Scientists at UC San Francisco have developed a revolutionary cancer treatment that precisely targets tumors with radiation while sparing healthy tissues.
By using a KRAS-targeting drug to mark cancer cells and attaching a radioactive antibody to eliminate them, this approach has successfully wiped out tumors in mice without the usual side effects of radiation.
Targeted Radiation: A Breakthrough in Cancer Treatment
Radiation is one of the most powerful tools for destroying tumors, but traditional radiation therapy can’t distinguish between cancerous and healthy cells, often causing harmful side effects.
Now, researchers at UC San Francisco have developed a way to make radiation more precise. Their new approach combines a specialized drug that marks cancer cells with a radioactive antibody that directly targets and destroys them.
In studies on mice, this treatment successfully eliminated bladder and lung tumors without causing common radiation side effects like lethargy or weight loss.
“This is a one-two punch,” said Charly Craik, PhD, a professor of pharmaceutical chemistry at UCSF and co-senior author of the study, published recently in the journal Cancer Research. “We could potentially kill the tumors before they can develop resistance.”
A Cancer Drug Becomes a Molecular Flag
The foundation for this breakthrough was laid a decade ago when UCSF’s Kevan Shokat, PhD, discovered how to target KRAS, a notorious cancer-causing protein. When mutated, KRAS drives uncontrolled cell growth and is responsible for up to a third of all cancers.
Shokat’s breakthrough led to the development of drugs that latched onto cancerous KRAS. But the drugs could only shrink tumors for a few months before the cancer came roaring back.
The drugs stayed bound to KRAS, however, and Craik, wondered whether they might make cancer cells more “visible” to the immune system.
“We suspected early on that the KRAS drugs might serve as permanent flags for cancer cells,” Craik said.
Harnessing Radiation for Precision Therapy
In 2022, a UCSF team that included Craik and Shokat demonstrated this was indeed possible.
The team designed an antibody that recognized the unique drug/KRAS surface fragment and beckoned to immune cells.
However, the approach needed the immune system to have the strength to beat the cancer by itself, which turned out not to be that effective.
Bringing Atomic-Level Radiation to Cancer Cells
Around the same time, Craik began working with Mike Evans, PhD, a professor of radiology at UCSF, to develop a different approach to destroy cancer cells.
They still used the K-RAS drug to flag cancerous cells, but this time they armed the antibodies with radioactive payloads.
The combination worked, eliminating lung cancer in mice with minimal side effects.
“Radiation is ruthlessly efficient in its ability to ablate cancer cells, and with this approach, we’ve shown that we can direct it exclusively to those cancers,” Evans said.
Added Craik, “The beauty of this approach is that we can calculate an extremely safe dose of radiation. Unlike external beam radiation, this method uses only the amount of radiation needed to beat the cancer.”
Customizing Treatment for More Patients
To make this therapy work in most patients, scientists will have to develop antibodies that account for the different ways that people’s cells display KRAS.
The UCSF team is now working on this – motivated by their own evidence that it can work.
Kliment Verba, PhD, an assistant professor of cellular and molecular pharmacology at UCSF, used cryo-electron microscopy to visualize the ‘radiation sandwich’ in atomic detail, giving the field a structure to develop even better antibodies.
“The drug bound to the KRAS peptide sticks out like a sore thumb, which the antibody then grabs,” said Verba, who like Craik is a member of UCSF’s Quantitative Biosciences Institute (QBI). “We’ve taken a significant step toward patient-specific radiation therapies, which could lead to a new paradigm for treatment.”
Reference: “Therapeutic Targeting and Structural Characterization of a Sotorasib-Modified KRAS G12C–MHC I Complex Demonstrate the Antitumor Efficacy of Hapten-Based Strategies” by Apurva Pandey, Peter J. Rohweder, Lieza M. Chan, Chayanid Ongpipattanakul, Dong hee Chung, Bryce Paolella, Fiona M. Quimby, Ngoc Nguyen, Kliment A. Verba, Michael J. Evans and Charles S. Craik, 15 January 2025, Cancer Research.
DOI: 10.1158/0008-5472.CAN-24-2450
Authors: In addition to Craik, Evans, and Verba, other UCSF authors are Apurva Pandey, PhD, Peter J. Rohweder, PhD, Lieza M. Chan, Chayanid Ongpipattanakul, PhD, Dong hee Chung, PhD, Bryce Paolella, Fiona M. Quimby, Ngoc Nguyen, MS.
Funding and disclosures: This work was supported by the NIH (T32 GM 064337, P41-GM103393, S10OD020054, S10OD021741, and S10OD026881), the UCSF Innovation Ventures Philanthropy Fund, the UCSF Marcus Program in Precision Medicine, and the Howard Hughes Medical Institute.
Craik, Evans, and Rohweder are inventors on a patent application covering part of this work and owned by UCSF. Craik, Ongpipattanakul, and Rohweder are inventors on a patent application related to this technology owned by UCSF. Craik and Rohweder are co-founders and shareholders of Hap10Bio and Evans and Paolella are shareholders of Hap10Bio.
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