Research Project
10255690
Project Summary/Abstract Health issues facing menopausal women are becoming much more prevalent due to their increasing longevity. Well-recognized short-term symptoms, such as hot flashes, sleep disturbances and mood swings lead to lower quality of life and loss of work productivity. Prolonged estrogen deficiency during menopause is associated with an increased incidence of chronic diseases, such as osteoporosis, obesity, diabetes, metabolic syndrome and cardiovascular disease. Menopausal hormone therapy (MHT) has been used to alleviate short-term menopausal symptoms and prevent some chronic conditions. The Women?s Health Initiative (WHI) found that the risk of long- term treatment outweighed the benefits. The use of MHT has dropped dramatically after the results of the WHI trial were reported. It is now approved to treat hot flashes and vaginal symptoms, but not for chronic disease prevention. MHT is currently recommended for short-term use of 5 years. Countless menopausal women continue to wait anxiously for a safe long-term MHT to improve their quality of life and health. Women who have vasomotor symptoms beyond 5 years and a history of low bone density, osteoporosis, and prediabetes would greatly benefit from long-term MHT. Unfortunately for menopausal women it is unlikely that the major pharmaceutical companies will have a long-term MHT product soon based on their longstanding pursuit of estrogen agonists and antagonists, which bind to the estradiol (E2) binding pocket. Nearly 80 years after MHT was approved it is clear that this strategy is not working since no long-term MHT is available. We decided to pursue a different approach by screening drugs that act synergistically with E2 rather than acting as an agonist or antagonist. We discovered a class of compounds termed estrogen receptor alpha (ER?) reprogramming coligands that reprogram the effects of E2 on gene expression and cell proliferation. We found that the combination of the reprogramming drug and E2 regulates genes that are not altered by the reprogramming drug or E2 alone, demonstrating that the combination induces a new set of genes. The reprogramming coligand blocked the proliferation of human breast cancer cells and growth of the mouse uterus in response to E2. Based on these findings our objective is to replace the progestin component in MHT with a reprogramming coligand and add it to the estrogen-alone formulation to generate an E2/coligand combination. Our hypothesis is that an E2/coligand combination will be safer than the current estrogen-alone and estrogen/progestin MHT formulations on the market for short-term menopausal symptoms, and can be used as long-term therapy to prevent chronic conditions associated with menopause. In this proposal, we will prepare synthetic analogs of our prototype reprogramming coligand and identify the best analogs to combine with E2 for future testing in animal models and other preclinical studies required for clinical development.
