As the leaders in pancreatic cancer research, we fund projects at every step in the drug development process. Drug development is the process of bringing a new treatment to patients either by working with existing drugs in new ways (such as identifying new combinations) or by creating a new compound through pre-clinical or basic research in the laboratory. Once that has been done, the compound or drug combination must be preliminarily tested through a clinical study. If it performs well in the study, it will then be tested in a clinical trial which consists of four phases. The treatment ultimately needs FDA approval before becoming a recognized new treatment option. While the entire drug development process is extremely complex, time-consuming and costly, it’s vital to alter the course of this disease and give patients more viable treatment options.
A new approach to fighting pancreatic cancer is to target cancer metabolism. In order to grow, cancer cells need to produce (metabolize) energy and build blocks for new cancer cells. To do that, cancer cells increase the uptake of nutrients from their environment by overproducing specific transporters or molecules.
David Sabatini, M.D., Ph.D., Whitehead Institute for Biomedical Research, has recently discovered a molecule called SLC38A9 that acts as a gate through which those nutrients are released to cells. If the SLC38A9 molecule is removed from pancreatic cancer cells, the nutrients are trapped inside, unable to fuel the cancer growth. The long-term goal is to create a drug that can stop the metabolism or cancer growth.
Changes in how nutrients are metabolized, or broken down for energy, contribute to both the development and progression of pancreatic cancer, but the complicated relationship between the cancer itself and a person’s body is not well understood. In previous work, Matthew Vander Heiden, M.D., Ph.D., Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, has shown that the breakdown of muscle tissue, which is common in pancreatic cancer patients, takes place early in their disease. Dr. Vander Heiden found that muscle breakdown releases branched chain amino acids (BCAAs), and he is now testing how the BCAAs affect the growth of the tumor and the patient’s metabolism. Dr. Vander Heiden’s objectives are to identify targets for new therapies to stop the growth of the cancer and counteract effects of the pancreatic cancer that hinder the use of existing therapies. A paper on this important work was published in the June 20, 2018 edition of Nature.
Genes encode proteins and proteins dictate cell function. Therefore, the thousands of genes expressed in a particular cell determine what that cell can do. Changes in cancer gene expression can be influenced by epigenetics factors. Epigenetic is the study of the biological mechanism that turns a cell “on or off.” Understanding the epigenetics of a tumor can lead to new treatments. Studies by our Lustgarten–funded researchers at Dana-Farber Cancer Institute, Johns Hopkins and the Salk Institute for Biological Studies are significantly advancing the research in this area.
David Pellman, M.D., Dana-Farber Cancer Institute, is studying why genome catastrophes, a phenomenon by which up to thousands of clustered chromosomal rearrangements (or abnormalities) occur in a single event, are so common in pancreatic cancer. He is working to identify the underlying causes and potential therapies for treating genome catastrophes to prevent pancreatic tumors from developing. Dr. Pellman and his team are using pancreatic organoid cultures to model the different stages in pancreatic cancer development.
Andrew Feinberg, M.D. ,and his team at Johns Hopkins University School of Medicine have identified new epigenetic defects—changes in the genes that occur during metastasis. By studying these defects, the team is creating compounds to prevent the tumor from spreading beyond the pancreas to organs such as the liver. If the tumor can be contained to the pancreas there is a much better chance at long-term survival.
A cancer biomarker refers to a molecule or protein secreted by a tumor or a specific bodily response that is indicative of the presence of cancer in the body. One of these cancer biomarkers that impacts pancreatic cancer is leukemia inhibitory factor (LIF), a normal protein found in cells. However, it’s overly produced in pancreatic cancer, encouraging tumor growth and inhibiting the body’s immune response to the tumor. Tony Hunter, Ph.D.,and his team at the Salk Institute for Biological Studies are working to determine if this protein can be used as a biomarker and determine how it can influence the immune system to target treatments. This work may also have implications for earlier detection.
Ronald Evans, Ph.D., Salk Institute for Biological Studies, is working to better understand the epigenetic factors that dictate the behavior of both the pancreatic cancer cells and the pancreatic stromal cells in hopes of identifying key signaling factors that can be targeted therapeutically. A chemically modified version of vitamin D called paricalcitol controls the “shut-off” valve on the gene, giving hope for a new way to slow tumor progression. Dr. Evans’ research shows that if patients’ tumors have this vitamin D receptor, they could be eligible for treatment with paricalcitol as part of their therapy. Our first trials in patients are already underway.
