Researchers have created an antibody that blocks the activation of the Dickkopf 1-Cytoskeleton-associated protein 4 (DKK1-CKAP4) pathway, significant for tumor development in various cancers, including pancreatic cancer. This new antibody, derived from a mouse antibody, has been adapted for potential use in humans (Hv1Lt1) and has shown effectiveness in preventing tumor growth in lab mice. When used alongside chemotherapy, it enhances the effectiveness of these drugs.
Pancreatic cancer is a severe illness with limited treatment options. Fortunately, researchers are diligently working to enhance treatment possibilities, and a team from Japan has recently revealed promising advancements.
In a study published this month in Cancer Science, a group of researchers from Osaka University introduced an antibody targeting the cytoskeleton-associated protein 4 (anti-CKAP4). This antibody inhibits the activity of another protein, Dickkopf 1 (DKK1), which activates the DKK1-CKAP4 pathway, crucial for the growth and multiplication of cancer cells.
To provide some background, CKAP4 is a receptor on cell surfaces that can be triggered by specific proteins. In this instance, DKK1 activates CKAP4, promoting tumor growth. Higher levels of DKK1 and CKAP4 in patients often indicate cancer progression and a poor prognosis. Therefore, the research team recognized the DKK1-CKAP4 pathway as a potential target for new treatment options.
Lead researcher Ryota Sada explains, “We started with a mouse antibody and aimed to create a humanized version that could replicate the effects observed in mouse models while ensuring safety for human use.”
To achieve this, the researchers first verified that the recombinant anti-CKAP4 antibody could successfully block DKK1-CKAP4 signaling and tumor growth in laboratory mice implanted with human tumors. They then developed the humanized antibody, Hv1Lt1, based on their initial findings. They discovered that Hv1Lt1 attached to CKAP4 even more effectively than the earlier antibody and inhibited tumor sphere formation, which indicates cancer stem cells’ ability to form colonies. “After creating the humanized antibody, we tested it on various pancreatic cancer mouse models with encouraging results,” says senior author Akira Kikuchi.
The team found that Hv1Lt1 effectively reduced tumor formation in mice receiving both mouse and human pancreatic cancer implants. Additionally, it helped boost anti-tumor immune responses. Their experiments showed that combining Hv1Lt1 with chemotherapy drugs was more effective than using the drugs alone.
One significant advantage of pairing antibodies with chemotherapy is the potential to counteract chemoresistance by inhibiting the AKT (Protein kinase B) pathway, which is activated by chemotherapy treatments. Combining Hv1Lt1 with chemotherapy may also allow for reduced drug doses and lower toxicity.
Overall, these exciting findings encourage further investigation into humanized antibodies, offering real hope for improving outcomes in patients dealing with one of the most challenging cancers.
