Why do alterations of certain genes cause cancer only in specific organs of the human body? Scientists at the German Cancer Consortium (DKTK), the Technical University of Munich (TUM), and the University Medical Center Göttingen have now demonstrated that cells originating from different organs are differentially susceptible to activating mutations in cancer drivers: The same mutation in precursor cells of the pancreas or the bile duct leads to fundamental different outcomes. The team discovered for the first time that tissue specific genetic interactions are responsible for the differential susceptibility of the biliary and the pancreatic epithelium towards transformation by oncogenes. The new findings could guide more precise therapeutic decision making in the future.
There have been no major improvements in the treatment of pancreatic and biliary tract cancer in the last decades and no effective targeted therapies are available to date. “The situation for patients with pancreatic and extrahepatic bile duct cancer is still very depressing with approximately only 10% of patients surviving five years,” says Dieter Saur, DKTK Professor for Translational Cancer Research at TUM’s university hospital Klinikum rechts der Isar, DKTK partner site Munich.
Matchmakers: How Basket Trials Match Patients With Drugs Based on Their Tumors
Drew Huggins was running out of options. After his diagnosis of metastatic pancreatic cancer two years ago, at age 47, he hadn’t had any luck with the treatments he’d tried so far.
His tumors didn’t respond to 13 cycles of FOLFIRINOX, an arduous four-drug chemotherapy combination. The chemo- therapy combination of gemcitabine
and paclitaxel didn’t work either. They only left him with severe neuropathy, which causes debilitating pain, weakness and numbness in his hands and feet, from which he is still trying to recover. Next, he enrolled in a clinical trial at The University of Texas MD Anderson Cancer Center in Houston that used an antibody-drug conjugate to try to attack the tumor. But while Huggins was on this drug, the tumor grew by 25%.
“After that, I pushed and said, ‘There’s got to be something else that can be done here,’” Huggins recalls.
It’s rare for pancreatic tumors to have a genetic mutation that drugs can target. But Huggins’ oncologist took a “we’ll never know till we try” approach, and it paid off. The doctor sent tissue from one of Huggins’ tumors to a lab to see if it had any gene mutations that might be vulnerable to existing targeted drugs.
Immune cells assemble – boosting the effects of chemotherapy in pancreatic cancer
A new study from Queen Mary University of London has demonstrated that immune cells can be stimulated to assemble into special structures within pancreatic cancer such that, at least in a pre-clinical model, researchers can demonstrate an improvement in the efficacy of chemotherapy.
The body’s immune system is a critical defence against illness such as infections, as has been highlighted by the recent COVID-19 pandemic. The same immune system can also help us fight cancer. However, pancreatic cancer is different; a key feature of this cancer type is that the pancreatic cancer cells are surrounded by a dense, impenetrable barrier known as the stroma, which often blocks the access of immune cells to the tumour. For this reason, immunotherapies – drugs that harness the power of the body’s immune system to kill cancer cells – have shown limited success in the treatment of pancreatic cancer, whilst they are effective in fighting other cancer types including skin and lung cancer.
Annual Report to the Nation: Rapid Decrease in Lung Cancer and Melanoma Deaths Lead Overall Continued Decline in Cancer Death Rate
Overall cancer death rates continue to decline in men and women for all racial and ethnic groups in the United States, according to the latest Annual Report to the Nation on the Status of Cancer. During 2001 to 2018, declines in lung cancer death rates accelerated, and death rates for melanoma declined considerably in more recent years, reflecting a substantial increase in survival for metastatic melanoma. However, the report finds that for several other major cancers, including prostate, colorectal and female breast cancers, previous declining trends in death rates slowed or disappeared.
The report, appearing in JNCI: The Journal of the National Cancer Institute, also finds that overall cancer incidence rates continue to increase among females, children, and adolescents and young adults (AYA). All trends in this report cover the period before the COVID-19 pandemic.
Personalized Medicine: Transforming Treatment Inside the Lustgarten Pancreatic Cancer Research Lab at Cold Spring Harbor Laboratory
By Kerri Kaplan
Score!
As hockey teams from the United States and Canada faced off recently to compete for the famed Stanley Cup, the leading cancer organizations in the US and Canada—the Lustgarten Foundation, Stand Up to Cancer, and Pancreatic Cancer Canada team up to fund a breakaway clinical trial to assist and save pancreatic cancer patients. During the June 30 LustgartenLIVE! research briefing: Personalized Medicine: Transforming Treatment, Dr. Dennis Plenker, technical manager of the state-of-the-art organoid facility at Cold Spring Harbor Laboratory (CSHL), articulated the objective of the new Pancreatic Cancer Signature Stratification (PASS) trial—use personalized medicine to give patients more shots on goal.