The tumor microenvironment is the area around the tumor that feeds the tumor cell. The microenvironment includes different kind of cells, molecules, and the stroma, which is the connective tissue and blood vessels surrounding the tumor. In pancreatic cancer, the stroma is extremely dense, making it very difficult for medication to penetrate the tumor. Our Chief Scientist Dr. Tuveson compares pancreatic cancer to an oatmeal-raisin cookie, where the raisins are the cancer cells. Not only is the “oatmeal” – the stromal tissue surrounding the cancer cells – denser than in other cancer types, some of its non-cancerous components promote tumor survival and growth.
Dr. Tuveson’s team recently discovered that one type of cells in the stroma, the fibroblasts, comes in at least two varieties. Understanding that the fibroblasts are not the same provides an opportunity to develop therapeutic agents to target the specific fibroblasts.
In addition to potentially impacting the pancreatic cancer tumor’s biology, vitamin D also has the potential to change the microenvironment. Part of the Pancreatic Cancer Collective, the SUC2-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team has found that the vitamin D receptor plays an important role in determining pancreatic cancer susceptibility to chemotherapeutic agents. This team is studying vitamin D receptors to determine if they are effective “super-enhancers” which improve patient response to chemotherapy.
Studying the Immune System of Long-Term Survivors
Why do some people survive pancreatic cancer, but most do not? By looking at individuals who have survived pancreatic cancer for long periods of time, the Pancreatic Cancer Collective SU2C-Lustgarten Foundation-Society for Immunotherapy and Cancer (SITC) Pancreatic Cancer Convergence Research Team has identified an initial set of high-quality neoantigens, or protein tags, on cancer cells that the immune system recognizes. They are now working to further understand neoantigens, with the goal of developing a method for creating vaccines to treat pancreatic cancers. This research will have a significant impact on understanding neoantigen T-cell immunobiology, and could improve the treatment prospects of pancreatic cancer patients.
Cancer immunotherapy is the use of the immune system to prevent or treat cancer. Unlike chemotherapy or radiation, it is a type of treatment that boosts the body’s natural defenses to fight cancer. It uses substances made by the body or in a laboratory to improve or restore immune system function. Through this therapy, the immune system is guided to attack and kill the cancer cells. Immunotherapy has been very successful in treating other types of cancer, which is why experts believe it has promise in pancreatic cancer, although much more work needs to be done in this area.
First Immunotherapy Treatment for Pancreatic Cancer
In May 2017, in an unprecedented, fast-tracked review, the FDA approved Keytruda® as the first immunotherapy treatment for advanced pancreatic cancer patients whose tumors are mismatch repair deficient (dMMR) or microsatellite instability – high (MSI-H). These terms are used interchangeably. This deficiency alters their capacity to repair DNA, which is a factor in cancer development. It is estimated that approximately 1 in 50 advanced pancreatic cancer patients have tumors that are mismatch repair deficient, making them candidates for this type of therapy. Keytruda is the first cancer drug based on a genetic characteristic, rather than tumor site, to be approved by the FDA for use in pancreatic cancer patients. The Lustgarten Foundation played a critical role in bringing this new treatment to patients by funding the research, encouraging patients to get tested and funding patients’ testing to determine if their tumors are mismatch repair deficient.
Bert Vogelstein, M.D., co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center who led this research, said, “Keytruda is the first example of ‘personalized immunotherapy.’ A specific immune treatment can now be recommended for patients based exclusively on the genetic characteristics of the tumor. If the tumor shows a repair defect, then it is very likely that it will respond to this drug, regardless of how advanced the cancer is at the time of treatment. This is a potential life-saving therapy for these patients.”
Stimulating the Immune System
Immunotherapies have shown benefits across a range of cancers, but so far have not worked well in pancreatic cancer patients with the exception of Keytruda, which works in patients with microsatellite instability (MSI). Recent evidence suggests that one major roadblock for the effective use of immunotherapies in pancreatic cancer patients is that the tumors are effectively hidden, preventing the immune system from recognizing and killing them. Daniel D. Von Hoff, M.D., the Translational Genomics Research Institute (TGen), and his team believe that therapies targeting the vitamin D receptor will perhaps “unmask” the pancreatic tumors and allow the immune cells to reach them, creating the possibility that immunotherapies will be effective. The goal is to test if targeting the vitamin D receptor will unlock the potential of immunotherapies to kill pancreatic cancer tumor cells and potentially establish a therapeutic combination for controlling advanced pancreatic cancer, extending patient survival, and reducing side effects. Additionally, Dr. Von Hoff and his team hope to identify features that drive patient responses to immunotherapy and gain insight into additional strategies for converting immunotherapy-resistant tumors into tumors that respond to treatment.
