Between research and computer-assisted robotic surgery approaches I think we’re really going to be able to make some progress.Kerrington Smith, MD
The pancreas is a six-inch long narrow organ that sits behind the stomach—kind of shaped like a fish with a “head” and a “tail,”—and functions as part of the digestive system. It produces pancreatic enzymes to aid in digestion and insulin to control blood sugar. For a fairly small organ, it is the source of a largely difficult cancer.
The challenges of pancreatic cancer
The American Cancer Society estimates that more than 53,600 people in the United States will be diagnosed with pancreatic cancer in 2017, with a death rate of about 80 percent. Pancreatic cancer accounts for about 3 percent of all cancers in the US and about 7 percent of all cancer deaths. Risk factors are difficult to identify, there are no or very subtle symptoms such as sudden-onset diabetes, and it remains one of the most challenging cancers to detect and diagnose early.
“Sixty percent of the cases we see are already Stage 4. Unfortunately, there isn’t a known cure at that stage,” explains Kerrington Smith, MD, division chief of Surgical Oncology, and member of the Molecular Therapeutics Research Program at Dartmouth-Hitchcock’s Norris Cotton Cancer Center (NCCC). “Pancreatic cancer just surpassed breast cancer as the third leading cause of cancer-related deaths and by 2020 is projected to surpass colon cancer as the second leading cause. It’s because other cancers have better treatment options,” he says.
Pioneering clinical trials
Smith is doing his part to change that. In addition to NCCC participation in two national group trials investigating new second-line chemotherapy regimens, Smith is leading two investigator-initiated clinical trials. The first is a National Cancer Institute-funded trial for earlier stage pancreatic cancer patients that tests the effectiveness of neoadjuvant therapy, or chemotherapy and/or radiation before surgery. NCCC has been practicing this novel concept for almost a decade, but only in the last five years has it become widely accepted. “There may be cancer cells that have already spread to other organs but don’t show up on CT scans or MRI. Chemotherapy given before surgery may kill these tumor cells before they have a chance to grow,” explains Smith.
Smith also designed and initiated a Phase III xenograft program, in which he implants patients’ actual tumor tissue cells from initial biopsy into immuno-compromised mouse models to study cancer. “These models have improved over the years such that when a pathologist looks at a patient-derived xenograft, or PDX, sample under the microscope, they can’t tell if it’s from a mouse or a human,” says Smith. “That’s a new and exciting development; however the problem is that there’s no immune system so we can’t incorporate recent advancements in immunology and cancer. We’re trying to make a humanized mouse with a human immune system and human tumor. Steve Fiering (PhD, NCCC researcher) and his lab have been able to humanize mice, so we’re trying to combine our expertise to develop a model that’s clinically relevant.” The hope is to develop personalized mouse models to discover effective treatments for individual patients, even if the treatment is intended for another type of cancer. For his work in targeted therapies using xenografts, Smith was awarded a 2017 Steven B. Currier Fund for Clinical Oncology scholarship, which supports moving key laboratory discoveries into a clinical setting.
Pulling double duty
The PDX models are also of use in the work of Yolanda Sanchez, PhD, Smith’s main research collaborator, who, after screening thousands of yeast compounds, has discovered several that have potential to become drugs that could target a particular gene mutation found in 90 percent of pancreatic cancers. “Dr. Sanchez needed to test models systems beyond yeast, so that’s where the PDX system came into play,” says Smith.
On the clinical side, Smith took an interest in the complexity and technical aspects of pancreatic surgery and a liking to the appreciative nature of the patients. “The future is in minimally invasive computer-assisted robotic surgery,” declares Smith. “We are pioneering that at Dartmouth-Hitchcock and have been for about a year now. In that time, including surgeries for cancer and other pancreatic diseases such as pancreatitis, we’ve done about 60 surgeries. No one in New England has that kind of record, and it’s just going to grow. The advantages are smaller incisions, less pain and trauma to the patient, and better visualization for the surgeon. It’s also remarkable how quickly the patients who have had robotic surgeries can recover and move on to their other treatments. There are controversies such as cost, but there are advantages from the cancer standpoint of getting people into treatment more quickly and in better shape to tolerate it.”
