Pancreatic Cancer: Research and Treatment

Though the five-year survival rate for pancreatic cancer has doubled from 6% to 12%, it’s still the third-leading cause of cancer deaths in the U.S.

Tricky to diagnose and stubborn to treat, pancreatic cancer is often symptomless until it metastasizes. However, innovative investigations by researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, are targeting causes and identifying effective treatments.

Working Downstream from a Cancer Gene

Mutations of the KRAS gene are present in up to 90% of pancreatic cancers. These mutations are logical targets for new drug therapies, according to Nipun Merchant, M.D., director of the Sylvester Pancreas Cancer Research Institute. Still, the multiple components in the KRAS pathway present a unique challenge.

Until recently, KRAS has been difficult to target pharmacologically.

“We have focused our efforts at targeting effectors that are downstream of KRAS,” said Dr. Merchant, also the Alan S. Livingstone Professor and chief of the Division of Surgical Oncology at the Miller School. He equates the movements of these mutations to a busy freeway under heavy construction. “If you cut off one exit, cancer cells will figure out how to get to another exit.”

Early-stage drug development involves combinations of drugs that target multiple resistance mechanisms.

“When we target the tumor with complementary drugs that overcome resistance pathways,” said Dr. Merchant, “we see dramatic improvements in tumor response and survival in mice.”

But treating human pancreatic tumors means recognizing their varied elements, including cancer cells, immune cells and stromal cells.

As many as 90% of pancreatic cancer tumors are composed of stromal cells that limit immune cells. But efforts to deplete stromal cells with drugs led to worse outcomes in clinical trials with patients.

Stromal cell complexity is not fully understood. They promote both tumor-restraining effects and tumor-promoting effects. Current studies seek to understand how stromal cells communicate with tumor and immune cells so more effective therapies can be developed, said Dr. Merchant.

Opportunity for Immunotherapy?

Some stromal cell behavior observed during Dr. Merchant’s study appeared favorable to immunotherapy, said Peter Hosein, M.D., associate director of clinical research, Sylvester Pancreatic Cancer Research Institute.

In a Sylvester trial based on Dr. Merchant’s work, Dr. Hosein’s team added immunotherapy to KRAS-targeted drug therapies. Results, said Dr. Hosein, also co-leader of Sylvester’s gastrointestinal cancers site disease group and associate professor of clinical medicine at the Miller School, will be known in the coming months.

BRCA Mutations and Immunotherapy

Patients with inherited BRCA 1 and BRCA 2 mutations that predispose them to pancreatic cancer have few options other than chemotherapy. But Jashodeep Datta, M.D., associate director of translational research at the Sylvester Pancreatic Cancer Research Institute, has a study underway that draws on patients Dr. Hosein successfully treated with immunotherapy.

The work of Dr. Datta, also Sylvester’s DiMare Family Endowed Chair in Immunotherapy, revealed a subset of these patients who fail to respond to chemotherapy but do respond to two types of immunotherapy. They had an impressive response rate, said Dr. Datta.

He is now trying to understand why patients who are resistant to chemotherapy and have the BRCA1 and 2 mutations can be sensitive to immunotherapy. Dr. Datta presented his findings at a recent American Association for Cancer Research Pancreatic Cancer meeting.

“This is the first time this particular phenomenon has been reported, and the mechanistic basis we uncovered is unique to our institution,” Dr. Datta said. “We are designing studies to target these novel vulnerabilities in such tumors and extending these therapies to our patients.”

Dr. Datta also recognizes the importance of treatment that corresponds with tumor biology.

“We are moving toward a personalized approach,” he said. “Our hope is that we will be at the point where we will have a reasonable and rational compendium of biomarkers we can get from each patient and then be able to say that certain patents will respond to certain therapies.”

Therapies, Dr. Datta added, that allow patients to live better lives by sparing them the potential toxicity of chemotherapy.

Racial Disparities in Pancreatic Cancer Treatments

A recent Sylvester study found that National Cancer Institute funding is higher for cancers that commonly afflict non-Hispanic whites than for cancers with high incidence rates in minority populations.

Pancreatic cancer has a higher incidence among Black people than any other racial or ethnic group. Sylvester Cancer Control Program researcher Shria Kumar, M.D., M.S.C.E. said that funding disparities for cancers that disproportionately impact racial and ethnic minorities need to be addressed.

“Disparities are very complex,” said Dr. Kumar, also an assistant professor in the Division of Digestive Health and Liver Diseases at the Miller School. “It’s not easy to identify one part of a demographic or a social determinant of health that leads to the disparity. They are often intertwined.”

Allocation based on the impact that cancer has on a racial or ethnic minority group is something we should be aware of, she said.

“It’s important to think can we beat this cancer, but does everyone have the same chance?” Dr. Kumar asked.

Tags: BRCA1, BRCA2, Dr. Jashodeep Datta, Dr. Nipun Merchant, Dr. Peter Hosein, Dr. Shria Kumar, immunotherapy, Sylvester Comprehensive Cancer Center