For pancreatic cancer patients and others with different forms of cancer, precision medicine means using drugs to target specific mutations in genes in hopes of slowing disease progression. For some cancers, such as certain forms of lung cancer, this targeted approach has changed treatment, allowing patients longer progression-free survivals.
But recent studies, including those published by researchers at the Broad Institute (Cambridge, Massachusetts), show that, among all the ̓omics (the biology disciplines with names that end in “omic,” including genomics), the mutations in a tumor may be the worst predictor of its response to drugs. Pancreatic cancer, in particular, is one of the toughest challenges oncologists face. And although it remains one of the most lethal of malignancies, there is hope in the research and clinical community that a better understanding of the key genetic players will lead to more effective regimens that target these alterations.
Some scientists are taking a different tack, focusing not on genes, but on proteins. If you remember your basic biology, genes are pieces of DNA, the genetic material of most organisms. Genes are responsible for the production of proteins, the workhorses that tell a cell what to do. A branch of science called systems biology may help researchers home in on a better approach to cancer treatment by precisely targeting proteins called master regulators, instead of mutations. Among those leading the way in systems biology is Dr. Andrea Califano, the Clyde and Helen Wu Professor of Chemical and Systems Biology at Columbia University Irving Medical Center (New York); he also serves as Chair of the Department of Systems Biology, and Director of the JP Sulzberger Columbia Genome Center, Herbert Irving Comprehensive Cancer Center.
The technology that he and colleagues developed is called OncoTreatTM. A new clinical trial at Columbia has recently opened to test the feasibility of administering personalized therapy to subjects with advanced pancreatic cancer using the novel OncoTreatTM platform.
The RNA Precision Oncology Trial
The study is called RNA Precision Oncology in Advanced Pancreatic Cancer (HIPPOCRATES) and aims to recruit 30 participants in the initial phase.
Participants will be assigned to one of two groups. In the experimental intervention arm, participants who meet the eligibility criteria based on a tissue sample they provided will be followed by the investigators to obtain medical information every four weeks. The information gathered will include a review of medical records, contact with the participant’s treating physician, or personal contact between the participant and the investigators at Columbia University Irving Medical Center. During the study, their tumor tissue will be evaluated to identify medications that may help treat the cancer.
The results of these tests will be reviewed by experts on a Precision Medicine Tumor Board. A Precision Medicine Tumor Board is comprised of a team of precision oncology clinical experts working together to identify the best treatment options. Usually, the board includes oncologists, pathologists, surgeons, radiologists, immunologists, genetic counselors and others who meet at regularly scheduled intervals to review each patient’s case and the newest potential treatments.
These experts may recommend a specific treatment to the participant or participant’s physician. The observation arm is for participants who don’t meet the eligibility criteria based on their tissue sample. These participants will be provided follow-up with their treating physicians up to every four weeks to gather clinical information related to their disease.
The primary outcome of the study is to determine whether a subject is assigned a therapy that they are able to begin in the study’s second phase. The therapy assignment is based on results from OncoTreatTM analysis and recommendations of the Precision Medicine Tumor Board, which includes assessment of availability and expected toxicity of identified agents
In early work on pancreatic cancer tumor samples, OncoTreatTM identified at least one matching drug for more than 90 percent of patients. The Columbia team of Califano and Kenneth Olive, Ph.D., assistant professor of medicine and assistant professor of pathology and cell biology, was awarded a $2.2 million grant by the Lustgarten Foundation to support a clinical trial of the OncoTreatTM framework in pancreatic cancer patients as well as associated preclinical studies.
“I’m extremely excited that we’re moving forward on this,” says Califano. “This can be a critical entry point for identifying potential combination therapies for (pancreatic) cancer patients. Indeed, we have recently shown that virtually all pancreatic cancers comprise cells in different transcriptional states and thus are sensitive to different drugs.
“This may explain why these tumors are so difficult to treat with conventional and targeted therapy, because only a fraction of their cells may respond while the others will plastically regenerate the entire tumor until they find the molecular recipe to elude even that initially effective treatment.”
Although going after DNA mutations makes sense, it’s important to remember that “pancreatic cancer isn’t like chronic myelogenous leukemia where you have a drug like imatinib (Gleevec) targeted against the dominant genetic driver of the disease, which absolutely transformed lives,” Olive told Let’s Win. “In pancreas cancer you have maybe about 15 percent of patients who have an actionable mutation that can be targeted.
“We need to be able to help the other 85 percent.”