Title: Prevention strategies for obesity-related endometrial cancer.
Funder: Department of Health and Social Care

Abstract: The number of women affected by womb cancer has increased year on year since the turn of the century. It is now the fourth most common cancer affecting British women. This is partly due to the obesity epidemic. Obese women are at greater risk of womb cancer than normal weight women. This may be because obesity increases the level of two hormones in the blood, oestrogen and insulin, that cause womb cells to multiply. Multiplying cells can be identified using ki-67, a molecular marker detected by a standard lab technique called immunohistochemistry (IHC). IHC can also reveal which molecular pathways are active in multiplying cells. Getting women to diet and lose weight is challenging, but weight loss surgery by gastric banding is very effective, and is known to reduce womb cancer risk. I will study the effects of obesity and weight loss on the lining of the womb. I will also study the effects of metformin and the Mirena coil on womb cancer and pre-cancer. The Mirena, coated with progesterone, will be used to treat womb pre-cancer and metformin, a type 2 diabetes drug, will be used to treat womb cancer. I will test womb samples before and after treatment with weight loss, the Mirena and metformin. I will look at how many cells are multiplying (ki-67) and identify critical molecular pathways that are switched off by treatment. This will help determine what molecular changes take place in the womb with treatments that reduce womb cancer risk. This in turn will help the design of large scale prevention studies of obese women (eg. with metformin or the Mirena) using these molecular changes as trial endpoints. This work will be conducted at St Mary's together with world-leading scientists with considerable expertise in this area, from the Universities of Manchester and Texas.

Lay abstract: The number of women affected by womb cancer has increased year on year since the turn of the century. It is now the fourth most common cancer affecting British women. This is partly due to the obesity epidemic. Obese women are at greater risk of womb cancer than normal weight women. This may be because obesity increases the level of two hormones in the blood, oestrogen and insulin, that cause womb cells to multiply. Multiplying cells can be identified using ki-67, a molecular marker detected by a standard lab technique called immunohistochemistry (IHC). IHC can also reveal which molecular pathways are active in multiplying cells. Getting women to diet and lose weight is challenging, but weight loss surgery by gastric banding is very effective, and is known to reduce womb cancer risk. I will study the effects of obesity and weight loss on the lining of the womb. I will also study the effects of metformin and the Mirena coil on womb cancer and pre-cancer. The Mirena, coated with progesterone, will be used to treat womb pre-cancer and metformin, a type 2 diabetes drug, will be used to treat womb cancer. I will test womb samples before and after treatment with weight loss, the Mirena and metformin. I will look at how many cells are multiplying (ki-67) and identify critical molecular pathways that are switched off by treatment. This will help determine what molecular changes take place in the womb with treatments that reduce womb cancer risk. This in turn will help the design of large scale prevention studies of obese women (eg. with metformin or the Mirena) using these molecular changes as trial endpoints. This work will be conducted at St Mary's together with world-leading scientists with considerable expertise in this area, from the Universities of Manchester and Texas.

Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS