Breaking the Silence
Advances in care and research shed new light on pancreatic cancer
One morning, Lenny White looked in the mirror and saw jaundiced eyes staring back at him. He checked another mirror to make sure it wasn’t poor lighting and immediately called his internist. Tests quickly revealed a life-altering diagnosis of pancreatic cancer. “I instantly knew the odds of survival weren’t good,” White says. Typically, by the time patients become symptomatic and present clinically with pancreatic cancer, 80 percent are inoperable, which means they cannot have surgery due to metastases or the location of the cancer around major blood vessels.
Pancreatic cancer remains one of the most challenging forms of cancer, with an annual death toll of more than 50,000 in the United States, and a survival rate that has improved little over the past 25 years. With only one-fifth of Americans diagnosed with pancreatic cancer surviving for a full year, it is the third leading cause of cancer death in the country, and that statistic is increasing. “More than 70 percent of Americans with potentially curable early-stage pancreatic cancer aren’t even offered surgery,” says A. James Moser, M.D., co-director of the Pancreas and Liver Institute at Beth Israel Deaconess Medical Center and renowned pancreatic surgeon. “That is how bad the rap is for this disease.”
According to the chief of BIDMC's Division of General Surgery, Mark Callery, M.D., White was actually one of the lucky ones. Callery successfully performed the Whipple procedure to remove White’s tumor, even though it was wedged between major vessels. “I feel there are two reasons I am here today,” says White. “Number one is God, and number two is God’s assistant, Dr. Callery. It’s as simple as that.”
While Callery, Moser, and their colleagues are providing the most comprehensive, advanced care possible for BIDMC patients, philanthropy from those grateful patients is critical as they try to find better solutions for this challenging disease. Thankful for his care, White donated $50,000 to the Callery Pancreatic Cancer Research Fund along with $250,000 to the medical center to advance its top priorities. Among many patient families who have contributed generously to Moser’s efforts for several years, the Alliance of Families Fighting Pancreatic Cancer, the Greg and Cathy Griffith Family Foundation, the John F. Fortney Charitable Pancreatic Cancer Research Group, the Woiner Foundation, and Project Purple have raised nearly $900,000 combined. While all share a painful history of pancreatic cancer, they also share a common passion for finding a cure.
Clinicians know the difficulty of identifying and treating pancreatic cancer is two-fold; not only is it an extremely aggressive disease, but it is stealthy, remaining asymptomatic until late stages when it’s very hard to treat. Once established, this cancer is typically resistant to nearly all therapies. “At the genetic level, it is a nasty disease,” says Manuel Hidalgo, M.D., Ph.D., director of the Leon V. & Marilyn L. Rosenberg Clinical Cancer Center and chief of the Division of Hematology and Oncology. “It contains a lot of gene mutations and alters the way a cell behaves in such a fundamental manner that is so hard to control.”
Researchers in the Pancreatic Cancer Research Program (PCRP) at BIDMC are determined to change these outcomes. Relying on grateful patient support, they are pursuing several new groundbreaking strategies and collaborations to identify biomarkers that could lead to earlier diagnoses and uncover more personalized treatment options. By analyzing each tumor’s genetic makeup and testing therapies through avatar mouse models and patient tumor–derived organoids—three-dimensional organ “mini tumors” that are generated from patients’ cancerous tissue and grown in our laboratories—researchers have made tremendous progress in developing methods to deliver the most efficient and precise treatments to patients. “We want to help oncologists make better choices of what drug to give the patient to increase the probability of response,” says Senthil Muthuswamy, Ph.D., director of BIDMC's Cell Biology Program and a pioneer in the development and use of three-dimensional organoid culture methods. “We want to bring cancer treatment at BIDMC to a state where a patient knows that his or her treatment is based on testing done using his or her own tumor cells—a new definition for precision medicine.”
