Blocking Sugar Intake May Reduce Cancer Risk or Progression in Certain Malignant Tumors
Blocking dietary sugar and its activity in tumor cells may reduce cancer risk and progression, according to researchers from the Icahn School of Medicine at Mount Sinai in New York. The study, conducted in fruit flies and published in the August issue of Cell, provides insight as to why metabolism-related diseases such as diabetes or obesity are associated with certain types of cancer, including pancreatic, breast, liver, and colon cancers.
Ross Cagan, PhD, Professor of Developmental and Regenerative Biology at Mount Sinai, has developed a cancer model in Drosophila that allows scientists to evaluate diseases in the context of the whole animal and multiple genetic targets, rather than just looking at the connection of one gene to one disease. In the current study, Dr. Cagan used fruit flies to understand the effects of diet and insulin resistance on cancer progression.
“Previous research has established a strong correlation between metabolic diseases and pancreatic, breast, liver, and colon cancers, but we have not determined how tumors grow so aggressively in this environment if they do not have the energy provided by glucose,” said Dr. Cagan, who is also Associate Dean of the Graduate School of Biomedical Sciences at Mount Sinai. “Using our fruit fly model, we discovered how tumors overcome insulin resistance in the body and turn metabolic dysfunction to their advantage.”
Study Details
Dr. Cagan and his team engineered fruit flies to express Ras and Src, two important oncogenes, resulting in the development of small head tumors. Next, they fed the flies with a high-sugar diet that promoted insulin resistance. They found that high dietary sugar acts together with Ras and Src to increase insulin sensitivity specifically in tumor cells. By ramping up signaling of the Wingless/Wnt pathway, they increased tumor cells’ insulin receptors to further promote insulin sensitivity. This cascade of activity changed these small, weak tumors and caused them to begin growing aggressively.
Armed with three new drug targets—glucose, the Ras/Src oncogenes, and Wingless/Wnt signaling—Dr. Cagan and his team identified compounds that can block the process. They treated the flies with acarbose, which blocked sugar conversion to glucose; the AD81 compound, which cut off Ras/Src and caused cell death; and pyrvinium, which inhibited Wingless/Wnt signaling. Taken together, this cocktail of drugs substantially reduced tumor size and progression.
“Our study shows that sugar activates oncogenes in the tumor, which then promote insulin sensitivity, meaning that the exorbitant glucose levels in the blood pour into the tumor, having nowhere else to go in the insulin-resistant body,” said Dr. Cagan. “We have identified a three-drug combination that stops this signaling activity and tumor growth in its tracks, without affecting normal cell function.”
Next, the research team plans to find out whether the same cascade of events is happening in humans with insulin resistance using tumor samples. Based on those findings, Dr. Cagan and his team will test compounds that exploit this oncogene/sugar cascade.
This work was supported through multiple grants from the National Institutes of Health.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
