Background and Earlier Work: Estrogens acting via the protein estrogen receptor alpha (ERa) stimulate the growth and metastases of most breast cancers. Endocrine therapy targeting these tumors uses tamoxifen and other antiestrogens that compete with estrogens for binding to ERa, and aromatase inhibitors that inhibit estrogen production. Tumors often develop resistance to endocrine therapy. The presence of ERa in many therapy-resistant tumors suggested targeting previously unidentified modes of ERa action. By high-throughput screening of 150,000 compounds, and follow-up assays, we identified the novel small molecule ERa inhibitor BHPI. At a low concentration, BHPI completely blocks growth and ultimately kills ERa-positive breast cancer cells resistant to tamoxifen and to fulvestrant/Faslodex. In a mouse tumor model of breast cancer, administering a low dose of BHPI for just 10 days induced rapid and substantial shrinkage (regression) of 48 out of 52 tumors. BHPI is effective in ERa-containing breast cancer cells resistant to current therapies because it targets a stress response pathway not previously linked to ERa action in breast cancer. When this pathway is weakly activated for a short time, it helps the breast cancer cells survive stress and resist anticancer drugs. But when it is hyperactivated and stays on, it kills the cells. BHPI hyperactivates this pathway and this shuts down the production of new protein, stopping growth and ultimately killing ERa-containing breast cancer cells.Late stage breast cancers may exhibit many regulatory alterations and, even if they contain ERa, they often no longer require estrogens for growth. Consequently, the common strategies of targeting estrogen or of identifying a drug candidate that blocks the action of one of the several pathways altered in these tumors are unlikely to be successful. Our novel approach uses BHPI to overstimulate a pathway that is normally protective in breast cancer and converts it from protective to lethal. Thus, BHPI stops the growth of breast cancer cells that survive current drugs by targeting a pathway whose expression levels rise in the resistant cells. Thus, it selectively targets the cancer cells and not normal cells.Objectives and Overarching Challenges Addressed: Although we have substantial preliminary data, one important goal of this work is to test the ability of BHPI to stop growth of breast tumors resistant to current therapies and induce tumor regression. We will use a mouse model for human breast cancer resistant to current therapies and a mouse model for metastatic breast cancer. This is directly related to the overarching challenge of 'eliminating the mortality associated with metastatic breast cancer.' BHPI is a well-tolerated targeted therapy, and this is related to the challenge of '...replacing drugs that have life-threatening toxicities.' BHPI targets ER-positive breast cancers. If successful, our tests using an animal model of therapy-resistant human breast cancer will identify BHPI as a novel therapeutic with potential for intensive development for treatment of women with late-stage ERa-positive breast cancer unresponsive to current therapeutics.A second goal is to fully test the hypothesis that weak activation of this stress pathway by estrogen-ERa is a new way that breast tumors subsequently resist later chemotherapy. A related goal is to determine whether the stress response pathway is activated by estrogen in tumors and has the potential to aid diagnosis. We will use a modern technique that allows visualization of tumors in mice to test our idea that estrogen induces the stress response pathway in tumors and that this induction is also seen in metastases. This research is directly relevant to the overarching challenges of 'distinguish aggressive from indolent cancers' and 'identify what drives breast cancer growth and metastases.' This work has the potential to lead quite rapidly to new prognostic markers for aggressive ERa-containing breast cancers. The idea that prior activation of the cancer cell's stress response pathway is a prognostic marker predicting aggressive, metastatic, therapy-resistant breast cancers is a novel concept and potentially provides a new prognostic biomarker, diagnostic marker, and therapeutic target. We attack this target, the breast cancer cell's stress response, with BHPI.Impact: We propose to further develop and evaluate BHPI and to determine whether BHPI has promise as a new treatment for women with aggressive ERa-positive breast cancer unresponsive to current therapeutics and to evaluate the role of the stress response pathway as a potential prognostic marker for tumors likely to be resistant to therapy.
|Effective start/end date||1/06/14 → 31/05/17|
- Congressionally Directed Medical Research Programs: $1,051,688.00