UC San Francisco researchers took on one of science's lost causes. Today, their work has finally ushered in hope for pancreatic cancer - one of medicine's most devastating diseases.
The Food and Drug Administration (FDA) recently approved daraxonrasib, the first drug shown to substantially extend life expectancy for pancreatic cancer patients. In clinical trials, including at UCSF, the once-daily medication doubled life expectancy to a median of more than 13 months in patients with metastatic pancreatic cancer whose cancer had progressed on standard chemotherapy compared with less than seven months for those who continued to receive standard chemotherapy.
Marketed as Rasonque, the drug targets a protein called RAS. RAS mutations are found in about 20% of all cancers. For more than three decades, scientists believed these mutations were impervious to treatment. In 2013, Professor of Cellular and Molecular Pharmacology Kevan Shokat , PhD, used technology developed by Pharmaceutical Chemistry Professor Jim Wells , PhD, to discover a tiny "pocket" on the surface of the mutated RAS protein that proved to be its Achilles' heel. Shokat's lab developed drugs that could snuggle into the pocket and bind to the protein, weakening and killing the cancerous cells.
Professor of Medicine Andrew Ko , MD, is a pancreatic cancer specialist at UCSF Health and led the daraxonrasib clinical trial at UCSF in partnership with Revolution Medicines, which Shokat co-founded.
Ko tells us what to know about the headline-grabbing drug and what's next for pancreatic cancer.
How does daraxonrasib work?
This is a targeted therapy that blocks KRAS signaling in cancer cells. Mutations in the RAS family of genes, and more specifically in KRAS, occur in upwards of 90% of pancreatic cancers. KRAS normally acts like an on-off switch for cell growth, but mutations can cause it to get stuck in the "on" position, signaling cancer cells to keep growing.
Through some brilliant work in understanding the structure and function of the RAS molecule - much of it done here at UCSF - scientists were able to develop drugs like daraxonrasib that disrupt the key driver of pancreatic cancer, basically stopping it in its tracks.
Who should get daraxonrasib?
Daraxonrasib is primarily intended for patients with stage four metastatic pancreatic cancer who have undergone chemotherapy. However, the FDA approval language leaves the door open for the use of this drug in patients who are newly diagnosed and who are not good candidates for chemotherapy.
There are ongoing studies, including at UCSF, testing whether daraxonrasib may be beneficial for newly diagnosed patients, with or without chemotherapy. Trials at UCSF are also looking at whether daraxonrasib could prevent recurrences in patients with early-stage disease.
Chemotherapy vs daraxonrasib: how do the side effects compare?
Side effects of traditional chemotherapy include hair loss, nausea, vomiting, fatigue, neuropathy, and immune suppression, which increases a person's risk of infection. With daraxonrasib, patients do not experience most of these side effects. However, almost all patients develop a rash that can involve the face, chest, or trunk. It can range from mild to pretty severe.
Can daraxonrasib's rash be treated?
Yes, in my experience, most patients develop a rash that is mild to moderate, and usually quite manageable. We preemptively start patients on oral antibiotics and sometimes topical steroids to prevent or reduce the rash. We ask patients to be diligent about using sunscreen and minimize time in the sun.
We're fortunate and blessed at UCSF Health to have dermatologists who partner with us in managing cancer patients who develop drug-related skin conditions.
What does the future hold for pancreatic cancer treatment?
Other exciting drugs are being explored in clinical trials, including at UCSF. One class of drugs, referred to as "degraders," uses the cells' own machinery to destroy specific cancer-causing proteins such as RAS. And there are a growing number of additional drug targets beyond RAS that are promising, many of which are being tested in clinical trials.
One of the other great frontiers is immune-based therapies, which have historically not been effective in treating pancreatic cancer. UCSF is participating in a clinical trial of a personalized mRNA vaccine intended to prevent recurrences in patients who have undergone surgery for their pancreatic cancer. I am working with other UCSF scientists to develop a novel pancreas-specific CAR T-cell product that we hope to advance to clinical trials by next year.