Douglas Fearon, M.D., of Cold Spring Harbor Laboratory and Weill Cornell Medical Center wanted to understand why immunotherapy has not been very effective in pancreatic cancer. He observed that mice with pancreatic cancer didn’t respond to experimental immunotherapy treatments that have been showing great promise in other types of cancer. The reason is that the T-cells, a key component of the immune system, were facing a road block and were unable to reach and attack the tumor.
“When we took a closer look at the tumors we could see that the T-cells were being excluded from the area around the tumor,” Dr. Fearon said. The T-cells were blocked by a molecule that coated the cancer cells – called CXCL12 – and that molecule was being produced by the cancer associated fibroblasts (CAF’s). The team then used a drug called AMD3100 that blocks an interaction between T-cells and the CXCL12 coating molecule. This freed up the T-cells to target the tumor cells. By combining the immunotherapy treatment with AMD3100, the cancer cells responded to the immunotherapy treatment. Soon, Dr. Fearon will be testing the drug combination in pancreatic cancer patients to see if the response is the same.
For an immune response against cancer to be effective, cells of the immune system known as T-cells must recognize the cancer by means of their T-cell receptors. Hidde Ploegh, Ph.D., Children’s Hospital Boston, is working on genetically engineering T-cells with new receptors that recognize targets on newly formed blood vessels in growing pancreatic cancers. Additionally, Dr. Ploegh’s team is producing biologically active molecules that can direct T-cells toward the location of pancreatic tumors to increase their ability to kill cancer cells. This team is also developing imaging agents in order to monitor the effectiveness of therapy in a non-invasive way.
We know that the immune system can unmask and destroy cancer cells. Elizabeth Jaffee, M.D., Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, has examined an important subset of immune cells that suppress the immune response. The drug Entinostat can decrease these immunosuppressive cells and allow access to tumor-killing T-cells. Dr. Jaffee is enrolling patients who have become resistant to chemotherapy and treating them with entinostat to determine if it can decrease the cells that are suppressing the immune system.
Learn more about this trial at ClinicalTrials.GOV
A renowned research team from the University of Pennsylvania, led by Carl June, M.D., is studying CAR T-cell immunotherapy in metastatic pancreatic cancer patients, looking for changes in DNA “on and off switches” (epigenetic changes) following treatment with CAR T. The goal of the research is to identify epigenetic changes that will facilitate better understanding of why certain patients respond to treatment compared to non-responders.
Another team at the University of Pennsylvania, led by Peter O’Dwyer, M.D., is investigating epigenetic variations in patients that influence the response to immunotherapy by using epigenetic therapeutics alone or in combination with immunotherapy to inhibit tumor progression as well as to overcome resistance to immunotherapy. The team is identifying genetic and epigenetic features in CAR T-cells and/or cancer cells that will help predict which patients will respond to the immunotherapy, with an eventual goal of initiating clinical trials that employ a combination of approaches to therapy.
David Ryan, M.D., Massachusetts General Hospital, and Alec Kimmelman, M.D., Ph.D., NYU Langone Perlmutter Cancer Center, are collaborating on research aimed at improving patient outcomes. Drs. Ryan and Kimmelman are using a comprehensive approach for patients with borderline resectable (operable) and locally advanced pancreatic cancer. Through a clinical trial, the team will evaluate the addition of Losartan, a medication used for high blood pressure that is thought to “open up the blood vessels,” combined with FOLFIRINOX. The objective of their research is to demonstrate that this treatment combination will shrink the patients’ tumors enough that they then become eligible for surgery. Which will result in their best chances for long-term survival. Additionally, since preliminary data suggest that Losartan therapy and radiation therapy alter the immune microenvironment, the team will also add immunotherapy to determine if this strategy can provide additional benefit.
Along with the clinical trial, patient biopsies will be grown into tumor organoids and exposed to the same treatment that the patients received to determine if the organoid was successful in indicating how the tumor would respond to therapy.