Personalized medicine for patients, one of Lustgarten’s three research pillars, customizes treatment options for a patient based on their genetics and that of their tumor. Under the direction of David Tuveson, MD, PhD, Lustgarten Chief Scientist and Director of the Lustgarten Foundation Pancreatic Cancer Research Laboratory at Cold Spring Harbor Laboratory, researchers pioneered the development of pancreatic cancer organoids, miniature 3-D structures grown in lab dishes from tiny bits of tumors taken from patients. Now, researchers are exploring the potential of organoids in personalized medicine—matching the right therapy to each patient—as well as discovering and developing new therapies. Dr. Plenker creates organoids for every patient on the PASS trial and tests them against the patient’s treatment plan.
Avatars
Linda Tantawi, Lustgarten’s CEO likens the organoids to avatars, whose graphic representation in video games acts as a proxy for a person. The organoid acts as a proxy for the patient, testing which drugs help shrink the patient’s tumor and which drugs are less effective. Currently, doctors still don’t know enough about the different types of pancreatic cancer to discover which treatment might work best, so patients can waste precious time taking drugs that won’t help them. In the PASS trial, patients are randomized to receive one of the two standard-of-care treatments and their tumor’s response to treatment is compared to the response of the organoid. The study aims to determine if the organoids can accurately predict the best treatment for patients in advance of a patient receiving therapy.
Proving the avatars are more than science fiction
As a medical school resident, Dr. Tuveson was bothered by the lack of hope for pancreatic cancer patients. So, as a physician scientist, he has dedicated his life to working both in the lab and clinic to change those patient outcomes. During his postdoctoral training, Dr. Tuveson learned to engineer mouse models to study human cancer. Later, he developed the first mouse model for pancreatic cancer—a revolutionary advancement at the time. Using these models, Dr. Tuveson has made several important discoveries in pancreatic cancer, including contributing to the discovery that the stroma surrounding the pancreatic tumor can act as a barrier against therapies.
Prior to opening the Lustgarten Foundation Dedicated Pancreatic Cancer Research Laboratory at CSHL, Dr. Tuveson heard about a promising project in the Netherlands. There, Hans Clevers M.D., Ph.D., president of the Royal Netherlands Academy of Arts and Sciences, was working with a then new model, organoids, which had proved effective in diseases such as cystic fibrosis and was just starting to be thought of as a tool for cancer. Believing the impact of organoids could be life changing for patients, Dr. Tuveson brought the idea of organoids for personalized medicine to the Lustgarten Foundation, where he was encouraged to make this the primary focus of his lab.
While early indications of the organoid’s ability to predict individual patient treatment response were positive, the five-month timeframe to grow the organoid was simply too long for pancreatic cancer patients. Dr, Tuveson presented the findings of the organoid work at scientific meetings, inviting young scientists to join him in his goal to make organoids faster and more effectively. In late-2017, Dr. Plenker accepted the challenge and joined the Tuveson Lab to work on optimizing the human organoid platform for pancreatic cancer.
Hope for Patients
While Dr. Plenker spends most of his time in the lab working with organoid models, he really enjoys attending the tumor board meetings with what he calls the Dream Team of Investigators collaborating on the PASS trial. These collaborators include two Canadian sites BC Cancer in Vancouver and Princess Margaret Cancer Center in Toronto; as well as Dana Farber Cancer Institute in Boston, Johns Hopkins in Baltimore, Memorial Sloan Kettering Cancer Center in New York City, and Northwell Health on Long Island.
Made possible in part through the support of the Gail V. Coleman and Kenneth M. Bruntell Organoids for Personalized Therapy Grant, Dr. Plenker tests organoids for sensitivity to the standard chemotherapies, comparing the results in the lab to the outcomes in the clinic. The data generated will help clinicians better predict which chemotherapies will be most effective for patients. Additionally, Dr. Plenker screens more than 100 drugs on each organoid to determine what therapy might be effective in second-line treatments. The twin goals of the clinical trial are to uncover more about how the existing treatments work, and to identify specific biomarkers indicating whether a pancreatic cancer will respond better to one treatment versus the other.
Wasif Saif, MD, Deputy Physician in Chief of the Northwell Health Cancer Institute,
has seen first-hand how patients can benefit from personalized medicine. He has treated BRCA+ patients with PARP inhibitors and platinum therapies and MSI+ patients with immunotherapy, which have shown to be much more effective than standard-of-care treatments. With the success of the PASS trial, he looks forward to no longer giving patients drugs that have little to no benefit while causing significant side effects.
Skate to where the puck is going, not where it is
What is Dr. Tuveson’s ultimate hope for the organoid program?