Finding it sooner
Presently, pancreatic cancer can only be detected after solid tumors have formed, which usually means the disease has already progressed to a later stage. One way to possibly reduce the mortality rate of pancreatic cancer is if it could be detected, diagnosed and treated much sooner, even before visible tumors form. In 2016, the research team led by Gregory Tsongalis, PhD, director of the Laboratory for Clinical Genomics and Advanced Technology (CGAT) and member of NCCC’s Molecular Therapeutics Research Program, received a Prouty Pilot grant to research liquid biomarkers, or circulating tumor DNA (ctDNA) in the bloodstream, before they progress to tumors. “We’re working on novel technologies to detect ctDNA in the plasma of cancer patients,” says Tsongalis. “We’re developing optimized protocols to isolate ctDNA from plasma samples and then assessing various molecular technologies to search for genetic variants that may be of clinical interest.”
My team continues to look at genetic variants (mutations) in pancreatic cancer and how that impacts tumor development, progression and response to therapy as part of our precision medicine initiative. We’re also actively looking at new biomarkers for this dreadful disease.Gregory Tsongalis, PhD
Working with Dartmouth’s Thayer School of Engineering, Tsongalis’ team developed a concept of nanorod probe sensors to capture circulating tumor or mutant DNA in the blood. The first year of the Prouty grant was dedicated in part to engineering and design of the nanorod sensor, led by John Zhang, PhD, Professor of Engineering at Thayer, and Amogha Tadimety, BSE, a graduate student and PhD Innovation Fellow.
The team engineered a system of gold nanorods affixed with recognition element probes designed to selectively bind to a complementary sequence of DNA. When white light is shone on the gold nanorods, they absorb most of the light at a particular wavelength, and when something is bound to the nanorods, that wavelength shifts. The team can use a read-out that shows a measured shift in wavelength peaks to determine if the nanorod sensor has bound to something, indicating a mutation in that DNA. This process happens within minutes and can measure down to a single molecule bound to a single nanorod. For perspective, 1,000 nanorods could fit on the end of a strand of hair.
“This biomarker, circulating DNA, has been shown to be present in the blood well before a tumor shows up on imaging. But the DNA is in such low concentration that it’s hard to capture and detect them and requires a lot of equipment and technical expertise,” says Tadimety. “Our technology is as simple as flowing a tiny amount of blood through a small device (see photo, right) and taking a measurement. We want to know both the concentration of DNA and what percentage of it is mutated. That’s what we’d need to know to make a diagnosis. The results are promising so far, showing that the nanorods are selectively binding to more of the mutated DNA than the wild-type.”
As engineering progresses, Tadimety and Zhang are working on altering the probe to increase further its preferential binding to mutant DNA over wild-type. “My team continues to look at genetic variants (mutations) in pancreatic cancer and how that impacts tumor development, progression and response to therapy as part of our precision medicine initiative,” explains Tsongalis. “We are also actively looking at new biomarkers for this dreadful disease.”
Tsongalis also co-authored a 2013 Cancer Genetics paper on microRNA analysis as a diagnostic marker for pancreatic cancer that continues to be one of the most highly cited papers since publication. “miRNAs play critical regulatory roles in many cell processes. They’re an exciting new biomarker for human disease because many are tissue and cell-type specific, unlike more traditional biomarkers,” explains Tsongalis. “We have identified a panel of five miRNAs that can help distinguish the various pathologies found in the pancreas, and we continue to validate this finding.”
Shaping the path forward
Incoming director of NCCC, Steven Leach, MD, also brings with him a wealth of experience in pancreatic cancer research, as a lab scientist and surgical oncologist himself, most recently from his lab at Memorial Sloan Kettering Cancer Center in New York. Leach is working to recruit new talent and expertise to complement the already strong research programs at NCCC. “He’s a nationally known pancreas cancer researcher and surgeon—he really walks in both the clinic world and the science world. I’m hoping that with his influence we can grow and offer better solutions to this problematic cancer,” says Smith. “Having Dr. Leach join NCCC is a major win for all of us, as his experience will help shape the path forward. His track record will most certainly help move new initiatives forward and bring a new perspective to our approaches to pancreatic cancer and other tumor-type research,” adds Tsongalis.
More information about pancreatic cancer and support can be found through the Pancreatic Cancer Action Network (PanCan) or National Pancreas Foundation (NPF).