Targeting Pancreatic Cancer: An Increased Focus on Developing New Clinical Trials

New initiatives are focused on clinical trials to target tumors in the pancreas.

New initiatives are focused on clinical trials to target tumors in the pancreas.

While long-term survival rates for many cancers are on the rise, it’s been difficult to improve outcomes for people with pancreatic cancer. Experts predict that by 2020, pancreatic cancer will be the second most common cause of cancer deaths — behind only lung cancer — despite nearly a dozen other cancers being more common.

But thanks to a collaboration funded by the nonprofit organization Pancreatic Cancer Action Network called Precision Promise, people with pancreatic cancer may soon have access to more clinical trials — and, hopefully, better standard treatments as well. The nationwide alliance involves 12 cancer centers around the United States, including Memorial Sloan Kettering, and seeks to develop large-scale precision-medicine trials.

“I think this is the most exciting thing we’ve done in years,” says MSK physician-scientist Steven Leach, who is serving as head of the Pancreatic Cancer Action Network’s Scientific and Medical Advisory Board. “It’s a whole new approach to treating pancreatic cancer, to be able to offer patients the chance to participate in a clinical trial that’s selected for them based on the molecular or other characteristics of their disease.”

I think this is the most exciting thing we've done in years. It's a whole new approach.
Steven D. Leach physician-scientist

In addition to their involvement in Precision Promise, MSK investigators are undertaking a number of other research efforts through projects conducted under the umbrella of the David M. Rubenstein Center for Pancreatic Cancer Research as well as collaborative studies funded by Stand Up To Cancer. Both efforts are eliciting answers to long-standing questions and helping to guide future research.

“We’re learning that not all pancreas cancers have the same genetic and molecular makeup, and that there are subclasses that can be defined based on these differences,” says MSK surgeon-scientist Vinod Balachandran. “We think it will greatly influence the design of clinical trials going forward.”

A Focus on Long-Term Survivors

One area where MSK is able to provide a unique approach is through an initiative to study long-term survivors of pancreatic cancer. The majority of people diagnosed with the disease die within a year, but about 7% of patients survive five or more years after treatment.

“To this day, we don’t know what makes these patients different from other people,” says Dr. Balachandran, who is focused on this project along with Dr. Leach and others.

MSK is perfectly positioned to gain insight into this mystery.

“The number of patients for which we have tissue samples and clinical data is significantly higher than what any other institution has,” Dr. Balachandran says. “Given our experience in following these patients over many years, as well as our ability to analyze their tumors on genetic, molecular, and cellular levels, we are beginning to understand what’s unique about them. We think these findings will eventually help us to harness new treatment strategies for all patients.”

Helping to Repair Damaged DNA

Analyses of the genetic and molecular characteristics of pancreatic cancer have shown that a significant number of these tumors have mutations in the genes that code for proteins that repair damage to DNA. When DNA damage cannot be repaired, cancer often results.

One of the most well known of these genes is BRCA2, which is linked to hereditary forms of breast, ovarian, and prostate cancer as well as some cases of hereditary pancreatic cancer. But BRCA2 mutations and other DNA repair–related mutations are not always inherited; some develop randomly in the cells later in life.

A class of drugs known as PARP inhibitors have shown promise in treating certain BRCA-induced cancers, especially ovarian cancer. Early-phase clinical trials led by MSK medical oncologist Eileen O’Reilly suggest that when combined with chemotherapy, PARP inhibitors may be effective against pancreas tumors that have BRCA mutations as well.

Pancreatic Tumor Registry
We are investigating the causes of pancreatic cancer in people with a family history of the illness.

“Although these mutations are associated with family heritage in some patients, we’re looking at this treatment strategy in a much bigger group of people who don’t have the inherited mutation but may still be susceptible based on other genetic changes in their cancer or their genetic makeup,” Dr. O’Reilly says.

Targeting the Cancer’s Environment

One of the reasons that pancreatic cancer is so resistant to current treatments like chemotherapy is that pancreas tumors are very good at insulating themselves. They recruit other cells, known as the stroma, to form a protective matrix around the tumor, squeezing the blood vessels and preventing chemotherapy drugs and immune cells from reaching it.

Preliminary data in mice have shown that a synthetic form of vitamin D could be used to dissolve that protective matrix, which would allow the blood vessels that feed the tumor to open up and let chemotherapy and immune cells enter the tumor more efficiently.

The focus on targeting the stroma is part of several collaborative research efforts at MSK. Patients would be selected for future trials based on a test that shows whether they have a high level of matrix chemicals in their tumor. If it proves effective, the stroma-targeting strategy could also be used in combination with other treatments such as targeted drugs and immunotherapy, Dr. Leach says.

Harnessing the Immune System

Developing immunotherapy strategies against pancreatic cancer is another area of research, both at MSK and as part of Precision Promise. Immunotherapy drugs called checkpoint inhibitors, which allow the immune system to recognize and attack cancer, have been proven to be effective in several cancers including lung cancer, melanoma, and bladder cancer. And although these drugs have not worked in pancreatic cancer, other immunotherapies could be on the horizon.

“As we learn more about the molecular signatures and unique aspects of long-term survivors of pancreatic cancer, it will help us to develop other immunotherapy approaches that may work better than checkpoint inhibitors,” Dr. Balachandran says.

We think these findings will eventually help us to harness new treatment strategies for all patients.
Vinod P. Balachandran surgeon-scientist

Whether repairing damaged DNA, targeting the stroma, developing a new immunotherapy, or something else entirely is the best approach for an individual patient, only more research will tell. For Dr. O’Reilly, these questions can only be answered through more research and greater clinical trial participation.

“Pancreatic cancer is probably the most challenging human malignancy,” she concludes. “A major mission for our pancreas cancer group and for the field in general is to have more people enrolled in clinical trials that are developed on the basis of patient data and the latest science.”