A team of researchers at the Francis Crick Institute in London, in the United Kingdom, set out to explore novel therapeutic options for treating bowel cancer. They found a drug target that promises to be less toxic than existing drugs.
In the United States, colorectal cancer is expected to affect 135,430 people in 2017, according to the American Cancer Society (ACS). Approximately 1 in 21 men and 1 in 23 women are at risk, according to ACS estimates.
Current treatment options for this disease include local treatments — such as surgery, radiation, or ablation — or systemic treatments, including chemotherapy, immunotherapy, and some forms of targeted therapy.
But as Vivian Li, the senior investigator on the new study, explains, "Current treatment for bowel cancer is mostly generic, while targeted therapy will help future development of personalized medicine."
The new research identifies a protein that "holds great promise as a therapeutic target for bowel cancer treatment," adds Li, who is also a group leader at the Francis Crick Institute.
Laura Novellasdemunt, a researcher at the Francis Crick Institute, is the first author of the paper, and its findings have been published in the journal Cell Reports.
Studying the APC gene and Wnt signaling
As the authors explain, colorectal cancer has been associated with a mutation in the so-called APC gene. In its healthy form, the APC gene is responsible for encoding the APC protein, which acts as a tumor suppressor.
The APC gene normally stops cells from going awry — effectively stopping cancer from spreading. However, a mutated form of the gene has been linked with various diseases, including colorectal cancer. In fact, the mutation has been associated with a 10–20 percent increase in the risk of developing colon cancer.
APC gene mutations seem to make a certain cell signaling pathway, called the Wnt pathway, hyperactive.
As Novellasdemunt and her colleagues explain, the Wnt pathway is key in controlling adult tissue homeostasis — or keeping the right balance between cell proliferation and cell death within the tissue.
For this reason, most therapeutic interventions targeting Wnt signaling prove toxic for multiple parts of the body.
"Drugging Wnt signaling will inevitably cause toxicity to Wnt-dependent normal tissue development such as [in the] intestine, thus limiting the full anti-tumor efficacy," write the authors.
New drug target may lead to better therapy
However, by using the CRISPR genome-editing tool, the researchers eliminated the APC gene at different points and found certain gene variants that activated Wnt at pathological levels.
The gene variants identified encoded a protein called USP7. Using gene-editing and drugs, the researchers were able to deplete this protein.
Depleting the protein led to a decrease in Wnt signaling in malignant cells and delayed tumor growth in mice. Significantly, the interventions targeted Wnt signaling exclusively in tumor cells, without disrupting the signaling in healthy cells.
"[The] Wnt-activating role of USP7 is specific to APC mutations, thus can be used as [a] tumor-specific therapeutic target for most [colorectal cancers]," the authors write.
"There has long been a need to find more effective and less toxic drugs to treat bowel cancer [...] We have found a novel drug target that could provide the basis for a better therapy in patients in the future."
Next, the researchers plan to investigate whether or not deleting the USP7 protein-encoding gene will altogether prevent colorectal cancer in mice.