We entered a new era in cancer care with the success of daraxonrasib, a new oral drug that nearly doubled survival in previously treated patients with metastatic pancreatic cancer.
Those findings from a phase 3 clinical trial, presented at this year’s American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, are likely to lead to a new standard of care for one of the deadliest cancers.
For cancer scientists like UF Health Cancer Institute member Maria Zajac-Kaye, Ph.D., the news is a scientific breakthrough. It’s just the beginning of a new era of cancer treatments that target the disease’s mechanisms and rely less on harsh chemotherapy, she said.
“It’s an incredible breakthrough in oncology to have an oral, targeted therapy that will double the overall survival in patients who were already treated and in addition improve their quality of life,” said Zajac-Kaye, a professor in the UF Department of Physiology and Aging who has been researching cancer-causing mechanisms for nearly four decades at the National Cancer Institute and University of Florida.
Daraxonrasib is part of a class of drugs called RAS inhibitors. It targets mutations in KRAS, part of the RAS family of genes. More than 90% of pancreatic cancers are driven by KRAS mutations, which also occur in other cancers like colorectal and lung.
KRAS acts as an on-off switch to regulate cell growth and division. KRAS mutations lock the cellular protein in the “on” position, so cancer cells keep growing out of control. For decades, it was considered “undruggable” because of its slippery surface. But scientists cracked the code, figuring out how to target the binding site to block its signaling.
“A new era of finding new inhibitors to treat mutant KRAS is officially here,” Zajac-Kaye said. “I’ve been waiting for years for the new KRAS drugs to show up.”
“A new era of finding new inhibitors to treat mutant KRAS is officially here.”
Zajac-Kaye’s lab is working on novel combination therapy approaches to treat pancreatic cancer using new drugs that target an enzyme called thymidylate synthase, or TYMS. The enzyme plays an important role in DNA repair and synthesis.
Her lab showed that overexpression of TYMS accelerates pancreatic cancer growth in mice with KRAS mutations. Zajac-Kaye’s team has since developed two new drugs that target TYMS that they’re studying in mice and moving toward testing in humans. Her lab is also studying how RAS inhibitors combined with the TYMS inhibitors work together to halt pancreatic cancer.
“The tumors grow quicker because of both those events, KRAS mutations and TYMS overexpression, which is why we’re studying a combination approach,” she said.
TYMS is the same enzyme that’s targeted by 5-FU, the mainstay of chemotherapy treatment for pancreatic cancer for the past five decades. But patients ultimately develop resistance to the chemotherapy drug. Zajac-Kaye’s research is looking at whether TYMS inhibitors will work better than 5-FU and not induce resistance.
“We’re trying to develop a better drug for patients, avoiding some of the toxic chemotherapy,” she said.
Zajac-Kaye is pursuing approval from the FDA to test TYMS inhibitors as investigational drugs in clinical trials in humans. Eventually, they would like to test these agents in combination with chemotherapy or RAS inhibitors.
One of the more promising avenues is using RAS inhibitors as the initial, or first-line, treatment that patients receive, Zajac-Kaye said. Daraxonrasib is being tested for that use in metastatic pancreatic cancer in an ongoing randomized clinical trial.
The possibilities for combination approaches and new trials are immensely promising, Zajac-Kaye said.
“I think the field is going to open up tremendously,” she said.
