Curbing Sugar Intake May Slash Risk of Cancer or Progression in the Diabetic and Obese

Dr. Cagan used fruit flies in his research to determine 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.”

Dr. Cagan and his team modified fruit flies to express Ras and Src, two key oncogenes, which resulted in the development of small head tumors. Next, they fed the flies with a high-sugar diet that triggered insulin resistance. They discovered that high dietary sugar acts together with Ras and Src to increase insulin sensitivity specifically in tumor cells. By increasing the signaling of an important pathway called Wingless/Wnt, they increased tumor cells’ insulin receptors to further promote insulin sensitivity. This cascade of activity altered 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 coworkers identified compounds that can block the process. They treated the flies with acarbose, a drug for diabetes treatment; a compound called AD81; and an agent called pyrvinium. Acarbose blocked sugar conversion to glucose; AD81 blocked Ras/Src and caused cell death; and pyrvinium suppressed Wingless/Wnt signaling. Combined, this blend of drugs considerably 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.”

In the next phase, the researcher plans to find out whether the same cascade of occurrences is happening in humans with insulin resistance using tumor samples. Based on those findings, Dr. Cagan and his team will evaluate substances that can manipulate this oncogene/sugar cascade.

Related Links:
Icahn School of Medicine at Mount Sinai