University of California, San Francisco (UCSF) scientists have taken a step toward patient-specific radiation therapies by repurposing the KRAS G12C inhibitor sotorasib to make it a target for radioactive antibodies when bound to tumor cells.
“This is a one-two punch,” said Charly Craik, PhD, a professor of pharmaceutical chemistry at UCSF and co-senior author of the study, which appears in Cancer Research. “We could potentially kill the tumors before they can develop resistance.”
The project began 10 years ago when UCSF’s Kevan Shokat, PhD, discovered how to attack the oncoprotein KRAS, which is mutated in around 20% of all cancers. His work led to the development of KRAS inhibitors like sotorasib but the drugs could only shrink tumors for six to twelve months before the cancer developed resistance.
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.
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, known as a hapten, and attracted immune cells to the tumor. The immune system, however, was not strong enough to beat the cancer on its own.
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 sotorasib to flag cancerous cells, but this time they armed the antibodies with radioactive payloads.
The combination eliminated tumors in mice bearing human bladder and lung cancer with minimal side effects. Furthermore, tumor growth inhibition was significantly greater in mice treated with sotorasib and the radioactive antibodies than in mice given either treatment in isolation.
“We were very pleased when the combination of the covalent drug, sotorasib, and the radiolabled antibody worked as well as it did,” Craik told Inside Precision Medicine. “Some on the team were surprised while others had predicted it. The exciting data showed us that this works so well that it could be used as a first line therapy at lower concentrations of sotorasib instead of waiting for resistance to develop and then trying to salvage the original impact of sotorasib.”
The approach allows radiation to be directed exclusively at cancers, which makes it safer. “Unlike external beam radiation, this method uses only the amount of radiation needed to beat the cancer,” said Craik.
Before the approach can be tested in the clinic, the researchers will need to develop antibodies that account for the different ways that people’s cells display KRAS. To address this, Kliment Verba, PhD, an assistant professor of cellular and molecular pharmacology at UCSF, has 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. “We’ve taken a significant step toward patient-specific radiation therapies, which could lead to a new paradigm for treatment.”
The study authors say their approach “offers the potential to not only improve the efficacy of inhibitor monotherapy but also a means to reclaim the therapeutic efficacy of Sotorasib in the case of acquired and innate resistance by repurposing Sotorasib as a hapten.”
To further the translational aspects of the project, the researchers now need to obtain resources to have it manufactured in a GMP facility before it can be tested in clinical trials.
Craik believes the work could impact precision medicine for people with cancer. “The antibody we identified could be used as a diagnostic tool by a pathologist to determine which patients would respond to the treatment,” he said. “This is the area of ‘theranostics,’ which uses the therapy both for treatment and for diagnostic applications like immunohistochemistry, imaging, or for monitoring circulating tumor cells. For example, our antibody could be used as an imaging agent for patients on sotorasib to confirm the antibody localizes to the treated tumors, directly identifying patients who are likely to respond to our therapy.”
