Estrogen Receptor Coligand Reprogramming of Menopausal Hormone Therapy

DESCRIPTION provided by applicant Our goal is to discover drugs that will make menopausal hormone therapy MHT safe for long term treatment of chronic conditions associated with menopause Due to the increasing longevity of women menopause has become a critical issue in Womenandapos s Health Life expectancy for women is now years Unlike just a century ago most women will reach menopause and live approximately one third of their life after menopause There are currently million menopausal women in the U S and the number is projected to soar to about million in years Unfortunately menopause is associated with an increase in the incidence of osteoporosis obesity diabetes and metabolic syndrome Long term exposure to MHT decreases the risk of these conditions MHT is approved for short term treatment of hot flashes and vaginal vulvar symptoms since long term treatment with MHT is associated with an increased risk of breast cancer cardiovascular risks and Alzheimerandapos s disease A major breakthrough in primary prevention for Womenandapos s Health would occur if safer MHT regimens could be developed for long term treatment We discovered compounds termed ER coligands that reprogram the effects of estradiol on gene expression and cell proliferation Our data indicate that the ER coligand binds to the surface of ER at a separate binding site than estrogens leading to an increase in binding of E to its binding site The binding of both ligands simultaneously to ER produces a change in conformation as demonstrated by an alteration in the melting temperature of ER These studies indicate that the conformation of the E ER ER coligand complex is distinct from the E ER complex leading to the reprogramming of the E transcriptional and cellular effects In fact we found that the E ER coligand combination reprograms E to regulate over unique genes in U OS cells These genes are not regulated by E or the ER coligand alone It is well established that E stimulates the proliferation of MCF breast cancer cells by binding to ER resulting in the activation of oncogenes such as c MYC We found that the ER coligand reprograms ER so E no longer causes cell proliferation nor does it stimulate c MYC production The ER coligand also blocked E stimulation of uterine growth in mice Based on these findings we hypothesize that ER coligands can be combined with existing estrogens used in MHT to block the adverse proliferative action of E to allow the ER coligand estrogen combination to be used safely for long term MHT treatment The aim of this phase I proposal is to select a lead ER coligand estrogen combination that has the best safety profile in cultured cells and animals prior to advancing it to Pharmacokinetic Pharmacodynamic and other pre clinical testing in a phase II proposal These studies have the potential to facilitate the early development of a new type of MHT that can be used for long term administration to prevent chronic diseases associated with menopause such as osteoporosis obesity diabetes and metabolic syndrome PUBLIC HEALTH RELEVANCE Estrogen Receptor Coligand Reprogramming of Menopausal Hormone Therapy Project Narrative Menopause is associated with chronic conditions such as osteoporosis obesity and diabetes While studies indicate that estrogens in menopausal hormone therapy MHT can prevent these conditions in postmenopausal women current MHT regimens are not approved for these indications because long term MHT can result in life threatening adverse events The objective of this proposal is to determine if an estrogen receptor coligand can reprogram estrogenandapos s effect in cancer cells and mice to block adverse proliferative effects These studies could facilitate the development of new safer MHT regimens that can be used for long term therapy to prevent chronic conditions associated with menopause