By Kerri Kaplan
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.
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:
Cornelia T. Bailey Foundation
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.