On May 17, 2021 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to treat ESR1-mutated metastatic breast and gynecological cancers, reported the publication of its scholarly article, "Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer," in the peer-reviewed journal Breast Cancer Research (Press release, Sermonix Pharmaceuticals, MAY 17, 2021, View Source [SID1234580244]). The paper details positive findings from a preclinical study of lasofoxifene, a selective estrogen receptor modulator (SERM), in mouse models of endocrine therapy-resistant breast cancer.
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In this study, luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S or D538G estrogen receptor alpha (ERα) mutations were injected into the mammary ducts of NSG mice, which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib, a CDK4/6 inhibitor that blocks cell-cycle progression. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements and histological analysis.
As a monotherapy, lasofoxifene was found to be more effective in this preclinical model than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone and brain), with the combination of lasofoxifene/palbociclib showing more potency than that of fulvestrant/palbociclib.
"The results of this study demonstrate, for the first time, the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer harboring ESR1 mutations, and its superiority to fulvestrant in this preclinical model," said Barry Komm, Ph.D., Sermonix chief scientific officer and co-author of the manuscript. "These findings support continued development of this promising compound in a clinical setting. I look forward to data from our ongoing ELAINE 1 Phase 2 clinical study, which is evaluating lasofoxifene versus fulvestrant, early next year."
Endocrine therapy resistance, driven in part by more widespread use of aromatase inhibitors, represents a significant challenge in the treatment of ER+ metastatic breast cancer and highlights the urgent need for more effective interventions, according to Dr. Geoffrey Greene, the study’s lead investigator.
"The results of this study convincingly demonstrate that lasofoxifene suppresses tumor growth and metastases in human-derived xenograft models harboring the Y537S and D538G ESR1 mutations, the most commonly observed ERα mutations," said Dr. Greene, M.D., Ph.D., chair of the Ben May Department for Cancer Research at the University of Chicago. "I believe this compound, with notable activity on breast cancer models with ESR1 mutations, combined with a long half-life and high bioavailability, has the potential to present a differentiated profile to current hormonal treatments in overcoming the acquired resistance that limits their long-term effectiveness. I am eager to see results from in-human studies."
The paper can be accessed online at: View Source