Glimmers of Hope for Pancreatic Cancer

Alex Trebek. Ruth Bader Ginsburg. Steve Jobs. Sally Ride. Patrick Swayze. The list of celebrity deaths from pancreatic cancer is long, but the disease can affect anyone.  More than 50,000 people in the United States are expected to die of pancreatic cancer this year alone, making it one of the deadliest cancers. The problem is twofold; a lack of good screening tests means that many patients don’t get diagnosed until their tumor has already spread to other parts of their body, and few drugs work against the disease, especially at late stages. 

After decades of effort, though, researchers are finally making some headway against pancreatic cancer.  

“There’s no question that we’re making meaningful progress in the fight against pancreatic cancer,” says Anil K. Rustgi, MD, Herbert and Florence Irving Director of the Herbert Irving Comprehensive Cancer Center (HICCC), whose research focuses on the complex interplay between cancer-driving genes and the tumor microenvironment. “For decades, the five-year survival rate was stuck at about 5%, but today it has climbed to around 13%. While it might seem modest, this improvement is significant for a disease as aggressive as pancreatic cancer.”  

Building the pancreatic cancer drug arsenal

New drugs just entering clinical trials have the potential to accelerate the field’s progress even more. Researchers at Columbia have been testing an experimental compound called RMC-6236, from Revolution Medicines in Redwood City, CA. The compound targets the KRAS protein, which is defective in most pancreatic tumors. KRAS has been considered ‘undruggable’ for decades, but this new drug and others are showing promise. 

“This is the good news that we have been waiting for. We now have drugs in our arsenal that appear to be effective and target a key protein responsible for pancreas cancer growth. In early clinical trials, the drug shrinks tumors for a meaningful duration,” says Gulam Manji, MD, PhD, who co-leads the Precision Oncology and Systems Biology (POSB) program at the HICCC.  

However, he adds that “it’s not the silver bullet.” In patients with late-stage disease, the tumors eventually become resistant to the drug and grow back. 

Manji is already working with Ken Olive, PhD, who is also co-leader of the POSB program at the HICCC, and a large team of international collaborators, to identify the mechanisms behind the tumors’ resistance. That work could eventually uncover additional ways to attack the disease. 

In the meantime, Manji’s team is running two clinical trials combining the new KRAS inhibitor with other existing chemotherapies. In addition to a phase 1 trial that’s underway now, a larger phase 3 trial is now enrolling patients.  

A new approach to dissolve the tumor shield

KRAS inhibitors are not the only promising new drug on the scene. Manji and his team are leading research on cytokine inhibitors, which work to “unmask” hidden tumor cells, allowing the immune system – and immunotherapies – to stop the cancer from spreading. Certain pancreatic tumor cells release cytokines, creating an immunosuppressive microenvironment that effectively acts as a "cloak," shielding them from the immune system's attack. 

As a fellow, Manji worked with Olive on preclinical studies demonstrating the effectiveness of a combination of chemotherapy, immunotherapy, and a CXCR4 inhibitor in enhancing the immune response for pancreatic cancer. That led Manji to initiate a small pilot study in patients, combining standard chemotherapy with a PD-1 inhibitor and the CXCR4 inhibitor motixafortide. “The results were encouraging, where 64% of patients had a tumor shrinkage of 30% or more, and some patients actually had prolonged responses,” he says. 

That pilot study has now advanced into a phase II trial, which is currently enrolling patients at Columbia and Brown University and will soon activate at additional sites. The trial is the first large, multicenter, randomized study evaluating motixafortide with a PD-1 inhibitor and first-line pancreatic adenocarcinoma chemotherapies.  

Screening solutions & "previvors"

While new treatments for late-stage disease can help, earlier diagnosis would be even better. As in other cancers, detecting pancreatic tumors early leads to much higher survival rates. Good screening tests for the general population remain elusive, but testing high-risk patients is already becoming the standard of care. 

“All patients with pancreatic cancer at Columbia now undergo germline testing, to see whether they inherited a gene mutation that predisposed them to it,” says Manji. Close relatives can then be tested for the same mutation and followed more closely, to catch any developing tumors while they’re still treatable. 

This approach enables tailored surveillance and the identification of "previvors," or those with a genetic predisposition but no cancer diagnosis. "The goal is to identify as many previvors as we can to offer them preventative screening, early detection, and preventative strategies," says Fay Kastrinos, MD, MPH, director of Columbia’s Muzzi Mirza Pancreatic Cancer Prevention and Genetics Program and member of the Cancer Population Sciences program at the HICCC. 

While progress may still feel incremental, “these recent breakthroughs offer hope to patients and researchers alike,” says Manji. “After years and years of little progress, it’s an exciting time to be a physician and scientist in this field.”