Combined RIT is promising for genetically mutated colorectal cancer

Radioimmunotherapy (RIT) has not been able to gain traction for a majority of solid tumor types, but new evidence could put Cu-64 labeled DOTA-cetuximab in line for difficult-to-treat colorectal tumors with specific genetic mutations, according to a study published July 19 in the Journal of Nuclear Medicine.

Yunjun Guo, from the Mallinckrodt Institute of Radiology at Washington University in St. Louis, and colleagues narrowed in on p35 and KRAS oncogene mutations that can render the cancer with the third-highest mortality rate completely unresponsive to therapy. The objective of the study was to reveal how targeted RIT changed treatment response in mice with KRAS-mutated HCT116 tumors.

“The occurrence rate of mutations in the KRAS protooncogene is as high as 35–40 percent, so there is an urgent need to develop salvage therapies for patients who have failed traditional chemotherapies and are diagnosed with KRAS-mutated tumors,” wrote Guo et al.

Mice with the mutated gene were treated with Cu-64 DOTA-cetuximab, a chimeric monoclonal antibody RIT, with or without cisplatin, an up-regulator of wild-type p35 expression, to assess any changes in therapy response.

“It is widely known that mutations in key proteins play a role in the success or failure of cancer therapies,” wrote the authors. “For example, the KRAS mutation is predictive of poor response to anti–epidermal growth factor receptor therapies in colorectal cancer, whereas p53 is frequently mutated in tumors, causing resistance to multiple therapeutic regimens.”

Researchers found that cisplatin increased expression of p53 when incubated in a cell culture. Following treatment, cisplatin improved localization of Cu-64 from C-64 acetate and Cu-64 DOTA-cetuximab in tumor cell nuclei and study results revealed that mice with p53-positive HCT116 tumors had significantly better survival rates. However, mice without p53-positive tumors showed no enhancement in localization of colorectal tumors.

“Together, these data suggest that Cu-64 specifically delivered to epidermal growth factor receptor–positive tumors by cetuximab can suppress tumor growth despite the KRAS status and present opportunities for personalized clinical treatment strategies in colorectal cancer,” the researchers wrote.

To read more about research involving cisplatin-enhanced therapies, click here.