DELIVERING SPECIALIZED, COMPREHENSIVE CARE
As a premier academic medical center that specializes in pancreatic cancer, BIDMC often sees the most serious cases and, despite the lack of a cure, has made tangible steps in improving quality of life for patients. When Moser joined the medical center in 2012, he established the multidisciplinary Pancreatic Cancer Program, which allows patients to see all members of their care team in one day. The program offers everything from medical, surgical, or radiation oncology treatment to genetic analysis and counseling, gastroenterology, and advanced radiology, as well as clinical trials teams, palliative care, and nutrition. By centralizing these services, the average time from diagnosis to treatment decreased from 49 days to 13–15 days. “Multidisciplinary care is important in the not-so-straightforward cases,” Callery says. “We now have patients coming in with borderline resectable tumors that 15 years ago would never have been removed. Now we take them out, but we’ve shifted the position of surgery on the continuum of care.”
What Callery means is that clinicians are now starting patients with chemotherapy or radiotherapy to shrink the cancer before surgery. Once in the operating room, BIDMC surgeons, who run the highest volume robotic pancreatic surgical center in New England, rely on their experienced assessment and prediction in high-acuity surgery and advanced technical innovations to remove the most challenging cancers. When surgery is not an option, clinical trials featuring the most advanced cancer research strategies are more readily available for patients at the medical center. “The strength of this program is having these components of clinical predictive modeling in pancreatic cancer, which is going to be married to the biological predictive modeling through organoids,” Callery says.
This group of people is highly motivated and, with the right set of donors, will really change the balance.A. James Moser, M.D.
Co-director, BIDMC Pancreas and Liver Institute
Surgery is still a rare cure for a patient with pancreatic cancer. But it is allowing researchers access to valuable pieces of information—tumor samples. “Every patient we operate on now, we identify biomarkers in parallel so we understand success and failure,” Moser says of the option that is available to every BIDMC patient. Moser is leading an initiative called Project Survival—a worldwide consortium of seven institutions, including the biopharmaceutical company Berg Health. This unique cross-sector collaboration is leading research efforts, including analyzing thousands of patient tumor samples, aimed at identifying diagnostic and treatment biomarkers for the disease. “Project Survival is about finding ways to pinpoint markers of the disease early on. It’s predictive medicine,” Moser says. Project Survival also encompasses several clinical trials for which BIDMC has served as a national leader. “One of the reasons we don’t cure more patients is because we don’t have any early diagnosis,” says Hidalgo. “We are determined to change this.”
Until that day comes, the researchers in the PCRP are leading innovative efforts focusing on developing improved treatment options. Hidalgo is a world leader in creating and employing avatar mouse models—also known as patient-derived xenografts. Researchers transplant human tumor tissue into a group of mice and administer a variety of targeted or combined therapies to determine their efficacy in halting the growth of each specific tumor. This established technique is now being used in conjunction with Muthuswamy’s exploration of patient tumor–derived organoids. These mini tumors closely mimic the matched patients’ cancers and are a critical improvement over the traditional method of culturing two–dimensional cells in a petri dish. “We see that the tumor organoids respond to some drugs the same way the same tumor responds in a mouse,” Muthuswamy says. “Although we are just beginning to compare organoid response with patient response, we are confident that this will be the way patient treatment decisions are made in the future.”
As a complement to Hidalgo’s mouse models, Muthuswamy’s organoid work offers fast and cost-effective results. Compared to growing tissue in xenograft models, which takes eight to ten months, tumor cells can be grown in organoids in a matter of weeks. BIDMC has designed a platform allowing for a much larger number of therapies to be tested on the organoids first, and then verified in the mouse models before reaching the patient. “This is the ultimate preclinical model,” says Hidalgo. “We won’t test anything in patients that hasn’t shown success in the organoid.”
Muthuswamy and Hidalgo are extending the organoid technology to generate a pancreas vaccine program alongside David Avigan, M.D., section chief of Hematologic Malignancies and Bone Marrow Transplantation. With experiments already underway, Muthuswamy, Hidalgo, and Avigan received a $600,000 grant from the V Foundation to support clinical trials that will test vaccines created using organoids within the year. “All of the talent and resources are here. Everything is in place for us to generate vaccines and test in patients,” says Muthuswamy. “That is why philanthropy will make a huge difference in this situation—unlike anything else I have worked on before.”
While these innovative platforms will yield better treatment options, the end goal, of course, is to find a cure for pancreatic cancer. “We need people to recognize that what we are doing is unique,” Moser says. “This group of people is highly motivated and, with the right set of donors, will really change the balance.”