Introduction

In a groundbreaking advancement for cancer treatment, scientists at the University of California, San Francisco (UCSF) have developed a new precision radiotherapy method that leverages existing cancer drug technology in a way that could dramatically improve patient outcomes. Specifically, researchers have found a way to repurpose the KRAS G12C inhibitor, sotorasib, allowing it to act as a target for radioactive antibodies when bound to tumor cells.

The 'One-Two Punch' Innovation

Charly Craik, PhD, a prominent pharmaceutical chemistry professor at UCSF and co-senior author of the study published in Cancer Research, referred to this innovation as a “one-two punch” that could potentially eliminate tumors before they have the chance to develop resistance to treatment.

Historical Context of KRAS Research

This pioneering work dates back a full decade when Kevan Shokat, PhD, also from UCSF, first discovered a method to defeat the oncoprotein KRAS, mutated in around 20% of all cancers. While earlier efforts with drugs like sotorasib successfully shrank tumors temporarily—usually for a window of six to twelve months—they ultimately fell short as tumors typically developed resistance.

Theory Behind Utilizing sotorasib

However, Dr. Craik theorized that sotorasib could make cancer cells more recognizable to the immune system. "We suspected early on that the KRAS drugs might serve as permanent flags for cancer cells," he explained.

Developing the Antibody for Treatment

In 2022, Craik and Shokat's team demonstrated this premise, creating an antibody capable of recognizing the unique drug/KRAS combination, or hapten, to draw immune cells towards the tumors. Unfortunately, while this attracted immune cells, it was not sufficient to eradicate cancer on its own.

Combination Treatment Results

As the research progressed, Craik, alongside radiology professor Mike Evans, PhD, developed a novel method that not only flagged the cancer cells but also armed the antibodies with radioactive payloads. The results were remarkable: in mice with human bladder and lung cancers, the combination treatment effectively eliminated tumors with fewer side effects compared to traditional therapies. In fact, the dual treatment was significantly more effective than either therapy used separately.

New Avenues in Cancer Therapy

"This successful integration of sotorasib with radioactive antibodies opens new doors," noted Craik. "Some were surprised by the results, while others predicted its efficacy. The positive outcomes suggest that this approach might serve as a first-line therapy, utilizing lower concentrations of sotorasib before resistance develops."

Minimizing Radiation Exposure

With the precision of targeting cancer cells directly, this innovative treatment method minimizes radiation exposure compared to conventional external beam radiation techniques. According to Craik, this approach uses “only the amount of radiation needed to beat the cancer.”

Future Clinical Applications

Looking ahead, UCSF researchers plan to address variations in how multiple patients’ cellular systems display KRAS before testing their method in clinical settings. To aid this endeavor, Kliment Verba, PhD, an assistant professor of cellular and molecular pharmacology, has utilized cryo-electron microscopy to visualize detailed structures of the treatment, paving the way for even more effective antibodies.

Impact on Diagnostics

The potential applications of this research extend beyond therapy into diagnostics as well. Craik envisions using the developed antibody as a diagnostic tool for pathologists to determine which patients are most likely to respond to the treatment. This interwoven approach known as 'theranostics' combines therapeutic and diagnostic capabilities, enabling better patient stratification.

Conclusion and Next Steps

As this innovative project heads towards clinical trials, the team seeks the necessary resources to manufacture their findings in a GMP facility. If successful, this transformative therapy could offer hope to countless cancer patients, heralding a new era of precision medicine in oncology.