk factor for pancreatic cancer, suggesting that better treatment of diabetes can help prevent pancreatic cancer.
Cedars-Sinai is concentrating its pancreatic research on efforts to better understand the molecular mechanisms of pancreatic diseases. Its multidisciplinary team consists of molecular biologists, cell biologists, computational chemists, population scientists, clinical scientists and physicians.
We have identified pathologic pathways and continue to find new ones involved in initiating the disease, as well as pathways that perpetuate the disease, resulting in chronic pancreatitis.
Figure 1 shows examples of stress that initiate pancreatitis; while Figure 2 shows molecular targets we are working on for therapy development.
Figure 1 — Pancreatic acinar cell function under stress: The arrows show steps along the enzyme “production line” for a normal pancreas. When parts of a cell such as the endoplasmic reticulum are “stressed” by insults such as gallstones, diabetes or alcohol abuse, the secretion process may stop, leaving digestive enzymes with nowhere to go. The unfortunate result is that the cell may “digest itself.”
Figure 2 — Potential targets for development of therapeutics for acute pancreatitis: This illustration of a pancreatic acinar cell and blood vessel shows therapeutic targets that provide potential treatment opportunities. We are developing agents that work on these targets, with the results leading to clinical trials.
We are researching the interactions between different types of cells in the tumor that contribute to the growth and metastasis of the disease. Our focus is to use this information to develop preventive strategies and treatments. (See Figure 3.)
Figure 3 — Components of pancreatic cancer.
We are taking a new approach to treating diabetes by focusing on the development of agents that can trigger gut endocrine cells to release into the blood the hormones called glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), which are able to regulate insulin secretion and glucose metabolism and suppress appetite. (See Figure 4.)
Figure 4 — Fluorescence microscopic image of an L cell in human intestinal mucosa: The green fluorescent stain represents an antibody to glucagon-like peptide 1; while the red fluorescent stain represents an antibody to a luminal facing sensor. The blue is staining nuclei of the intestinal mucosa.
We have several ongoing and developing research projects designed to make a significant impact on these diseases. As illustrated in Figure 5, projects that collect vital information from patients with pancreatic diseases is stored in our MetaBank biorespository.
The MetaBank stores biospecimens and clinical, demographic and epidemiologic data from patients who are at risk for or diagnosed with pancreatic cancer, pancreatitis or Type 2 diabetes.
This information informs our basic research projects so that the experiments are relevant to the human situation. Promising new treatments originating from basic research projects for pancreatic cancer, pancreatitis and diabetes are then applied back to patients in clinical trials to determine the treatments' effectiveness.
Figure 5 — Overall organization of pancreatic research at Cedars-Sinai
Examples of clinical research projects:
- A comparison of salivary and other bio-markers in subjects highly suspect for pancreatic disease or cancer:
Cedars-Sinai's pancreatic research team and the UCLA Department of Dentistry are collecting salivary secretions and measuring several types of RNA in the secretion in order to develop a test for early diagnosis of pancreatic cancer and other pancreatic diseases such as chronic pancreatitis. This 3,300-subject clinical study includes a comprehensive questionnaire that is combined with the data from the salivary marker to enhance the predictability of pancreatic diseases.
- Enhanced chemotherapy and radiotherapy for pancreatic cancer:
The pancreatic research team is working with Cedars-Sinai's Samuel Oschin Comprehensive Cancer Institute on approaches to enhancing chemotherapy and radiotherapy for pancreatic cancer. Gemcitabine chemotherapy and radiotherapy, given concurrently, remain mainstay treatments for patients with locally advanced pancreatic cancer (LAPC) that cannot be surgically removed and has not spread to other areas of the body. Both gemcitabine and radiotherapy kill tumor cells by interfering with their DNA. Veliparib is a poly (ADP-ribose) polymerase (PARP)1/2 inhibitor; PARP1/2 proteins are also involved in DNA repair. Our lab work has shown excellent synergy between veliparib (a "PARP inhibitor" involved), radiotherapy and gemcitabine in killing pancreatic cancer cells grown in culture, and in prolonging survival in mice with pancreatic tumors. Based on these promising results, we are conducting a first-in-human investigational clinical study to test the safety and efficacy of veliparib in combination with gemcitabine and radiotherapy for patients with LAPC.
- Heparin binding proteins, biomarkers of pancreatic cancer:
The pancreatic research team is working with researchers at the Samuel Oschin Comprehensive Cancer Institute and Cedars-Sinai's Clinical and Translational Research Center on a 30-subject observational pilot study to correlate heparin-binding proteins in the blood of pancreatic cancer patients with the stage of the disease. Comparisons will be made between patients diagnosed with pancreatic cancer or pancreatitis and normal controls with no pancreatic disease found. The pilot study's results will demonstrate the usefulness of these proteins for the early diagnosis of pancreatic cancer.
- MRI and chronic pancreatitis pain/sphincter of Oddi dysfunction:
Cedars-Sinai's pancreatic research team and researchers at the UCLA Center for Neurobiology of Stress are using functional MRI to evaluate brain activity in patients with chronic pancreatitis and sphincter of Oddi dysfunction. In this 20-subject pilot study, comparisons are made to brain scans of normal subjects to better understand the causes of the symptoms of chronic pancreatitis and sphincter of Oddi dysfunction. The analysis of such differences may justify a larger and more robust trial to determine the diagnostic utility of functional MRI in the diagnosis of pancreatic disease.
- Development of a new drug for pancreatic cancer
Researchers in our group are involved in several studies to develop new therapies, biomarkers for early disease diagnosis and better imaging methods for both pancreatitis and pancreatic cancer.
The group has recently published a high impact paper in the journal Gastroenterology that they have developed a new drug that has multiple features that can combat pancreatic cancer. The drug is called Metavert and developed by our Senior Scientist, Mouad Edderkaoui, PhD, and Stephen Pandol, MD, Director of Basic and Translational Pancreas Research.
Pancreatic cancer is the third-leading cause of cancer-related death in the United States, according to the American Cancer Society. About 55,000 people in the U.S. will be diagnosed with the disease in 2018, killing more than 44,000 people, making it one of the deadliest cancers. The five-year survival rate is 7 percent.
The study results presented in journal Gastroenterology was done using pre-clinical animal models of pancreatic cancer that highly replicate the human disease. The study showed that Metavert increases survival but also has multiple other beneficial effects including preventing metastasis of the cancer; reversing the resistance that develops with other chemotherapeutic drugs; and improving the body’s immune response to fighting the cancer.
These beneficial responses are setting the stage for initiation of clinical trials to apply this treatment to patients in the middle of 2019.