For decades, pancreatic cancer has been one of medicine’s toughest adversaries.
A “silent killer,” the disease frequently produces few symptoms until it has spread beyond the pancreas. By the time patients are diagnosed, surgery often is no longer an option, and treatments are focused on slowing the cancer rather than curing it. Despite many advances in chemotherapy and immunotherapy, pancreatic cancer remains one of the deadliest forms of cancer, with survival rates for advanced disease typically measured in months rather than years.
Now researchers are unabashedly celebrating a breakthrough treatment that targets one of the disease’s most powerful driving forces – a genetic mutation known as KRAS.
The Food and Drug Administration recently granted accelerated approval to daraxonrasib, a new targeted therapy designed to block certain KRAS mutations that help fuel cancer growth. While the drug is not a cure, oncologists say it represents an important step forward in the effort to turn some advanced cancers into manageable chronic diseases.
“One of the fundamental differences between a benign cell and a cancerous cell is that cancerous cells don’t really follow the circle of life,” explained oncologist Dr. Vinarsky. “When you get born, you divide and then you die. Cancer cells continue to divide.”
Scientists have known for decades that KRAS plays a critical role in that process. The gene acts like an accelerator pedal for cell growth. When mutated, it can become permanently stuck in the “on” position, continuously signaling cells to grow and divide.
“The KRAS appears to be crucial in stimulating cancer cells to continue to grow rather than die,” Dr. Vinarsky said.
The mutation does more than simply encourage growth. It also helps create an environment that protects tumors from attack.
“The general consensus is that cancer cells need glucose to grow,” he explained. “When you activate KRAS, it actually increases glucose uptake by the cancer cell, making it faster growing.”
At the same time, KRAS helps create what researchers call an inflammatory microenvironment around the tumor.
“It makes it very difficult for traditional chemotherapy to penetrate cancer cells and for the immune system to go after it,” Dr. Vinarsky said.
That combination of rapid growth and built-in protection has made KRAS one of the most attractive targets in cancer research. But it has also proved to be one of the most difficult to hit.
For years, scientists referred to KRAS as “undruggable” because its structure offered few places where medications could effectively attach and block its activity. But recent advances in molecular medicine changed that outlook, leading to the development of drugs capable of targeting specific KRAS mutations.
“Essentially, it’s a unique target that we knew for a long time had a lot to do with the growth of a cancer cell,” Dr. Vinarsky said. “Up until recently, we did not have any ability to do anything about this target. But we do now.”
The discovery is especially important in pancreatic cancer because KRAS mutations are prevalent in the disease.
“What’s unique about pancreatic cancer is that KRAS appears to be expressed in close to 90 percent of traditional pancreatic cancer patients,” he said.
While chemotherapy remains the standard first-line treatment for most patients with advanced pancreatic cancer, oncologists often face difficult decisions when those treatments stop working.
“We do have a couple of decent options for first-line treatment,” Dr. Vinarsky said. “It’s when the first-line treatment fails and you have to transition to a next treatment where most of us struggle because traditional chemotherapy works in a small percentage of patients and works for a very short interval of time.”
That is where daraxonrasib is set to have its greatest impact.
The medication is taken as a pill and works by blocking specific KRAS signaling pathways that cancer cells rely on for survival and growth.
“It’s a pill that blocks the KRAS receptor,” Dr. Vinarsky explained. “Essentially, it blocks the cancer cell from being able to grow and from being able to avoid being targeted by the body’s immune system. For all practical purposes, it holds up the proliferation and growth of the cancerous cell.”
The FDA granted approval on May 30 based on encouraging clinical trial results in patients whose cancers had progressed despite earlier treatments. Although the gains may seem modest, they are meaningful in a disease where therapeutic options are limited.
“The average improvement in survival was still … a matter of six months,” Dr. Vinarsky noted.
For patients facing advanced pancreatic cancer, six additional months can mean valuable time with family, the opportunity to participate in other emerging therapies, or simply more time with a good quality of life.
Dr. Vinarsky cautions that the approval is still very new.
“I have not had a chance to treat anybody with this medication,” he said. “The Food and Drug Administration just approved it.”
Researchers are also excited because KRAS mutations are not limited to pancreatic cancer.
Similar mutations occur in colorectal cancer, lung cancer, and several other malignancies, opening the door to a broader generation of precision medicines.
“This is a very exciting target, not just in pancreatic cancer, but in other cancers as well,” Dr. Vinarsky said. “Specifically, colon cancer and lung cancer.”
Scientists have already developed several KRAS inhibitors, and more are being tested. Different drugs are designed to target different KRAS subtypes, reflecting the growing trend toward highly personalized cancer treatment.
“The KRAS receptor by itself can be subdivided into different receptors,” Dr. Vinarsky explained. “Different drugs can target different receptors.”
Progress in treating pancreatic cancer reflects a larger shift in cancer care. Rather than searching for a single cure that works for everyone, researchers are increasingly developing treatments tailored to the unique genetic fingerprints of individual tumors.
Dr. Vinarsky believes that approach may ultimately transform the future of cancer treatment.
“I think eventually every incurable cancer will become a chronic disease,” he said. “As is currently the case with diabetes or high blood pressure, patients may simply take a pill and maintain it. I think that’s a lot more doable than a cure.”
While cures remain the ultimate goal, the ability to control cancer for years rather than months represent a remarkable achievement.
“I think we’ll cure a good percentage of cases,” Dr. Vinarsky said. “But some will simply be maintained where patients can live with a close to normal quality of life.”
For a disease long defined by limited options and grim statistics, that possibility alone offers pancreatic cancer patients something they haven’t had much of up until now – hope.
Dr. Simon Vinarsky has practiced oncology for more than 20 years since completing his medical school training at Dnepropetrovsk State Medical Academy in Ukraine; his residency at New York Methodist Hospital, Brooklyn; and a fellowship at Long Island Jewish Medical Center, New Hyde Park, N.Y. He sees patients at the Scully-Welsh Cancer Center, on the campus of Cleveland Clinic Indian River Hospital, 3555 10th Court, Vero Beach. You can call 866-223-8100 for appointments.