The standard-of-care treatments can be effective, but they are not a cure. Dr. Tuveson envisions the organoids as a tool enabling doctors to pick the right standard-of-care therapy for each patient at the on-set of their treatment. While a patient’s biopsy is being analyzed to confirm the presence of cancer, it also will be used to grow an organoid. Ideally, by the time the patient is ready to start their first treatment, the organoid will have determined the best treatment option. This personalized chemotherapy treatment will shrink the cancer in preparation for life-saving personalized immunotherapy or targeted therapy. While the patient is receiving the chemotherapy predicted by the organoid, the organoid will then test various immunotherapies, informing the doctor which will work for a patient. This one-two punch may be the future way of treating, and hopefully curing, this disease.
LustgartenLive! is made possible by the generous support of Ipsen.
Thank you to the following donors for supporting the Foundation’s personalized medicine projects:
The Gail V. Coleman and Kenneth M. Bruntel Organoids for Personalized Therapy Project
Cornelia T. Bailey Foundation
Recent Posts
- Personalized Medicine: Transforming Treatment Inside the Lustgarten Pancreatic Cancer Research Lab at Cold Spring Harbor Laboratory
A Juneteenth Conversation:
Health Disparities in Pancreatic Cancer- Life Lessons from an Unpredictable Diagnosis
Our Hearts are Broken with the Passing of Steve Price
Lustgarten Foundation-AACR
Career Development Awards
MasSpec Pen shows promise in pancreatic cancer surgery
A diagnostic tool called the MasSpec Pen has been tested for the first time in pancreatic cancer patients during surgery. The device is shown to accurately identify tissues and surgical margins directly in patients and differentiate healthy and cancerous tissue from banked pancreas samples. At about 15 seconds per analysis, the method is more than 100 times as fast as the current gold standard diagnostic, Frozen Section Analysis. The ability to accurately identify margins between healthy and cancerous tissue in pancreatic cancer surgeries can give patients the greatest chance of survival.
The results, by a team from The University of Texas at Austin and Baylor College of Medicine, are published this week in the Proceedings of the National Academy of Sciences.
Can mRNA Vaccines Fight Pancreatic Cancer? MSK Clinical Researchers Are Trying to Find Out
Messenger RNA (mRNA) vaccines may be the hottest thing in science now as they help turn the tide against COVID-19. But even before the pandemic began, Memorial Sloan Kettering researchers had already been working to use mRNA vaccine technology to treat cancer.
Vinod Balachandran a physician-scientist affiliated with the David M. Rubenstein Center for Pancreatic Cancer Research and a member of the Human Oncology and Pathogenesis Program and the Parker Institute for Cancer Immunotherapy, discusses how a collaboration with BioNTech — which developed the Pfizer-BioNTech COVID-19 vaccine — has led to a potential treatment for pancreatic cancer now in clinical trials.
RWJBarnabas Health Pioneers Innovative Pancreatic Cyst Surveillance Program
The incidental identification of pancreatic cysts has become more common with the increasing use of imaging modalities in clinical practice. Currently, an estimated 15% of Americans are believed to harbor a pancreatic cyst.1 Unlike other cysts within the body, pancreatic cysts are unique in that many pose an increased risk for development of pancreas cancer over a patient’s lifetime. Although certain cysts can be benign, when mucinous, such as intraductal papillary mucinous neoplasms or mucinous cystic neoplasms, these cysts are a marker of increased pancreatic cancer risk—even when small and without high-risk features.2,3 In fact, for certain pancreatic cysts, like main duct intraductal papillary mucinous neoplasm, the risk of pancreatic cancer can be as high as 70%.4 Therefore, those with pancreatic cysts require lifelong surveillance and certain patients also need surgical intervention to decrease their risk of developing pancreas cancer.
Blood test to spot pancreatic cancer: Pioneering check-up that can give early diagnosis of the disease could be available within months
A test that spots pancreatic cancer from a single drop of blood could improve survival rates. The first blood test for early diagnosis of the hard-to-spot disease, it could be available within months.
Pancreatic cancer has the lowest survival rate of the common cancers, with 7.3 per cent of patients alive five years after diagnosis, compared to 58.4 per cent of bowel cancer patients and 85 per cent of breast cancer patients.
The disease is one of the hardest to diagnose early. This is partly because the pancreas — a pear-shaped gland that makes digestive juices and hormones including insulin — is hidden behind the stomach, making it difficult for tumours to be felt or seen on scans.
Mouse Study Reveals New Therapeutic Target in Pancreatic Cancer
The general five-year survival rate for people with pancreatic cancer is 10%. Survival rates and individual outcomes are based on many factors, including the specific stage of disease when it is diagnosed. Cancer cells can quickly become resistant to treatments through adaptation. Now, new research by scientists at Columbia University Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center and with collaborators at the University of Pennsylvania, demonstrates that lowering levels of the hormone PTHrP can prevent metastases and improve survival in mice with pancreatic cancer.
Their findings are published in the journal, Cancer Discovery, in a paper titled, “PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability.”
