For years, a pancreatic cancer diagnosis has come with a devastating prognosis of only a few years. 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; lack of an effective screening test which means that most patients don’t get diagnosed until their tumor has already spread to other parts of their body, and that few drugs work against the disease, particularly at later 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.”
New Targets, New Therapies in Clinical Trials Show Promise
Researchers at Columbia have been testing a new drug from Revolution Medicines in Redwood City, CA, called daraxonrasib. 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, associate professor of medicine at the Columbia University Vagelos College of Physicians and Surgeons (VP&S).
Daraxonrasib was recently granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA), based on encouraging phase 1 clinical trial results. This designation could help ‘fast-track’ the drug, with positive results from the ongoing clinical trials.
Manji’s team is running two clinical trials with daraxonrasib. The first is testing daraxonrasib alone in a large phase 3 trial in patients whose tumor was not effectively treated with chemotherapy. The second phase 1 trial is combining daraxonrasib with standard chemotherapy. Both trials are actively enrolling patients.
‘Unmasking’ Pancreas Tumors and Enlisting the Immune System
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 target potential sanctuary sites where the cancer may be hiding.
Some subtypes of fibroblasts (cells within the tumor) cooperate with the cancer cells and release cytokines, creating an immunosuppressive microenvironment that effectively acts as a "cloak," shielding the cancer cells from the immune system's attack.
Based on his lab findings, Gulam Manji (right) and Columbia collaborator Kenneth Olive (left) opened a clinical trial for pancreatic cancer patients.
As a fellow, Manji worked with Kenneth Olive, PhD, 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 striking, with 64% of patients having a tumor shrinkage of 30% or more. Clinical trial results for pancreas cancer therapies are often incremental. Manji is hopeful about the responses he is seeing.
“The pilot trial’s results are very encouraging,” says Manji. “One patient, Jeff, had a pathological complete response, meaning that his pancreas cancer is completely undetectable. This is extremely rare in this type of cancer,” he says.
After participating in a Columbia clinical trial that combined standard chemotherapy with a PD-1 inhibitor with the CXCR4 inhibitor motixafortide,
Jeff's cancer is undetectable.
Now in an ongoing large phase II trial, Manji anticipates seeing more promise from this potential therapy. “The key test now is to demonstrate that patients who receive the combination therapy do better than patients who receive standard chemotherapy alone.”
Manji’s team will also analyze tumor samples from the larger study to identify markers which may predict which patients could preferentially benefit from this therapy.
Intercepting Pancreas Cancer for Better Outcomes
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 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.”
