Grant: Project Grant

Chemotherapy and radiotherapy (RT) are an essential treatment for eliminating cancer cells. These treatments often fail and the tumour spreads to other organs. Also, a common side effect of RT is scarring. About 60% of breast cancer patients have tumours removed surgically (lumpectomy). They are then treated with 16 daily doses of RT to the remaining breast. This causes inflammation and production of a compound called LPA. Repeating the RT amplifies this effect. LPA protects cancer cells from being killed by RT and it is also responsible for scarring, which occurs in 28% of breast cancer patients. Scarring causes pain, distress and shrinkage of the breast, which in severe cases requires cosmetic correction. We discovered that an anti-inflammatory agent (dexamethasone) blocks the effects of LPA. This decreases scarring in the breast and underlying lungs, which are damaged by collateral radiation. Dexamethasone could be used to improve the outcomes of patients from RT, but we will study other anti-inflammatory agents that have fewer side effects. These include a new drug that blocks LPA formation. This compound halts the progression of idiopathic pulmonary fibrosis where scarring develops in the absence of RT. Compounds, which are designed to block the effects of LPA, have never been used in cancer treatments. This provides an ideal opportunity to improve the outcomes of breast cancer patients from RT and chemotherapy. To translate our work into clinical practice, we will perform the first studies on how breast cancer patients treated with RT activate the effects of LPA. We predict that those patients who show the highest and longest LPA responses will be the ones to develop fibrosis. This work will lay the foundations for designing a clinical trial where we will test if blocking the effects of LPA prevents long-term fibrosis. This work can be extended to other cancers where RT produces such severe scarring that its use is restricted.