Research in the Miller Laboratory focuses on the identification of cancer signaling pathways and the development of targeted therapies for breast cancer. Our work spans the spectrum of basic cancer biology, through translational studies in mouse models and human tissues, and engages with early-phase clinical trials. We use an array of methods and technologies in these endeavors, including mammalian tissue culture, gene and protein expression and activation profiling, metabolic profiling, chromatin immunoprecipitation, massively parallel DNA sequencing, bioinformatics, mouse models, and live animal imaging.
Therapeutically targeting metabolic vulnerabilities in breast cancer
Mitochondria are a major site of fatty acid oxidation, the process through which fatty acids are broken down to yield substrates that feed the TCA cycle and, ultimately, provide metabolites that feed mitochondrial respiration. A high-fat diet promotes anti-estrogen resistance in ER+ breast cancer in mice. We are currently testing the therapeutic potential of inhibiting fatty acid uptake and synthesis by ER+ breast cancer cells.
Developing a precision medicine basis for estrogen therapy for breast cancer
Our studies are providing insight into the mechanism(s) underlying sensitivity of anti-estrogen-resistant breast cancers to estrogen therapy, 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.
Delineating cellular adaptations to dormancy in breast cancer
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.