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Discovering therapeutic strategies to combat breast cancer

Research in the Miller Laboratory focuses on the identification of cancer signaling pathways and the development of targeted therapies for breast and other cancers. Our work spans the spectrum of basic cancer biology, through translational studies in mouse models and human tissues, and engages with Phase 1/2 clinical trials. We use an array of methods and technologies in these endeavors, including mammalian tissue culture, gene and protein expression and activation profiling, chromatin immunoprecipitation, massively parallel DNA sequencing, bioinformatics, mouse models, and live animal imaging.

Cancer dormancy and the importance of timing in precision oncology

Patients with a primary tumor (i.e., untreated and located in the organ of origin) often undergo surgery to remove their tumor. Such patients may then receive “adjuvant” therapy with a drug following surgery to target undetectable “micro-metastatic” dormant cancer cells to prevent tumor recurrence and metastasis. In some cases, this therapy may be given prior to surgery (“neoadjuvant” therapy) to also help shrink the primary tumor, but the main purpose is to target micro-metastatic cancer cells.

In patients with recurrent or metastatic cancer, tumors are detectable by routine imaging methods (MRI, PET/CT). A one-centimeter tumor contains around one billion cells and its own micro-environment, complete with blood vessels, regional areas of hypoxia and pH variations, immune cell infiltrate, inflammation, and structural support cells (i.e., fibroblasts, mesenchymal stem cells).

Precision oncology requires delivering the right drug to the right patient at the right time, but “time” is rarely studied in cell culture and animal models before a new drug enters clinical trials. The existing paradigm in clinical drug development is to demonstrate that a new drug is effective against recurrent/metastatic tumors, and then test that drug in the (neo)adjuvant setting to target micro-metastatic cancer cells. This paradigm makes the unfounded assumption that cancer cells within a growing tumor have the same vulnerabilities as dormant cancer cells. As a result, drugs shown to prevent progression of advanced/metastatic solid tumors are sometimes found to be ineffective at preventing cancer recurrence when administered in the (neo)adjuvant setting. The long-term clinical benefit realized from (neo)adjuvant therapies lies in anti-cancer effects on micro-metastatic, dormant cancer cells; the biology underlying such anti-cancer effects is practically unknown, creating a gap for evaluating new drugs.

Understanding how clinically dormant cancer cells vs. established tumors respond to a novel therapy will guide clinical testing in the appropriate disease setting(s), and reveal targets for combination therapies to enhance efficacy. More thorough characterization of drug efficacy in relevant preclinical models will increase the drug success rate in clinical trials, thus decreasing the cost of drug development. Estrogen receptor alpha (ER)-positive breast cancer presents a scenario in which understanding responses of clinically dormant cancer cells vs. established tumors to treatment with novel therapies would have a significant global impact. ER+ breast cancer causes more recurrences and deaths than all other breast cancer subtypes combined. Patients with early-stage (non-metastatic) ER+ breast cancer are treated with adjuvant anti-estrogen therapies that block ER activity and reduce breast cancer recurrence. However, approximately 1/3 of these patients (~300,000 women per year worldwide) ultimately experience local and/or distant recurrence. Despite adjuvant anti-estrogen therapies, micro-metastatic dormant BC cells persist, suggesting that such cells are growth-suppressed but not eliminated by anti-estrogens; eliminating such clinically dormant BC cells would prevent recurrence.

We and others have implicated activation of the phosphatidylinositol 3-kinase (PI3K) pathway in anti-estrogen resistance, and PI3K inhibitors (PI3Ki) are in clinical development in combination with anti-estrogens. Identification of mechanisms of sensitivity and resistance to anti-estrogen/PI3Ki therapy will offer strategies to enhance and preserve treatment cytotoxicity and prevent drug resistance. Therapeutic strategies targeting dormant ER+ breast cancer cells could be developed as adjuvant treatments, such as short-term PI3Ki during long-term adjuvant anti-estrogen therapy. Microenvironmental cytokines that confer resistance to anti-estrogen or anti-estrogen/PI3Ki therapies are candidate extracellular drug targets for ER+ breast cancer.

Developing a precision medicine basis for estrogen therapy

Following recurrence of ER+ breast cancer, advanced/metastatic disease is managed with further anti-estrogen therapies, targeted therapies, and DNA-damaging chemotherapies; nearly all metastatic breast cancers eventually become completely refractory to these therapies.

Prior to the approval of tamoxifen, estrogens were frequently used for the treatment of breast cancer. This may seem counterintuitive since we now rely on anti-estrogens for disease management, but response rates to estrogens are similar to those of anti-estrogens in the setting of advanced disease. Approximately 1/3 of anti-estrogen-resistant breast cancers respond to estrogen therapy, translating into ~100,000 new patients each year who could benefit. Similarly, some cancers respond to withdrawal of anti-estrogen therapy, which may be caused by ER reactivation. Breast tumor responses to estrogen therapies and anti-estrogen withdrawal have been observed for >70 years, but the lack of A) understanding of the therapeutic mechanism(s), and B) criteria to identify patients likely to benefit have hindered clinical use.

Studies ongoing in the Miller Laboratory will provide insight into the mechanism(s) underlying sensitivity of anti-estrogen-resistant breast cancers to anti-estrogen withdrawal and estrogen therapies, which will significantly and durably impact the understanding and clinical management of ER+ breast cancer. Identifying molecular markers that predict benefit from estrogen therapy, and the optimal duration of therapy required to maximize anti-cancer effects, will be critical to legitimize this inexpensive, widely accessible, relatively safe and tolerable treatment option, and to provide a precision medicine basis to limit its use to patients with cancers likely to respond. Understanding this mechanism will also reveal candidate drug targets to enhance the anti-cancer effects of ER reactivation.