Project Details
Description
About 75% of all breast cancers are estrogen receptor (ER)-positive, and although most ER-positive breast tumors initially respond well to endocrine therapy (tamoxifen or aromatase inhibitors), the majority ultimately relapse over time. Moreover, when these tumors relapse, they become more aggressive and less sensitive to many different forms of therapy. As these cancers become 'endocrine-resistant,' patients suffer both the morbidity from taking less effective and more toxic therapies (e.g., chemotherapy) and ultimately mortality as all forms of therapy eventually fail.
The current endocrine therapies available to patients include aromatase inhibitors that block the formation of the hormone estradiol, which helps activate ER; tamoxifen, which binds to ER and prevents estradiol from binding; and fulvestrant, which inhibits ER activity by degrading the ER. One of the major mechanisms leading to acquired resistance to endocrine therapy involves mutations in ER that activate the receptor even when there is no estradiol available. Because these mutant ERs become activated even in the absence of estradiol, aromatase inhibitors do not work against these mutant ERs, and antiestrogens such as tamoxifen are also not effective. The mutant ERs are inhibited to some extent by fulvestrant; however, the higher dose required for complete inhibition renders it clinically untenable. One of the most effective strategies to overcome drug resistance is to employ drugs that have novel chemical structure and mechanism of action. However, a majority of the current antiestrogen drugs are modifications of the three well-known fundamental chemical scaffolds that were discovered 25-50 years ago. No new class of antiestrogens has been discovered during the last 24 years. Therefore, there is an unmet need for development of novel antiestrogens that are not only structurally distinct from the existing ones but that can also provide safe and effective treatment of endocrine-resistant metastatic breast cancer.
We have recently identified a new class of antiestrogens that bind to ER and induce degradation of ER. These compounds also strongly inhibit the proliferation of breast cancer cells that possess the highly aggressive mutant ERs. The chemical structure and mechanism of action of these compounds is distinct from all of the previously known antiestrogens. The objective of this proposal is to transform this fundamentally novel class of antiestrogens into effective agents for treatment of endocrine-resistant metastatic breast cancer. Based on our initial data, we plan to design and synthesize several other members of this new class of antagonists to increase their potency in inhibiting the action of all the different mutant ERs in breast cancer. These new antiestrogens will be tested in several breast cancer cells and endocrine therapy-resistant breast tumor models possessing normal and mutant ERs. We will also test these new drug candidates in cell lines that model the various other known mechanisms of endocrine resistance. Through collaboration, we will use X-ray crystallography to study how these novel antagonists bind to the mutant ERs.
This proposal addresses two overarching challenges posed by the Breast Cancer Research Program (BCRP) Breakthrough Awards: (i) eliminating the mortality associated with metastatic breast cancer and (ii) revolutionizing treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective.
By the end of 3 years of research, we expect to identify 1-2 highly potent, novel antiestrogens whose inhibitory activity on mutant ER-driven metastatic breast cancer exceeds the activity of current clinical standards such as tamoxifen and fulvestrant. These lead candidates will be advanced to clinical trials, and, if successful in further studies, these novel ER antagonists will offer a safer therapeutic alternative to patients with endocrine-resistant metastatic breast cancer by sparing them treatment with chemo- or radiotherapies that have toxic side effects. Moreover, this project is also expected to provide the first novel class of ER antagonists in more than two decades. This will significantly expand the effectiveness of endocrine therapy that has otherwise relied on only three different types of antiestrogens. Collectively, these advances will significantly accelerate progress on the BCRP's mission of ending breast cancer.
Status | Finished |
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Effective start/end date | 1/03/19 → 28/02/22 |