Leveraging Antiprogestins in the Treatment of Metastatic Breast Cancer

Abstract

Although incurable, the prognosis for patients with metastatic breast cancer (MBC) has considerably improved with the approvals of multiple targeted and cytotoxic therapies. For hormone receptor-positive (HR+), i.e., estrogen receptor and progesterone receptor positive (ER+/PgR+) and Human Epidermal Growth Factor Receptor-2 negative (i.e.,ERBB2 gene non-amplified or HER2-) MBC, current approved treatment options include palliative endocrine therapy (ET), Cyclin-Dependent Kinase (CDK 4/6) inhibitors, mTOR inhibitors, and PI3 kinase inhibitors. Most treatments target ER+ disease regardless of PgR status. Although the presence of PgR is crucial for ER+ cell proliferation in both normal and malignant mammary tissue, currently, no approved treatments specifically target PgR. Recent literature has demonstrated, the potential of antiprogestins in the treatment of MBC both in preclinical and clinical studies.Antiprogestins, including selective PgR modulators (SPRMs) that act as PgR antagonists, are a promising class of therapeutics for overcoming endocrine resistance in patients who develop activating estrogen receptor 1 (ESR1) and phosphatidylinositol 3-kinase (PI3K) gene mutations after prior endocrine therapy. Herein, we summarize the role of PgR and antiprogestins in the treatment of MBC. Other aspects on the use of functional imaging, clinical trials incorporating novel antiprogestins and potential treatment combinations to overcome endocrine resistance will be briefly discussed.

Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism

“…EPT exposure in existing breast cancers could also be detrimental as a meta-analysis found that tumors expressing high levels of glycolytic proteins corresponded to shorter overall survival of breast cancer patients [ 52 ]. Anti-progestins are being explored for treatment of metastatic ER+ breast cancer [ 53 ], although their role in modulation of breast cancer metabolism is unknown.…”

CmP signaling network unveils novel biomarkers for triple negative breast cancer in African American women

“…As a well-known antagonist of PRG, MIF has been regarded as a great candidate for the treatment of breast, prostate, ovarian, endometrial cancers, and endometriosis (Bakker et al, 1990;Lanari et al, 2012) and is currently on many active interventional clinical trials (Goyeneche and Telleria, 2015;Kamaraju et al, 2021;Klijn et al, 1994). Some data demonstrated that a growth inhibitory agent, elevated levels of MIF, can enhance the growth inhibition and induction of apoptosis triggered by high doses of progesterone in either nPR(+/-) cancer cells (Fjelldal et al, 2010;Moe et al, 2009).…”

Molecular Imaging of Steroid Receptors in Breast Cancer

“…114 Mounting research suggests a further bidirectional link between ER and PR in cell signaling (i.e., crosstalk), [115][116][117] and PR-targeted therapies have had renewed interest in clinical trials. 118,119 Therefore, accurate determination of PR status is clinically significant and may help when selecting an optimal treatment regimen for patients with breast cancer. 114,120,121 Multiple PR-targeted positron-emitting radiopharmaceuticals have been developed for imaging since the late 1980s, but translation to clinical use has proved challenging.…”