Sunday, May 5, 2024
5/5/2024
PROJECT SUMMARY Estrogen receptor (ER) signaling is the main driver of tumorigenesis in ER+ breast cancers by inducing proliferation and survival through genomic and non-genomic means. Therefore, inhibition of ER signaling has been a mainstay of treatment for decades. While primary ER+ breast cancer has a relatively good initial prognosis, ~30% of patients will develop treatment-refractory recurrence or metastasis within their lifetime, with bone metastasis being twice as likely for patients with hormone receptor positive disease. Despite the frequency of diagnosis, breast-to-bone metastasis of ER+ breast cancer remains an incurable condition. Treatment includes administration of ER antagonists like Fulvestrant or aromatase inhibitors, often in combination with a CDK4/6 inhibitor, which negatively regulates the cell cycle downstream of ER activity. These treatments are designed to slow progression of disease but are incapable of eliminating metastatic cells. A new endocrine- targeted therapy, Elacestrant, has been approved by the FDA for the treatment of ER+, ESR1-mutant advanced or metastatic breast cancer. Interestingly, this compound shows selective agonist activity in the bone microenvironment, and antagonist activity in cancer cells. Although Elacestrant has been approved by the FDA, the compound is understudied and is only approved for a fraction of patients. This proposal will utilize in vitro, in vivo, and ex vivo models of breast-to-bone metastasis of ER+ breast cancer to evaluate the efficacy of Elacestrant versus the standard of care, as well as dissect the transcriptional landscape which is promoted by its ER modulation in the treatment setting. Intra-Iliac artery injection of PDX cells in pre-clinical rodent models will be used to model metastasis and evaluate progression free survival following treatment with Elacestrant as a mono-agent, in combination with CDK4/6 inhibitors, as well as in novel therapeutic combinations. Because Elacestrant-induced ER-controlled transcriptional regulation is context dependent, NanoString GeoMx spatial transcriptomic sequencing, ER ChIP-seq, and rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) will be used to begin to determine how one drug can act as an antagonist and agonist in different contexts. The overarching hypothesis of this proposal is that Elacestrant will extend progression free survival in pre-clinical models of bone metastasis because it displays context dependent agonist and antagonist activity. This study will not only lead to a more complete understanding of ER biology in the bone metastatic microenvironment but will also provide insights which could lead to improved patient outcomes. This project will also afford me the outstanding training experience to work with multidisciplinary leaders across multiple fields of biology while I work to complete my PhD training at Virginia Commonwealth University.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
