Personalized medicine is an important and evolving research area for pancreatic cancer. It focuses on learning about a person’s genetic and tumor make-up and identifying mutations. With this information, doctors can create treatment strategies that are customized to each patient’s needs. Our research is exploring various approaches and technologies for the most effective way to personalize medicine.
Developed by our Chief Scientist David Tuveson, M.D., Ph.D. and his collaborator Hans Clevers, M.D., Ph.D., president of the Royal Netherlands Academy of Arts and Sciences, organoids are hollow spheres that grow from samples of pancreatic tissue. Organoids have been successfully used for other cancers; however, under the leadership of Dr. Tuveson, we are spearheading the use of organoids in pancreatic cancer through our research at our dedicated laboratory at Cold Spring Harbor Laboratory. Organoids enable researchers to observe pancreatic cancer from its beginning and test new diagnostics and therapies in the lab. The development of the organoid system was a monumental step forward in pancreatic cancer research because it brings the laboratory closer to the clinic.
In our organoid research project, a patient’s organoid is genetically sequenced and its genetic makeup is characterized. It is then “treated” with many compounds and combinations of compounds to determine which are most effective in killing the cancer cells. This process is the essence of personalized medicine, where the precise treatment for each patient is selected based on the makeup of his/her tumor. In fact, researchers recently demonstrated that organoids can quickly and accurately predict how patients with pancreatic cancer will respond to a variety of treatments.
“We’ve been able to identify an approach to prioritize treatment strategies for pancreatic cancer patients, with the goal of giving them the best chance for survival and a good quality of life,”said Hervé Tiriac, Ph.D., a senior researcher in Dr. Tuveson’s lab.
The team assessed RNA (which acts as a messenger carrying instructions from DNA for controlling the synthesis of proteins) levels in individual organoids to determine gene signatures predictive of sensitivity to the five standard chemotherapies administered to pancreatic cancer patients. Three of these signatures correctly identified large numbers of patients who had responded to these drugs, and showed that those responding patients lived much longer before the cancer progressed. The signatures should enable physicians to choose the correct chemotherapy for pancreatic cancer patients for first-line treatment.
The researchers demonstrated that the organoids provide an effective precision-medicine “pharmacotyping,” or drug-testing, pipeline. To do this, the organoid from the patient’s cancer was cultured, and then used to test all possible standard-of-care chemotherapy drugs. They found that many of the organoids that did not respond well to chemotherapy were responsive to a variety of investigational drugs based on their gene signatures that occur as a result of tumor development.
Dr. Tuveson and his team plan to further refine the gene signatures through additional experiments, then test the genes’ ability to predict treatment sensitivity in clinical trials. In fact, Brian Wolpin, M.D., MPH, director of the Hale Center for Pancreatic Cancer Research and the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute, is in the very early stages of utilizing the organoid technology on patients. The organoid research study was published in the May 31, 2018 edition of Cancer Discovery.
DNA and RNA Sequencing
DNA sequencing is the process of determining the precise order of nucleotides — the basic building blocks — within a DNA molecule. Knowledge of DNA sequences has become critical in cancer research. RNA sequencing is very similar to DNA sequencing, as it refers to techniques used to determine the sequence of RNA molecules that are also part of the pancreatic cancer tumor.
In a study published in Cancer Discovery genomic analyses of metastatic pancreatic cancers have suggested that approximately one third of pancreatic cancer patients may have a genomic alteration that could impact treatment decisions and guide doctors to choose a specific therapy for a personalized medicine approach.
The study describes a metastatic tumor biopsy protocol now being used at Dana-Farber Cancer Institute called PancSeq, which was implemented to perform whole exome-DNA and RNA-sequencing for patients with advanced pancreatic cancer. Additionally, both tumor DNA and inherited DNA were sequenced for all patients. The analyzed data were then given to their clinicians to assist in the patients’ care.
Forty-eight percent of patients within this group had cancers with at least one genomic alteration that could potentially be eligible for current clinical trials or support off-label usage of a drug approved for another indication. A total of 24% of patients enrolled in the PancSeq study were treated with an experimental agent, either through enrollment in a clinical trial or through off-label use of an approved agent. Overall, 30% of enrolled patients had a change in their clinical care as a result of their genomic data, including the recommendation for some patients that family members consider genetic testing due to a potential inherited predisposition to pancreatic cancer.
These data demonstrate how the timely collection of genetic information can impact treatment decision-making in pancreatic cancer through enrollment of patients in clinical trials or the use of off-label targeted therapies.
“OncoTreat”— a tool being used by a team of researchers led by Kenneth Olive, Ph.D. and Andrea Califano, Ph.D., at Columbia University Medical Center — is a computational framework that pairs patients with optimal treatments based on gene expression data from their tumors. Rather than using DNA mutations, the approach reads the dynamic messages found in the RNA of tumor cells and interprets these to identify critical weak spots where the tumor may be attacked.
The team is also making organoids for each patient, analyzing the RNA of the tumor and using artificial intelligence to predict which drug could work for that specific patient based on his/her RNA profiling, then treating each patient with that drug. Additionally, Drs. Olive and Califano are conducting a clinical trial in second-line metastatic pancreatic cancer patients with the primary goals of assessing safety/feasibility and identifying early indications of efficacy.